Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia.

PubMed

Farré, Daniel; Muñoz, Ana; Moreno, Estefanía; Reyes-Resina, Irene; Canet-Pons, Júlia; Dopeso-Reyes, Iria G; Rico, Alberto J; Lluís, Carme; Mallol, Josefa; Navarro, Gemma; Canela, Enric I; Cortés, Antonio; Labandeira-García, José L; Casadó, Vicent; Lanciego, José L; Franco, Rafael

2015-12-01

Radioligand binding assays to rat striatal dopamine D1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D1 receptors heteromerize with dopamine D3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D3 and D1-D3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-L-alanine (L-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D3 agonist led in dyskinetic, but not in lesioned or L-DOPA-treated rats, to a higher dopamine sensitivity. Upon D3-receptor activation, the affinity of agonists for binding to the right striatal D1 receptor increased. Excess dopamine coming from L-DOPA medication likely activates D3 receptors thus making right and left striatal D1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D1 receptor-mediated neurotransmission.

In vitro pharmacology of aripiprazole, its metabolite and experimental dopamine partial agonists at human dopamine D2 and D3 receptors.

PubMed

Tadori, Yoshihiro; Forbes, Robert A; McQuade, Robert D; Kikuchi, Tetsuro

2011-10-15

Aripiprazole is the first dopamine D(2)/D(3) receptor partial agonist successfully developed and ultimately approved for treatment of a broad spectrum of psychiatric and neurological disorders. Aripiprazole's dopamine D(2) and serotonin 5-HT(1A) receptor partial agonist activities have been postulated to confer clinical efficacy without marked sedation, and a relatively favorable overall side-effect profile. Using aripiprazole's unique profile as a benchmark for new dopamine partial agonist development may facilitate discovery of new antipsychotics. We conducted an in vitro comparative analysis between aripiprazole, and its human metabolite OPC-14857 (7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl)butoxy)-2(1H)-quinolinone)); RGH-188 (trans-1-[4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl]-3,3-dimethylurea), and its metabolite didesmethyl-RGH-188 (DDM-RGH-188); as well as bifeprunox, sarizotan, N-desmethylclozapine (NDMC; clozapine metabolite), and SDZ 208-912 (N-[(8α)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide). In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cell lines expressing D(2S), D(2L), D(3) Ser-9 and D(3) Gly-9 for human dopamine receptors. All test compounds behaved as dopamine D(2)/D(3) receptor partial agonists. Aripiprazole's intrinsic activity at dopamine D(2S) and D(2L) receptors was similar to that of OPC-14857 and RGH-188; lower than that of dopamine and bifeprunox; and higher than that of DDM-RGH-188, SDZ 208-912, sarizotan, and NDMC. Aripiprazole's intrinsic activity at dopamine D(3) Ser-9 and D(3) Gly-9 receptors was similar to that of OPC-14857 and sarizotan; lower than that of dopamine, bifeprunox, RGH-188 and DDM-RGH-188; and higher than that of SDZ 208-912 and NDMC. A consolidated assessment of these findings may help defining the most appropriate magnitude of intrinsic activity at dopamine D(2)/D(3) receptors for clinical efficacy and safety. Copyright © 2011 Elsevier B.V. All rights reserved.

Dopamine D2-like receptor signaling suppresses human osteoclastogenesis.

PubMed

Hanami, Kentaro; Nakano, Kazuhisa; Saito, Kazuyoshi; Okada, Yosuke; Yamaoka, Kunihiro; Kubo, Satoshi; Kondo, Masahiro; Tanaka, Yoshiya

2013-09-01

Dopamine, a major neurotransmitter, transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. Although the relevance of neuroendocrine system to bone metabolism has been emerging, the precise effects of dopaminergic signaling upon osteoclastogenesis remain unknown. Here, we demonstrate that human monocyte-derived osteoclast precursor cells express all dopamine-receptor subtypes. Dopamine and dopamine D2-like receptor agonists such as pramipexole and quinpirole reduced the formation of TRAP-positive multi-nucleated cells, cathepsin K mRNA expression, and pit formation area in vitro. These inhibitory effects were reversed by pre-treatment with a D2-like receptor antagonist haloperidol or a Gαi inhibitor pertussis toxin, but not with the D1-like receptor antagonist SCH-23390. Dopamine and dopamine D2-like receptor agonists, but not a D1-like receptor agonist, suppressed intracellular cAMP concentration as well as RANKL-meditated induction of c-Fos and NFATc1 mRNA expression in human osteoclast precursor cells. Finally, the dopamine D2-like receptor agonist suppressed LPS-induced osteoclast formation in murine bone marrow culture ex vivo. These findings indicate that dopaminergic signaling plays an important role in bone homeostasis via direct effects upon osteoclast differentiation and further suggest that the clinical use of neuroleptics is likely to affect bone mass. Copyright © 2013 Elsevier Inc. All rights reserved.

Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole.

PubMed

MacDonald, Hayley J; Stinear, Cathy M; Ren, April; Coxon, James P; Kao, Justin; Macdonald, Lorraine; Snow, Barry; Cramer, Steven C; Byblow, Winston D

2016-07-01

Dopamine agonists can impair inhibitory control and cause impulse control disorders for those with Parkinson disease (PD), although mechanistically this is not well understood. In this study, we hypothesized that the extent of such drug effects on impulse control is related to specific dopamine gene polymorphisms. This double-blind, placebo-controlled study aimed to examine the effect of single doses of 0.5 and 1.0 mg of the dopamine agonist ropinirole on impulse control in healthy adults of typical age for PD onset. Impulse control was measured by stop signal RT on a response inhibition task and by an index of impulsive decision-making on the Balloon Analogue Risk Task. A dopamine genetic risk score quantified basal dopamine neurotransmission from the influence of five genes: catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3. With placebo, impulse control was better for the high versus low genetic risk score groups. Ropinirole modulated impulse control in a manner dependent on genetic risk score. For the lower score group, both doses improved response inhibition (decreased stop signal RT) whereas the lower dose reduced impulsiveness in decision-making. Conversely, the higher score group showed a trend for worsened response inhibition on the lower dose whereas both doses increased impulsiveness in decision-making. The implications of the present findings are that genotyping can be used to predict impulse control and whether it will improve or worsen with the administration of dopamine agonists.

A comparison of the effects of the dopamine partial agonists aripiprazole and (-)-3-PPP with quinpirole on stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry in vitro.

PubMed

O'Connor, John J; Lowry, John P

2012-07-05

The effects of aripiprazole, (-)-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP) and quinpirole on single and multiple pulse stimulated dopamine release were investigated using the technique of fast cyclic voltammetry (FCV) in isolated rat striatal slices. Aripiprazole and (-)-3-PPP had no significant effect on single pulse dopamine release at concentrations from 10nM to 10μM indicating low agonist activity. The compounds failed to potentiate 5 pulse stimulated release of dopamine although inhibitory effects were seen at 10μM for aripiprazole. Both compounds were tested against the concentration-response curve for quinpirole's inhibition of stimulated single pulse dopamine release. Aripiprazole and (-)-3-PPP shifted the concentration-response curve for quinpirole to the right. In each case this was greater than a 100-fold shift for the 10μM test compound. Whilst these results indicate that both compounds show little agonist activity on dopamine release and significant antagonism of the inhibitory effect of quinpirole on dopamine release, whether they are functionally selective dopamine D(2) ligands remains controversial. Copyright © 2012 Elsevier B.V. All rights reserved.

Observations on Sleep-Disordered Breathing in Idiopathic Parkinson’s Disease

PubMed Central

Valko, Philipp O.; Hauser, Sabrina; Sommerauer, Michael; Werth, Esther; Baumann, Christian R.

2014-01-01

Background This study has two main goals: 1.) to determine the potential influence of dopaminergic drugs on sleep-disordered breathing (SDB) in Parkinson’s disease (PD) and 2.) to elucidate whether NREM and REM sleep differentially impact SDB severity in PD. Methods Retrospective clinical and polysomnographic study of 119 consecutive PD patients and comparison with age-, sex- and apnea-hypopnea-index-matched controls. Results SDB was diagnosed in 57 PD patients (48%). Apnea-hypopnea index was significantly higher in PD patients with central SDB predominance (n = 7; 39.3±16.7/h) than obstructive SDB predominance (n = 50; 20.9±16.8/h; p = 0.003). All PD patients with central SDB predominance appeared to be treated with both levodopa and dopamine agonists, whereas only 56% of those with obstructive SDB predominance were on this combined treatment (p = 0.03). In the whole PD group with SDB (n = 57), we observed a significant decrease of apnea-hypopnea index from NREM to REM sleep (p = 0.02), while controls revealed the opposite tendency. However, only the PD subgroup with SDB and treatment with dopamine agonists showed this phenomenon, while those without dopamine agonists had a similar NREM/REM pattern as controls. Conclusions Our findings suggest an ambiguous impact of dopamine agonists on SDB. Medication with dopamine agonists seems to enhance the risk of central SDB predominance. Loss of normal muscle atonia may be responsible for decreased SDB severity during REM sleep in PD patients with dopamine agonists. PMID:24968233

Effects of amantadine on modification of dopamine dependent behaviours by molindone.

PubMed

Dhaware, B S; Balsara, J J; Nandal, N V; Chandorkar, A G

2000-08-01

Amantadine, a dopamine agonist is reported to act by releasing dopamine from the dopaminergic nerve terminals as an anti-Parkinsonian drug. In the present behavioural study in the rat, molindone-induced catalepsy and ptosis, which are dopamine dependent-behaviors are reversed by amantadine. Amantadine has also revered molindone-induced inhibition of traction response in mice. Our study indicates that amantadine, like other DA agonists, e.g. amphetamine and apomorphine can antagonize or even reverse the neuroleptic induced dopaminergic behaviors.

A review of dopamine agonist therapy in type 2 diabetes and effects on cardio-metabolic parameters.

PubMed

Lamos, E M; Levitt, D L; Munir, K M

2016-02-01

Dopamine action appears to play a role in changes that are seen in obesity, metabolic syndrome and type 2 diabetes mellitus. Bromocriptine-QR (Quick Release), a dopamine agonist, is approved for use in treatment of type 2 diabetes. It has demonstrated modest improvement in glycemic parameters, cholesterol and weight in certain cohorts. Limited data using cabergoline, a long-acting dopamine agonist, also demonstrate glycemic efficacy. Additionally, bromocriptine-QR appears to have a favorable cardiovascular risk reduction. The direct mechanism by which bromocriptine-QR, or central dopamine agonism, achieves modest glycemic control and favorable cardio-metabolic profile is unclear. This relationship appears to be more complex than the historical explanation of "resetting" the circadian clock and may further be elucidated using data in individuals with hyperprolactinemia and prolactinoma. Copyright © 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

The Transfection of BDNF to Dopamine Neurons Potentiates the Effect of Dopamine D3 Receptor Agonist Recovering the Striatal Innervation, Dendritic Spines and Motor Behavior in an Aged Rat Model of Parkinson’s Disease

PubMed Central

Razgado-Hernandez, Luis F.; Espadas-Alvarez, Armando J.; Reyna-Velazquez, Patricia; Sierra-Sanchez, Arturo; Anaya-Martinez, Veronica; Jimenez-Estrada, Ismael; Bannon, Michael J.; Martinez-Fong, Daniel; Aceves-Ruiz, Jorge

2015-01-01

The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson’s disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF) and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT) administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection) that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old), immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy for restoring dopamine neurons in Parkinson’s disease. PMID:25693197

The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa.

PubMed

Frank, Guido K W; Shott, Megan E; Hagman, Jennifer O; Schiel, Marissa A; DeGuzman, Marisa C; Rossi, Brogan

2017-04-01

Finding medication to support treatment of anorexia nervosa has been difficult. Neuroscience-based approaches may help in this effort. Recent brain imaging studies in adults and adolescents with anorexia nervosa suggest that dopamine-related reward circuits are hypersensitive and could provide a treatment target. Here, we present a retrospective chart review of 106 adolescents with anorexia nervosa some of whom were treated with the dopamine D2 receptor partial agonist aripiprazole during treatment in a specialized eating disorder program. The results show that aripiprazole treatment was associated with greater increase in body mass index (BMI) during treatment. The use of dopamine receptor agonists may support treatment success in anorexia nervosa and should be further investigated. © 2017 Wiley Periodicals, Inc.

Neonatal (+)-methamphetamine exposure in rats alters adult locomotor responses to dopamine D1 and D2 agonists and to a glutamate NMDA receptor antagonist, but not to serotonin agonists

PubMed Central

Graham, Devon L.; Amos-Kroohs, Robyn M.; Braun, Amanda A.; Grace, Curtis E.; Schaefer, Tori L.; Skelton, Matthew R.; Williams, Michael T.; Vorhees, Charles V.

2015-01-01

Neonatal exposure to (+)-methamphetamine (Meth) results in long-term behavioural abnormalities but its developmental mechanisms are unknown. In a series of experiments, rats were treated from post-natal days (PD) 11–20 (stage that approximates human development from the second to third trimester) with Meth or saline and assessed using locomotor activity as the readout following pharmacological challenge doses with dopamine, serotonin and glutamate agonists or antagonists during adulthood. Exposure to Meth early in life resulted in an exaggerated adult locomotor hyperactivity response to the dopamine D1 agonist SKF-82958 at multiple doses, a high dose only under-response activating effect of the D2 agonist quinpirole, and an exaggerated under-response to the activating effect of the N-methyl-D-aspartic acid (NMDA) receptor antagonist, MK-801. No change in locomotor response was seen following challenge with the 5-HT releaser p-chloroamphetamine or the 5-HT2/3 receptor agonist, quipazine. These are the first data to show that PD 11-20 Meth exposure induces long-lasting alterations to dopamine D1, D2 and glutamate NMDA receptor function and may suggest how developmental Meth exposure leads to many of its long-term adverse effects. PMID:22391043

The four As associated with pathological Parkinson disease gamblers: anxiety, anger, age, and agonists.

PubMed

Shapiro, Michael A; Chang, Yu Ling; Munson, Sarah K; Jacobson, Charles E; Rodriguez, Ramon L; Skidmore, Frank M; Okun, Michael S; Fernandez, Hubert H

2007-02-01

Several studies have related pathological gambling in PD to dopamine agonist therapy. A mail-in survey was sent to PD patients seen at the University of Florida Movement Disorders Center to determine gambling frequency and behavior, and any lifestyle or environmental factors associated with compulsive gambling in PD. 462 surveys were sent and 127 completed surveys were returned, of which ten were from patients who met criteria for compulsive gambling. All ten were taking dopamine agonists coincident with the compulsive gambling. Compulsive gamblers were younger, and psychological distress measures revealed that compulsive gamblers exhibited higher levels of anxiety, anger, and confusion. Thus in this cohort, we have uncovered the several characteristics of the most likely PD compulsive gambler, namely: (young) age, "angry", "anxious", and using a (dopamine) agonist.

Dopamine and the Biology of Creativity: Lessons from Parkinson’s Disease

PubMed Central

Lhommée, Eugénie; Batir, Alina; Quesada, Jean-Louis; Ardouin, Claire; Fraix, Valérie; Seigneuret, Eric; Chabardès, Stéphan; Benabid, Alim-Louis; Pollak, Pierre; Krack, Paul

2014-01-01

Background: Parkinson’s disease (PD) is characterized by reduced flexibility, conceptualization, and visuo-spatial abilities. Although these are essential to creativity, case studies show emergence of creativity during PD. Knowledge about the role of dopamine in creativity so far only stems from a few case reports. We aim at demonstrating that creativity can be induced by dopaminergic treatments in PD, and tends to disappear after withdrawal of dopamine agonists. Methods: Eleven consecutive creative PD patients were selected from candidates for subthalamic nucleus deep brain stimulation (STN DBS) surgery, and compared to 22 non-creative control PD patients. Motor disability (UPDRS III), cognition (Frontal score, Mattis scale), and behavior (Ardouin scale) were assessed before surgery and 1 year after. Results: Before surgery, whereas cognitive and motor assessments were similar between groups, dopamine agonist (but not levodopa) dosages were higher in creative patients (p = 0.01). The Ardouin scale revealed also a specific psycho-behavioral profile of creative patients which had higher scores for mania (p < 0.001), hobbyism (p = 0.001), nocturnal hyperactivity (p = 0.041), appetitive functioning (p = 0.003), and ON euphoria (p = 0.007) and lower scores for apathy and OFF dysphoria (p = 0.04 for each). Post-operative motor, cognitive, and behavioral scores as dopaminergic treatment dosages were equivalent between groups. Motor improvement allowed for a 68.6% decrease in dopaminergic treatment. Only 1 of the 11 patients remained creative after surgery. Reduction of dopamine agonist was significantly correlated to the decrease in creativity in the whole population of study (Spearman correlation coefficient ρ = 0.47 with confidence index of 95% = 0.16; 0.70, p = 0.0053). Conclusion: Creativity in PD is linked to dopamine agonist therapy, and tends to disappear after STN DBS in parallel to reduction of dopamine agonists, which are relatively selective for the mesolimbic D3 dopamine receptors. PMID:24795692

The novel antidyskinetic drug sarizotan elicits different functional responses at human D2-like dopamine receptors.

PubMed

Kuzhikandathil, Eldo V; Bartoszyk, Gerd D

2006-09-01

Sarizotan (EMD 128130) is a chromane derivative that exhibits affinity at serotonin and dopamine receptors. Sarizotan effectively suppresses levodopa-induced dyskinesia in primate and rodent models of Parkinson's disease, and tardive dyskinesia in a rodent model. Results from clinical trials suggest that sarizotan significantly alleviates levodopa-induced dyskinesia. The functional effects of sarizotan on individual dopamine receptor subtypes are not known. Here we report the functional effects of sarizotan on human D2-like dopamine receptors (D2S, D2L, D3, D4.2 and D4.4) individually expressed in the AtT-20 neuroendocrine cell line. Using the coupling of D2-like dopamine receptors to G-protein coupled inward rectifier potassium channels we determined that sarizotan is a full agonist at D3 and D4.4 receptors (EC50=5.6 and 5.4 nM, respectively) but a partial agonist at D2S, D2L and D4.2 receptors (EC50=29, 23 and 4.5 nM, respectively). Consistent with its partial agonist property, sarizotan is an antagonist at D2S and D2L receptors (IC50=52 and 121 nM, respectively). Using the coupling of D2-like dopamine receptors to adenylyl cyclase we determined that sarizotan is a full agonist at D2L, D3, D4.2 and D4.4 receptors (EC50=0.51, 0.47, 0.48 and 0.23 nM, respectively) but a partial agonist at D2S receptors (EC50=0.6 nM).

Monoamine oxidase-B inhibitors in the treatment of Parkinson's disease: clinical-pharmacological aspects.

PubMed

Riederer, Peter; Müller, Thomas

2018-03-22

This invited narrative review emphasizes the role of MAO-B inhibition in the drug portfolio for dopamine substitution in patients with Parkinson's disease. Neuronal and glial MAO-B inhibition contributes to more stable levels of dopamine and other biogenic amines in the synaptic cleft. Accordingly, symptomatic effects of MAO-B inhibition for a limited amelioration of impaired motor behaviour and wearing-off phenomena in patients with Parkinson's disease are well proven, even when MAO-B inhibitors are only applied together with dopamine agonists. Delay of disease progression by MAO-B inhibition is under debate despite positive experimental findings. This discussion does not consider, that levodopa, respectively, dopamine agonists, are substrates, respectively, inhibitors of the ABCB1 (P-gp, MDR1, and CD243) transporter system. It supports toxin efflux over the blood-brain barrier. ABCB1 transporters have a limited capacity. MAO-B inhibitors do not weaken it. Treatment with MAO-B inhibitors is advantageous as it enables sparing of dopamine agonist and levodopa dosing.

Single or combined treatment with L-DOPA and quinpirole differentially modulate expression and phosphorylation of key regulatory kinases in neuroblastoma cells.

PubMed

Fuzzati-Armentero, Marie Therese; Ghezzi, Cristina; Nisticò, Robert; Oda, Adriano; Blandini, Fabio

2013-09-27

In the past decades, the clinical use of dopamine agonists has expanded from adjunct therapy in patients with a deteriorating response to L-3,4-dihydroxyphenylalanine (L-DOPA) to monotherapy for the treatment of early PD. Dopamine agonists provide their antiparkinsonian benefit through stimulation of brain postsynaptic type 2 dopamine receptors that exert their effect through classical cAMP-dependent mechanisms, as well as cAMP-independent cellular signaling cascades, including the Akt/glycogen synthase kinase 3 (GSK3) pathway. Alterations of Akt/GSK3 have been observed and may contribute to the neurodegenerative processes and the development of L-DOPA-induced dyskinesia. The effects L-DOPA and quinpirole, a dopamine agonist, on the two key regulatory kinases, Akt and GSK3, were evaluated in neuroblastoma cell line. L-DOPA and dopamine agonist dose-dependently and differentially modulated Akt and GSK3 expression and phosphorylation when added alone or combined. The combined treatment inverted or potentiated the modulatory properties of the single compound. The drug- and concentration-dependent balance of dopamine receptor stimulation over auto-oxidation may distinctively modulate GSK3 isoforms and Akt. Our results indicate that particular attention must be given to drug concentration and combination when multiple therapies are applied for the clinical treatment of PD patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

The four As associated with pathological Parkinson disease gamblers: anxiety, anger, age, and agonists

PubMed Central

Shapiro, Michael A; Chang, Yu Ling; Munson, Sarah K; Jacobson, Charles E; Rodriguez, Ramon L; Skidmore, Frank M; Okun, Michael S; Fernandez, Hubert H

2007-01-01

Several studies have related pathological gambling in PD to dopamine agonist therapy. A mail-in survey was sent to PD patients seen at the University of Florida Movement Disorders Center to determine gambling frequency and behavior, and any lifestyle or environmental factors associated with compulsive gambling in PD. 462 surveys were sent and 127 completed surveys were returned, of which ten were from patients who met criteria for compulsive gambling. All ten were taking dopamine agonists coincident with the compulsive gambling. Compulsive gamblers were younger, and psychological distress measures revealed that compulsive gamblers exhibited higher levels of anxiety, anger, and confusion. Thus in this cohort, we have uncovered the several characteristics of the most likely PD compulsive gambler, namely: (young) age, “angry”, “anxious”, and using a (dopamine) agonist. PMID:19300546

Pharmacological characterization of extracellular acidification rate responses in human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells

PubMed Central

Coldwell, M C; Boyfield, I; Brown, A M; Stemp, G; Middlemiss, D N

1999-01-01

This study characterized pharmacologically the functional responses to agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) zreceptors separately expressed in cloned cells using the cytosensor microphysiometer. Dopaminergic receptor agonists caused increases in extracellular acidification rate in adherent Chinese hamster ovary (CHO) clones expressing hD2, hD3 or hD4 receptors. Acidification rate responses to agonists in other cell lines expressing these receptors were smaller than those in adherent CHO cells. The time courses and maximum increases in acidification rate of the agonist responses in adherent CHO cells were different between the three dopamine receptor clones. Responses were blocked by pretreatment of cells with pertussis toxin or amiloride analogues. Most agonists had full intrinsic activity at each of the dopamine receptor subtypes, as compared to quinpirole, however both enantiomers of UH-232 and (−)3-PPP were partial agonists in this assay system. The functional potency of full agonists at each of the three receptors expressed in CHO cells was either higher than, or similar to, the apparent inhibition constants (Ki) determined in [125I]-iodosulpride competition binding studies. Functional selectivities of the agonists were less than radioligand binding selectivities. The rank orders of agonist potencies and selectivities were similar, but not identical, to the rank orders of radioligand binding affinities and selectivities. The dopamine receptor antagonists, iodosulpride and clozapine, had no effect on basal acidification rates but inhibited acidification responses in CHO cells to quinpirole in an apparently competitive manner. Antagonist potencies closely matched their radioligand binding affinities in these cells. PMID:10455259

Lack of cocaine-like discriminative-stimulus effects of σ-receptor agonists in rats.

PubMed

Hiranita, Takato; Soto, Paul L; Tanda, Gianluigi; Katz, Jonathan L

2011-09-01

Previous studies demonstrated the effectiveness of selective σ-receptor (σR) agonists [1,3-di-o-tolylguanidine (DTG), PRE-084] as reinforcers in rats trained to self-administer cocaine. Similar to cocaine, these drugs increased nucleus accumbens shell dopamine levels, and effects of DTG, but not PRE-084, on dopamine seemed to be mediated by σRs. In addition, σR antagonists blocked self-administration of σR agonists, but were inactive against reinforcing and neurochemical effects of cocaine. Thus, pharmacologically distinct mechanisms likely underlie the reinforcing and neurochemical effects of σR agonists and cocaine. This study further examined the cocaine-like effects of σR agonists in rats trained to discriminate injections of cocaine from saline to assess the similarity of their subjective effects. Standard dopamine-uptake inhibitors (WIN 35,428, methylphenidate), but neither σR agonist (PRE-084, DTG), produced full cocaine-like discriminative-stimulus effects. The lack of effects of σR agonists was obtained regardless of route of administration (intraperitoneal, subcutaneous, or intravenous) or pretreatment time (5 or 30 min before sessions). The present results demonstrate differences in the discriminative-stimulus effects of cocaine and selective σR agonists, indicating that an overlap of subjective effects is not necessary for σR agonist self-administration. The previously found differences in neurochemical effects of cocaine and σR agonists may contribute to their different subjective effects.

Lack of Cocaine-Like Discriminative-Stimulus Effects of σ Receptor Agonists in Rats

PubMed Central

Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi; Katz, Jonathan L.

2013-01-01

Previous studies demonstrated effectiveness of selective sigma-receptor (σR) agonists (DTG, PRE-084) as reinforcers in rats trained to self-administer cocaine. Like cocaine, these drugs increased nucleus accumbens shell dopamine levels, and effects of DTG, but not PRE-084, on dopamine appeared to be mediated by σRs. Additionally, σR antagonists blocked self-administration of σR agonists, but were inactive against reinforcing and neurochemical effects of cocaine. Thus pharmacologically distinct mechanisms likely underlie the reinforcing and neurochemical effects of σR agonists and cocaine. The present study further examined the cocaine-like effects of σR agonists in rats trained to discriminate injections of cocaine from saline to assess the similarity of their subjective effects. Standard dopamine-uptake inhibitors (WIN 35,428, methylphenidate), but neither σR agonist (PRE-084, DTG) produced full cocaine-like discriminative-stimulus effects. The lack of effects of σR agonists was obtained regardless of route of administration (i.p., s.c. or i.v.) or pretreatment time (5- or 30-min before sessions). The present results demonstrate differences in the discriminative-stimulus effects of cocaine and selective σR agonists, indicating that an overlap of subjective effects is not necessary for σR agonist self-administration. The previously found differences in neurochemical effects of cocaine and σR agonists may contribute to their different subjective effects. PMID:21808192

Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques

PubMed Central

Siciliano, Cody A.; Calipari, Erin S.; Yorgason, Jordan T.; Lovinger, David M.; Mateo, Yolanda; Jimenez, Vanessa A.; Helms, Christa M.; Grant, Kathleen A.; Jones, Sara R.

2016-01-01

Rationale Hypofunction of striatal dopamine neurotransmission, or hypodopaminergia, is a consequence of excessive ethanol use, and is hypothesized to be a critical component of alcoholism, driving alcohol intake in an attempt to restore dopamine levels; however, the neurochemical mechanisms involved in these dopaminergic deficiencies are unknown. Objective Here we examined the specific dopaminergic adaptations that produce hypodopaminergia and contribute to alcohol use disorders using direct, sub-second measurements of dopamine signaling in nonhuman primates following chronic ethanol self-administration. Methods Female rhesus macaques completed one year of daily (22 hr/day) ethanol self-administration. Subsequently, fast-scan cyclic voltammetry was used in nucleus accumbens core brain slices to determine alterations in dopamine terminal function, including release and uptake kinetics, and sensitivity to quinpirole (D2/D3 dopamine receptor agonist) and U50,488 (kappa-opioid receptor agonist) induced inhibition of dopamine release. Results Ethanol drinking greatly increased uptake rates, which were positively correlated with lifetime ethanol intake. Furthermore, the sensitivity of dopamine D2/D3 autoreceptors and kappa-opioid receptors, which both act as negative regulators of presynaptic dopamine release, were moderately and robustly enhanced in ethanol drinkers. Conclusions Greater uptake rates and sensitivity to D2-type autoreceptor and kappa-opioid receptor agonists could converge to drive a hypodopaminergic state, characterized by reduced basal dopamine and an inability to mount appropriate dopaminergic responses to salient stimuli. Together, we outline the specific alterations to dopamine signaling that may drive ethanol-induced hypofunction of the dopamine system, and suggest that the dopamine and dynorphin/kappa-opioid receptor systems may be efficacious pharmcotherapeutic targets in the treatment of alcohol use disorders. PMID:26892380

Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques.

PubMed

Siciliano, Cody A; Calipari, Erin S; Yorgason, Jordan T; Lovinger, David M; Mateo, Yolanda; Jimenez, Vanessa A; Helms, Christa M; Grant, Kathleen A; Jones, Sara R

2016-04-01

Hypofunction of striatal dopamine neurotransmission, or hypodopaminergia, is a consequence of excessive ethanol use and is hypothesized to be a critical component of alcoholism, driving alcohol intake in an attempt to restore dopamine levels; however, the neurochemical mechanisms involved in these dopaminergic deficiencies are not fully understood. Here we examined the specific dopaminergic adaptations that produce hypodopaminergia and contribute to alcohol use disorders using direct, sub-second measurements of dopamine signaling in nonhuman primates following chronic ethanol self-administration. Female rhesus macaques completed 1 year of daily (22 h/day) ethanol self-administration. Subsequently, fast-scan cyclic voltammetry was used in nucleus accumbens core brain slices to determine alterations in dopamine terminal function, including release and uptake kinetics, and sensitivity to quinpirole (D2/D3 dopamine receptor agonist) and U50,488 (kappa opioid receptor agonist) induced inhibition of dopamine release. Ethanol drinking greatly increased uptake rates, which were positively correlated with lifetime ethanol intake. Furthermore, the sensitivity of dopamine D2/D3 autoreceptors and kappa opioid receptors, which both act as negative regulators of presynaptic dopamine release, was moderately and robustly enhanced in ethanol drinkers. Greater uptake rates and sensitivity to D2-type autoreceptor and kappa opioid receptor agonists could converge to drive a hypodopaminergic state, characterized by reduced basal dopamine and an inability to mount appropriate dopaminergic responses to salient stimuli. Together, we outline the specific alterations to dopamine signaling that may drive ethanol-induced hypofunction of the dopamine system and suggest that the dopamine and dynorphin/kappa opioid receptor systems may be efficacious pharmacotherapeutic targets in the treatment of alcohol use disorders.

Opposing Effects of Dopamine D1- and D2-Like Agonists on Intracranial Self-Stimulation in Male Rats

PubMed Central

Lazenka, Matthew F.; Legakis, Luke P.; Negus, S. Stevens

2016-01-01

Dopamine acts through dopamine type 1 receptors (comprised of D1 and D5 subtypes) and dopamine type 2 receptors (comprised of D2, D3 and D4 subtypes). Intracranial self-stimulation (ICSS) is one experimental procedure that can be used to evaluate abuse-related effects of drugs targeting dopamine receptors. This study evaluated effects of dopamine receptor ligands on ICSS in rats using experimental procedures that have been used previously to examine abused indirect dopamine agonists such as cocaine and amphetamine. Male Sprague-Dawley rats responded under a fixed-ratio 1 schedule for electrical stimulation of the medial forebrain bundle, and frequency of stimulation varied from 56–158 Hz in 0.05 log increments during each experimental session. Drug potency and time course were determined for the D1 ligands A77636, SKF82958, SKF38393, fenoldopam and SCH39166 and the D2/3 ligands sumanirole, apomorphine, quinpirole, PD128907, pramipexole, aripiprazole, eticolopride and PG01037. The high-efficacy D1 agonists A77636 and SKF82958 produced dose-dependent, time-dependent, and abuse-related facilitation of ICSS. Lower efficacy D1 ligands and all D2/3 ligands failed to facilitate ICSS at any dose or pretreatment time. A mixture of SKF82958 and quinpirole produced a mixture of effects produced by each drug alone. Quinpirole also failed to facilitate ICSS after regimens of repeated treatment with either quinpirole or cocaine. These studies provide more evidence for divergent effects of dopamine D1- and D2-family agonists on ICSS procedure in rats and suggest that ICSS may be a useful complement to other approaches for preclinical abuse potential assessment, in part because of the reproducibility of results. PMID:26987070

Low levels of PRB3 mRNA are associated with dopamine-agonist resistance and tumor recurrence in prolactinomas.

PubMed

Wang, Fei; Gao, Hua; Li, Chuzhong; Bai, Jiwei; Lu, Runchun; Cao, Lei; Wu, Yongtu; Hong, Lichuan; Wu, Yonggang; Lan, Xiaolei; Zhang, Yazhuo

2014-01-01

Prolactinomas, or prolactin-secreting adenomas, constitute the most common type of hyperfunctioning pituitary adenoma. Dopamine agonists are used as first-line medication for prolactinomas, but the tumors are resistant to the therapy in 5-18 % of patients. To explore potential mechanisms of resistance to bromocriptine (a dopamine agonist), we analyzed six responsive prolactinomas and six resistant prolactinomas by whole-exome sequencing. We identified ten genes with sequence variants that were differentially found in the two groups of tumors. The expression of these genes was then quantified by real-time reverse-transcription PCR (RT-qPCR) in the 12 prolactinomas and in six normal pituitary glands. The mRNA levels of one of the genes, PRB3, were about fourfold lower in resistant prolactinomas than in the responsive tumors (p = 0.02). Furthermore, low PRB3 expression was also associated with tumor recurrence. Our results suggest that low levels of PRB3 mRNA may have a role in dopamine-agonist resistance and tumor recurrence of prolactinomas.

Developments in impulse control behaviours of Parkinson's disease.

PubMed

Zurowski, Mateusz; O'Brien, Jonathan Darcy

2015-08-01

Impulse control behaviours (ICBs) are a frequent comorbidity for patients with Parkinson's disease. They consist of impulse control disorders, dopamine dysregulation syndrome, and punding. The field continues to evolve in the understanding of impulsivity and assessment of risk factors in the development of these behaviours and their appropriate management in patients with Parkinson's disease. Impulsivity is a multifaceted concept that is surprisingly common in untreated patients with Parkinson's disease. The incidence of ICBs increases with demographic, clinical, and biochemical risk factors. Treatments rely on reduction of dopamine agonists with exception of cognitive behavioural therapy and possibly repetitive transcranial magnetic stimulation. Reduction of dopamine agonist dose is the mainstay of treatment of ICBs. Other forms of dopaminergic treatment such as deep brain stimulation or jejunal infusion are alternative treatments but may be complicated by dopamine agonist withdrawal syndrome. Other therapies show promise but data are insufficient to suggest their regular use.

Association between REM sleep behaviour disorder and impulse control disorder in patients with Parkinson's disease.

PubMed

Bellosta Diago, E; Lopez Del Val, L J; Santos Lasaosa, S; López Garcia, E; Viloria Alebesque, A

2017-10-01

The relationship between impulse control disorder (ICD) and REM sleep behaviour disorder (RBD) has not yet been clarified, and the literature reports contradictory results. Our purpose is to analyse the association between these 2 disorders and their presence in patients under dopaminergic treatment. A total of 73 patients diagnosed with Parkinson's disease and treated with a single dopamine agonist were included in the study after undergoing clinical assessment and completing the single-question screen for REM sleep behaviour disorder and the short version of the questionnaire for impulsive-compulsive behaviours in Parkinson's disease. Mean age was 68.88 ± 7.758 years. Twenty-six patients (35.6%) were classified as probable-RBD. This group showed a significant association with ICD (P=.001) and had a higher prevalence of non-tremor akinetic rigid syndrome and longer duration of treatment with levodopa and dopamine agonists than the group without probable-RBD. We found a significant correlation between the use of oral dopamine agonists and ICD. Likewise, patients treated with oral dopamine agonists demonstrated a greater tendency toward presenting probable-RBD than patients taking dopamine agonists by other routes; the difference was non-significant. The present study confirms the association between RBD and a higher risk of developing symptoms of ICD in Parkinson's disease. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

An observational study of rotigotine transdermal patch and other currently prescribed therapies in patients with Parkinson's disease.

PubMed

Müller, Thomas; Tolosa, Eduardo; Badea, Letitia; Asgharnejad, Mahnaz; Grieger, Frank; Markowitz, Michael; Nondonfaz, Xavier; Bauer, Lars; Timmermann, Lars

2018-06-01

Real-world data from large cohorts of patients with Parkinson's disease on the long-term effectiveness of different dopamine-substituting drug therapies are rare. The objective of this study was to obtain information on real-world management of PD with dopamine-substituting drugs. SP0854 (NCT00599339) was a prospective, multicenter, non-interventional, multiple-cohort, post-authorization safety study of rotigotine versus other dopaminergic therapies. The study was also part of a European Medicines Agency risk-management plan for the non-ergoline dopamine agonist rotigotine, focussing on cardiovalvular fibrosis. Eligible patients requiring monotherapy with a dopamine agonist, or levodopa in combination with a dopamine agonist were followed for ≤ 33 months; 1531 of 2195 patients completed the study. Mean motor scores improved for all dopamine-substituting treatments. Patients with more severe motor-symptoms/increased disability were more likely to receive levodopa alone or in combination with a DA at study onset. More patients who started on combination therapy with levodopa remained on this treatment versus those starting on dopaminergic monotherapy. This real-world study showed that the dopamine-substituting therapies were efficacious, with a safety profile consistent with that expected of dopaminergic treatments. Cardiovalvular pathology was rare and not found to be causally-related to rotigotine.

Sodium ion modulates D2 receptor characteristics of dopamine agonist and antagonist binding sites in striatum and retina

PubMed Central

Makman, Maynard H.; Dvorkin, B.; Klein, Patrice N.

1982-01-01

Sodium ion (Na+) influences binding of both dopamine agonists and antagonists to D2 receptors in striatum and retina. Also, Na+ markedly potentiates the loss of high-affinity agonist binding due to the GTP analogue p[NH]ppG. 2-Amino-6, 7-dihydroxy-1,2,3,4-tetrahydro[5,8-3H]naphthalene ([3H]ADTN) binds exclusively to an agonist conformation of D2 receptor in both striatum and retina, distinct from the antagonist conformation labeled by [3H]spiroperidol or [3H]domperidone in striatum or by [3H]spiroperidol in retina. Na+ is not required for interaction of [3H]ADTN or antagonist radioligand sites with the selective D2 agonist LY-141865, the D2 antagonist domperidone, or nonselective dopamine agonists or antagonists; however, Na+ is necessary for high affinity interaction of those radioligand sites with the D2 antagonists molindone and metoclopramide. With Na+ present, striatal sites for [3H]ADTN, [3H]spiroperidol, and [3H]domperidone have similar affinities for antagonists but only [3H]ADTN sites have high affinity for agonists. Na+ further decreases the low affinity of dopamine agonists for [3H]spiroperidol binding sites. Also, Na+ enhances [3H]spiroperidol and decreases [3H]ADTN binding. Na+ alone causes bound [3H]ADTN to dissociate from at least 30% of striatal and 50% of retinal sites, and with Na+ present [3H]ADTN rapidly dissociates from the remaining sites upon addition of p[NH]ppG. It is proposed that D2 receptors in striatum and retina exist in distinct but interconvertible conformational states, with different properties depending on the presence or absence of Na+ and of guanine nucleotide. PMID:6213964

Self-Administration of Cocaine Induces Dopamine-Independent Self-Administration of Sigma Agonists

PubMed Central

Hiranita, Takato; Mereu, Maddalena; Soto, Paul L; Tanda, Gianluigi; Katz, Jonathan L

2013-01-01

Sigma1 receptors (σ1Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective σ1R agonists (PRE-084, (+)-pentazocine) lacked reinforcing effects in drug-naive rats, over the course of 28 experimental sessions, which was more than sufficient for acquisition of cocaine self-administration, responding was not maintained by either σ1R agonist. In contrast, after subjects self-administered cocaine σ1R agonists were readily self-administered. The induced reinforcing effects were long lasting; a response for which subjects had no history of reinforcement was newly conditioned with both σ1R agonists, extinguished when injections were discontinued, and reconditioned when σ1R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of σ1R agonist reinforcement. Although a variety of dopamine receptor antagonists blocked cocaine self-administration, consistent with its dopaminergic mechanism, PRE-084 self-administration was entirely insensitive to these drugs. Conversely, the σR antagonist, BD1063, blocked PRE-084 self-administration but was inactive against cocaine. In microdialysis studies i.v. PRE-084 did not significantly stimulate dopamine at doses that were self-administered in rats either with or without a cocaine self-administration experience. The results indicate that cocaine experience induces reinforcing effects of previously inactive σ1R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced σ1R mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse. PMID:23187725

Self-administration of cocaine induces dopamine-independent self-administration of sigma agonists.

PubMed

Hiranita, Takato; Mereu, Maddalena; Soto, Paul L; Tanda, Gianluigi; Katz, Jonathan L

2013-03-01

Sigma(1) receptors (σ(1)Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective σ(1)R agonists (PRE-084, (+)-pentazocine) lacked reinforcing effects in drug-naive rats, over the course of 28 experimental sessions, which was more than sufficient for acquisition of cocaine self-administration, responding was not maintained by either σ(1)R agonist. In contrast, after subjects self-administered cocaine σ(1)R agonists were readily self-administered. The induced reinforcing effects were long lasting; a response for which subjects had no history of reinforcement was newly conditioned with both σ(1)R agonists, extinguished when injections were discontinued, and reconditioned when σ(1)R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of σ(1)R agonist reinforcement. Although a variety of dopamine receptor antagonists blocked cocaine self-administration, consistent with its dopaminergic mechanism, PRE-084 self-administration was entirely insensitive to these drugs. Conversely, the σR antagonist, BD1063, blocked PRE-084 self-administration but was inactive against cocaine. In microdialysis studies i.v. PRE-084 did not significantly stimulate dopamine at doses that were self-administered in rats either with or without a cocaine self-administration experience. The results indicate that cocaine experience induces reinforcing effects of previously inactive σ(1)R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced σ(1)R mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse.

Analysis of the actions of the novel dopamine receptor-directed compounds (S)-OSU6162 and ACR16 at the D2 dopamine receptor

PubMed Central

Kara, Elodie; Lin, Hong; Svensson, Kjell; Johansson, Anette M; Strange, Philip G

2010-01-01

BACKGROUND AND PURPOSE The two phenylpiperidines, OSU6162 and ACR16, have been proposed as novel drugs for the treatment of brain disorders, including schizophrenia and Huntington's disease, because of their putative dopamine stabilizing effects. Here we evaluated the activities of these compounds in a range of assays for the D2 dopamine receptor in vitro. EXPERIMENTAL APPROACH The affinities of these compounds for the D2 dopamine receptor were evaluated in competition with [3H]spiperone and [3H]NPA. Agonist activity of these compounds was evaluated in terms of their ability to stimulate [35S]GTPγS binding. KEY RESULTS Both compounds had low affinities for inhibition of [3H]spiperone binding (pKi vs. [3H]spiperone, ACR16: <5, OSU6162: 5.36). Neither compound was able to stimulate [35S]GTPγS binding when assayed in the presence of Na+ ions, but if the Na+ ions were removed, both compounds were low-affinity, partial agonists (Emax relative to dopamine: ACR16: 10.2%, OSU6162:54.3%). Schild analysis of the effects of OSU6162 to inhibit dopamine-stimulated [35S]GTPγS binding indicated Schild slopes of ∼0.9, suggesting little deviation from competitive inhibition. OSU6162 was, however, able to accelerate [3H]NPA dissociation from D2 dopamine receptors, indicating some allosteric effects of this compound. CONCLUSIONS AND IMPLICATIONS The two phenylpiperidines were low-affinity, low-efficacy partial agonists at the D2 dopamine receptor in vitro, possibly exhibiting some allosteric effects. Comparing their in vitro and in vivo effects, the in vitro affinities were a reasonable guide to potencies in vivo. However, the lack of in vitro–in vivo correlation for agonist efficacy needs to be further addressed. PMID:20804495

Effect of reducing milk production using a prolactin-release inhibitor or a glucocorticoid on metabolism and immune functions in cows subjected to acute nutritional stress.

PubMed

Ollier, S; Beaudoin, F; Vanacker, N; Lacasse, P

2016-12-01

When cows are unable to consume enough feed to support milk production, they often fall into severe negative energy balance. This leads to a weakened immune system and increases their susceptibility to infectious diseases. Reducing the milk production of cows subjected to acute nutritional stress decreases their energy deficit. The aim of this study was to compare the effects on metabolism and immune function of reducing milk production using quinagolide (a prolactin-release inhibitor) or dexamethasone in feed-restricted cows. A total of 23 cows in early/mid-lactation were fed for 5 d at 55.9% of their previous dry matter intake to subject them to acute nutritional stress. After 1 d of feed restriction and for 4 d afterward (d 2 to 5), cows received twice-daily i.m. injections of water (control group; n=8), 2mg of quinagolide (QN group; n=7), or water after a first injection of 20mg of dexamethasone (DEX group; n=8). Feed restriction decreased milk production, but the decrease was greater in the QN and DEX cows than in the control cows on d 2 and 3. As expected, feed restriction reduced the energy balance, but the reduction was lower in the QN cows than in the control cows. Feed restriction decreased plasma glucose concentration and increased plasma nonesterified fatty acid (NEFA) and β-hydroxybutyrate (BHB) concentrations. The QN cows had higher glucose concentration and lower BHB concentration than the control cows. The NEFA concentration was also lower in the QN cows than in the control cows on d 2. Dexamethasone injection induced transient hyperglycemia concomitant with a reduction in milk lactose concentration; it also decreased BHB concentration and decreased NEFA initially but increased it later. Feed restriction and quinagolide injections did not affect the blood concentration or activity of polymorphonuclear leukocytes (PMN), whereas dexamethasone injection increased PMN blood concentration but decreased the proportion of PMN capable of inducing oxidative burst. Incubation of peripheral blood mononuclear cells in serum harvested on d 2 of the restriction period reduced their ability to react to mitogen-induced proliferation, and injection of quinagolide or dexamethasone could not alleviate this effect. This experiment shows that prolactin-release inhibition could be an alternative to dexamethasone for reducing milk production and energy deficit in cows under acute nutritional stress, without disturbing immune function. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Dopamine agonist suppression of rapid-eye-movement sleep is secondary to sleep suppression mediated via limbic structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miletich, R.S.

The effects of pergolide, a direct dopamine receptor agonist, on sleep and wakefulness, motor behavior and /sup 3/H-spiperone specific binding in limbic structures and striatum in rats was studied. The results show that pergolide induced a biphasic dose effect, with high doses increasing wakefulness and suppressing sleep while low dose decreased wakefulness, but increased sleep. It was shown that pergolide-induced sleep suppression was blocked by ..cap alpha..-glupenthixol and pimozide, two dopamine receptor antagonists. It was further shown that pergolide merely delayed the rebound resulting from rapid-eye-movement (REM) sleep deprivation, that dopamine receptors stimulation had no direct effect on the period,more » phase or amplitude of the circadian rhythm of REM sleep propensity and that there was no alteration in the coupling of REM sleep episodes with S/sub 2/ episodes. Rapid-eye-movement sleep deprivation resulted in increased sensitivity to the pergolide-induced wakefulness stimulation and sleep suppression and pergolide-induced motor behaviors of locomotion and head bobbing. /sup 3/H-spiperone specific binding to dopamine receptors was shown to be altered by REM sleep deprivation in the subcortical limbic structures. It is concluded that the REM sleep suppressing action of dopamine receptor stimulation is secondary to sleep suppression per se and not secondary to a unique effect on the REM sleep. Further, it is suggested that the wakefulness stimulating action of dopamine receptor agonists is mediated by activation of the dopamine receptors in the terminal areas of the mesolimbocortical dopamine projection system.« less

Intravitreally-administered dopamine D2-like (and D4), but not D1-like, receptor agonists reduce form-deprivation myopia in tree shrews.

PubMed

Ward, Alexander H; Siegwart, John T; Frost, Michael R; Norton, Thomas T

2017-01-01

We examined the effect of intravitreal injections of D1-like and D2-like dopamine receptor agonists and antagonists and D4 receptor drugs on form-deprivation myopia (FDM) in tree shrews, mammals closely related to primates. In eleven groups (n = 7 per group), we measured the amount of FDM produced by monocular form deprivation (FD) over an 11-day treatment period. The untreated fellow eye served as a control. Animals also received daily 5 µL intravitreal injections in the FD eye. The reference group received 0.85% NaCl vehicle. Four groups received a higher, or lower, dose of a D1-like receptor agonist (SKF38393) or antagonist (SCH23390). Four groups received a higher, or lower, dose of a D2-like receptor agonist (quinpirole) or antagonist (spiperone). Two groups received the D4 receptor agonist (PD168077) or antagonist (PD168568). Refractions were measured daily; axial component dimensions were measured on day 1 (before treatment) and day 12. We found that in groups receiving the D1-like receptor agonist or antagonist, the development of FDM and altered ocular component dimensions did not differ from the NaCl group. Groups receiving the D2-like receptor agonist or antagonist at the higher dose developed significantly less FDM and had shorter vitreous chambers than the NaCl group. The D4 receptor agonist, but not the antagonist, was nearly as effective as the D2-like agonist in reducing FDM. Thus, using intravitreally-administered agents, we did not find evidence supporting a role for the D1-like receptor pathway in reducing FDM in tree shrews. The reduction of FDM by the dopamine D2-like agonist supported a role for the D2-like receptor pathway in the control of FDM. The reduction of FDM by the D4 receptor agonist, but not the D4 antagonist, suggests an important role for activation of the dopamine D4 receptor in the control of axial elongation and refractive development.

Intravitreally-administered dopamine D2-like (and D4), but not D1-like, receptor agonists reduce form-deprivation myopia in tree shrews

PubMed Central

Ward, Alexander H.; Siegwart, John T.; Frost, Michael R.; Norton, Thomas T.

2017-01-01

We examined the effect of intravitreal injections of D1-like and D2-like dopamine receptor agonists and antagonists and D4 receptor drugs on form-deprivation myopia (FDM) in tree shrews, mammals closely related to primates. In eleven groups (n = 7 per group), we measured the amount of FDM produced by monocular form deprivation (FD) over an 11-day treatment period. The untreated fellow eye served as a control. Animals also received daily 5 μL intravitreal injections in the FD eye. The reference group received 0.85% NaCl vehicle. Four groups received a higher, or lower, dose of a D1-like receptor agonist (SKF38393) or antagonist (SCH23390). Four groups received a higher, or lower, dose of a D2-like receptor agonist (quinpirole) or antagonist (spiperone). Two groups received the D4 receptor agonist (PD168077) or antagonist (PD168568). Refractions were measured daily; axial component dimensions were measured on day 1 (before treatment) and day 12. We found that in groups receiving the D1-like receptor agonist or antagonist, the development of FDM and altered ocular component dimensions did not differ from the NaCl group. Groups receiving the D2-like receptor agonist or antagonist at the higher dose developed significantly less FDM and had shorter vitreous chambers than the NaCl group. The D4 receptor agonist, but not the antagonist, was nearly as effective as the D2-like agonist in reducing FDM. Thus, using intravitreally-administered agents, we did not find evidence supporting a role for the D1-like receptor pathway in reducing FDM in tree shrews. The reduction of FDM by the dopamine D2-like agonist supported a role for the D2-like receptor pathway in the control of FDM. The reduction of FDM by the D4 receptor agonist, but not the D4 antagonist, suggests an important role for activation of the dopamine D4 receptor in the control of axial elongation and refractive development. PMID:28304244

Regulation of bat echolocation pulse acoustics by striatal dopamine.

PubMed

Tressler, Jedediah; Schwartz, Christine; Wellman, Paul; Hughes, Samuel; Smotherman, Michael

2011-10-01

The ability to control the bandwidth, amplitude and duration of echolocation pulses is a crucial aspect of echolocation performance but few details are known about the neural mechanisms underlying the control of these voice parameters in any mammal. The basal ganglia (BG) are a suite of forebrain nuclei centrally involved in sensory-motor control and are characterized by their dependence on dopamine. We hypothesized that pharmacological manipulation of brain dopamine levels could reveal how BG circuits might influence the acoustic structure of bat echolocation pulses. A single intraperitoneal injection of a low dose (5 mg kg(-1)) of the neurotoxin 1-methyl-4-phenylpyridine (MPTP), which selectively targets dopamine-producing cells of the substantia nigra, produced a rapid degradation in pulse acoustic structure and eliminated the bat's ability to make compensatory changes in pulse amplitude in response to background noise, i.e. the Lombard response. However, high-performance liquid chromatography (HPLC) measurements of striatal dopamine concentrations revealed that the main effect of MPTP was a fourfold increase rather than the predicted decrease in striatal dopamine levels. After first using autoradiographic methods to confirm the presence and location of D(1)- and D(2)-type dopamine receptors in the bat striatum, systemic injections of receptor subtype-specific agonists showed that MPTP's effects on pulse acoustics were mimicked by a D(2)-type dopamine receptor agonist (Quinpirole) but not by a D(1)-type dopamine receptor agonist (SKF82958). The results suggest that BG circuits have the capacity to influence echolocation pulse acoustics, particularly via D(2)-type dopamine receptor-mediated pathways, and may therefore represent an important mechanism for vocal control in bats.

Regulation of bat echolocation pulse acoustics by striatal dopamine

PubMed Central

Tressler, Jedediah; Schwartz, Christine; Wellman, Paul; Hughes, Samuel; Smotherman, Michael

2011-01-01

SUMMARY The ability to control the bandwidth, amplitude and duration of echolocation pulses is a crucial aspect of echolocation performance but few details are known about the neural mechanisms underlying the control of these voice parameters in any mammal. The basal ganglia (BG) are a suite of forebrain nuclei centrally involved in sensory-motor control and are characterized by their dependence on dopamine. We hypothesized that pharmacological manipulation of brain dopamine levels could reveal how BG circuits might influence the acoustic structure of bat echolocation pulses. A single intraperitoneal injection of a low dose (5 mg kg–1) of the neurotoxin 1-methyl-4-phenylpyridine (MPTP), which selectively targets dopamine-producing cells of the substantia nigra, produced a rapid degradation in pulse acoustic structure and eliminated the bat's ability to make compensatory changes in pulse amplitude in response to background noise, i.e. the Lombard response. However, high-performance liquid chromatography (HPLC) measurements of striatal dopamine concentrations revealed that the main effect of MPTP was a fourfold increase rather than the predicted decrease in striatal dopamine levels. After first using autoradiographic methods to confirm the presence and location of D1- and D2-type dopamine receptors in the bat striatum, systemic injections of receptor subtype-specific agonists showed that MPTP's effects on pulse acoustics were mimicked by a D2-type dopamine receptor agonist (Quinpirole) but not by a D1-type dopamine receptor agonist (SKF82958). The results suggest that BG circuits have the capacity to influence echolocation pulse acoustics, particularly via D2-type dopamine receptor-mediated pathways, and may therefore represent an important mechanism for vocal control in bats. PMID:21900471

The outcome of hypophysectomy for prolactinomas in the era of dopamine agonist therapy.

PubMed

Soule, S G; Farhi, J; Conway, G S; Jacobs, H S; Powell, M

1996-06-01

Dopamine agonists are the primary therapeutic modality for the majority of patients with prolactinomas, with pituitary surgery reserved for those patients intolerant of or resistant to these agents. Most published surgical series, however, contain patients treated by surgery as the primary therapeutic modality. Previous exposure to dopamine agonists or the selection of patients with prolactinomas resistant to conventional therapy may potentially compromise the surgical success rate. The purpose of this study was to evaluate the efficacy and safety of pituitary surgery for prolactinomas in a tertiary referral centre where the majority of patients were operated on after treatment with dopamine agonists. A retrospective review of the outcome of pituitary surgery for prolactinomas performed at a tertiary neurosurgical centre by a single neurosurgeon. Twenty-three patients underwent excision of a macro and 11 excision of a micro-prolactinoma. Pituitary tumour diameter was determined by CT or MRI imaging. Pre and post-operative measurements were made of serum PRL concentration (off dopamine agonist therapy), free T4, free T3, LH and testosterone (males). Post-operative restoration of a menstrual cycle was taken to indicate resolution of hypogonadism in female patients. The majority (73.9%) of the patients with macro and all with micro-prolactinomas had received dopamine agonists preoperatively. Of the 23 patients with macroprolactinomas, in whom the median preoperative PRL concentration was 13255 mU/l, 17 (73.9%) had radiological evidence of suprasellar extension and 5 (21.7%) cavernous sinus invasion. Only 4 (17.4%) of the patients with macroprolactinomas had a normal serum PRL post-operatively, although there was an improvement in visual fields in 66% of those with preoperative defects. The median preoperative PRL concentration was 4309 mU/l in the patients with microprolactinomas, significantly lower than in the macroprolactinoma group (P = 0.02). Despite a significant fall in serum PRL postoperatively (median PRL 860 mU/l, P = 0.0001), only 45.5% of patients had a normal serum PRL concentration after surgery. The cure rate following pituitary surgery for prolactinomas in a tertiary referral centre was low when compared with previous series in which surgery was used as the primary therapeutic modality. We suggest this may result both from dopamine agonist pretreatment and the referral of prolactinomas resistant to conventional therapy. The outcome is probably a more realistic reflection of the results of pituitary surgery for prolactinomas as currently practised in the majority of neuroendocrine centres.

AFRRI Reports, First Quarter 1994

DTIC Science & Technology

1994-06-01

cholinergic agonists (as assessed by examining oxotremorine enhancement of K+-evoked release of dopamine from neostriatal slices) in animals that had been...protein interface and by comparing the response to oxotremorine -en- hanced K+-evoked release of dopamine. Results showed that al- though oxotremorine ...muscarinic acetylcholine receptors (mAChR)4 to stimula- tion by muscarinic agonists. This latter assessment was made by examining the oxotremorine (OXO

Working memory span capacity improved by a D2 but not D1 receptor family agonist.

PubMed

Tarantino, Isadore S; Sharp, Richard F; Geyer, Mark A; Meves, Jessica M; Young, Jared W

2011-06-01

Patients with schizophrenia exhibit poor working memory (WM). Although several subcomponents of WM can be measured, evidence suggests the primary subcomponent affected in schizophrenia is span capacity (WMC). Indeed, the NIMH-funded MATRICS initiative recommended assaying the WMC when assessing the efficacy of a putative therapeutic for FDA approval. Although dopamine D1 receptor agonists improve delay-dependent memory in animals, evidence for improvements in WMC due to dopamine D1 receptor activation is limited. In contrast, the dopamine D2-family agonist bromocriptine improves WMC in humans. The radial arm maze (RAM) can be used to assess WMC, although complications due to ceiling effects or strategy confounds have limited its use. We describe a 12-arm RAM protocol designed to assess whether the dopamine D1-family agonist SKF 38393 (0, 1, 3, and 10 mg/kg) or bromocriptine (0, 1, 3, and 10 mg/kg) could improve WMC in C57BL/6N mice (n=12) in cross-over designs. WMC increased and strategy usage decreased with training. The dopamine D1 agonist SKF 38393 had no effect on WMC or long-term memory. Bromocriptine decreased WMC errors, without affecting long-term memory, consistent with human studies. These data confirm that WMC can be measured in mice and reveal drug effects that are consistent with reported effects in humans. Future research is warranted to identify the subtype of the D2-family of receptors responsible for the observed improvement in WMC. Finally, this RAM procedure may prove useful in developing animal models of deficient WMC to further assess putative treatments for the cognitive deficits in schizophrenia. Copyright © 2011 Elsevier B.V. All rights reserved.

Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging.

PubMed

Smith, Roy G; Sun, Yuxiang; Jiang, Hong; Albarran-Zeckler, Rosie; Timchenko, Nikolai

2007-11-01

Administration of an orally active agonist (MK-0677) of the growth hormone secretagogue receptor (GHS-R1a) to elderly subjects restored the amplitude of endogenous episodic growth hormone (GH) release to that of young adults. Functional benefits include increased lean mass and bone density and modest improvements in strength. In old mice, a similar agonist partially restored function to the thymus and reduced tumor cell growth and metastasis. Treatment of old mice with the endogenous GHS-R1a agonist ghrelin restored a young liver phenotype. The mechanism involves inhibition of cyclin D3:cdk4/cdk6 activity and increased protein phosphatase-2A (PP2A) activity in liver nuclei, which stabilizes the dephosphorylated form of the transcription factor C/EBPalpha preventing the age-dependent formation of the C/EBPalpha-Rb-E2F4-Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de-repressed and C/EBPalpha regulated expression of Pepck, a regulator of gluconeogenesis, is normalized, thereby restoring a young liver phenotype. In the brain, aging is associated with decline in dopamine function. We investigated the potential neuromodulatory role of GHS-R1a on dopamine action. Neurons were identified in the hippocampus, cortex, substantia nigra, and ventral tegmental areas that coexpressed GHS-R1a and dopamine receptor subtype-1 (D1R). Cell culture studies showed that, in the presence of ghrelin and dopamine, GHS-R and D1R form heterodimers, which modified G-protein signal transduction resulting in amplification of dopamine signaling. We speculate that aging is associated with deficient endogenous ghrelin signaling that can be rescued by intervention with GHS-R1a agonists to improve quality of life and maintain independence.

α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands.

PubMed

Sánchez-Soto, Marta; Casadó-Anguera, Verònica; Yano, Hideaki; Bender, Brian Joseph; Cai, Ning-Sheng; Moreno, Estefanía; Canela, Enric I; Cortés, Antoni; Meiler, Jens; Casadó, Vicent; Ferré, Sergi

2018-03-18

The poor norepinephrine innervation and high density of Gi/o-coupled α 2A - and α 2C -adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D 2 -like receptor ligands, such as the D 3 receptor agonist 7-OH-PIPAT and the D 4 receptor agonist RO-105824, to α 2 -adrenoceptors in cortical and striatal tissue, which express α 2A -adrenoceptors and both α 2A - and α 2C -adrenoceptors, respectively. The affinity of dopamine for α 2 -adrenoceptors was found to be similar to that for D 1 -like and D 2 -like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α 2A - and α 2C -adrenoceptors. Their ability to activate Gi/o proteins through α 2A - and α 2C -adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α 2 -adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α 2A - and α 2C -adrenoceptors was nearly identical to its binding to the crystallized D 3 receptor. Therefore, we provide conclusive evidence that α 2A - and α 2C -adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D 2 -like receptor ligands, which calls for revisiting previous studies with those ligands.

Active-State Model of a Dopamine D2 Receptor - Gαi Complex Stabilized by Aripiprazole-Type Partial Agonists

PubMed Central

Kling, Ralf C.; Tschammer, Nuska; Lanig, Harald; Clark, Timothy; Gmeiner, Peter

2014-01-01

Partial agonists exhibit a submaximal capacity to enhance the coupling of one receptor to an intracellular binding partner. Although a multitude of studies have reported different ligand-specific conformations for a given receptor, little is known about the mechanism by which different receptor conformations are connected to the capacity to activate the coupling to G-proteins. We have now performed molecular-dynamics simulations employing our recently described active-state homology model of the dopamine D2 receptor-Gαi protein-complex coupled to the partial agonists aripiprazole and FAUC350, in order to understand the structural determinants of partial agonism better. We have compared our findings with our model of the D2R-Gαi-complex in the presence of the full agonist dopamine. The two partial agonists are capable of inducing different conformations of important structural motifs, including the extracellular loop regions, the binding pocket and, in particular, intracellular G-protein-binding domains. As G-protein-coupling to certain intracellular epitopes of the receptor is considered the key step of allosterically triggered nucleotide-exchange, it is tempting to assume that impaired coupling between the receptor and the G-protein caused by distinct ligand-specific conformations is a major determinant of partial agonist efficacy. PMID:24932547

Recruitment of β-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling

PubMed Central

Klewe, Ib V.; Nielsen, Søren M.; Tarpø, Louise; Urizar, Eneko; Dipace, Concetta; Javitch, Jonathan A.; Gether, Ulrik; Egebjerg, Jan; Christensen, Kenneth V.

2013-01-01

Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson’s disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through β-arrestin. In this study we describe the establishment of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human β-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit marked concentration dependent increases in the BRET signal signifying β-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating β-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine and ziprasidone all fully inhibited the dopamine induced β-arrestin2 recruitment to D2 receptor (short variant) in a concentration dependent manner. We conclude that most anti-psychotics are incapable of stimulating β-arrestin2 recruitment to the dopamine D2 receptor, in accordance with their antagonistic properties at the level of G-protein coupling. PMID:18455202

MitoPark mice, an animal model of Parkinson's disease, show enhanced prepulse inhibition of acoustic startle and no loss of gating in response to the adenosine A(2A) antagonist SCH 412348.

PubMed

Grauer, Steven M; Hodgson, Robert; Hyde, Lynn A

2014-04-01

Psychoses are debilitating side effects associated with current dopaminergic treatments for Parkinson's disease (PD). Prepulse inhibition (PPI), in which a non-startling stimulus reduces startle response to a subsequent startle-eliciting stimulus, is important in filtering out extraneous sensory stimuli. PPI deficits induced by dopamine agonists can model symptoms of psychosis. Adenosine A(2A) receptor antagonists, being developed as novel PD treatments, indirectly modulate dopamine signaling in the basal ganglia and may have an improved psychosis profile which could be detected using the PPI model. The aims of this study is to characterize PPI in MitoPark mice, which exhibit progressive loss of dopamine signaling and develop a Parkinson-like motor phenotype, and assess standard and novel PD treatment effects on PPI in MitoPark mice, which more closely mimic the basal ganglia dopamine status of PD patients. MitoPark mice displayed enhanced PPI as dopamine tone decreased with age, consistent with studies in intact mice that show enhanced PPI in response to dopamine antagonists. Paradoxically, older MitoParks were more sensitive to PPI disruption when challenged with dopamine agonists such as apomorphine or pramipexole. Alternatively, SCH 412348, an adenosine A(2A) antagonist, did not disrupt PPI in MitoPark mice at doses that normalized hypoactivity. Use of MitoPark mice in the PPI assay to assess the potential for PD treatment to produce psychoses likely represents a more disease-relevant model. SCH 412348 does not differentially disrupt PPI as do dopamine agonists, perhaps indicative of an improved psychosis profile of adenosine A(2A) antagonists, even in PD patients with decreased dopamine tone in the basal ganglia.

Dopamine modulation of transient receptor potential vanilloid type 1 (TRPV1) receptor in dorsal root ganglia neurons.

PubMed

Chakraborty, Saikat; Rebecchi, Mario; Kaczocha, Martin; Puopolo, Michelino

2016-03-15

The transient receptor potential vanilloid type 1 (TRPV1) receptor plays a key role in the modulation of nociceptor excitability. To address whether dopamine can modulate the activity of TRPV1 channels in nociceptive neurons, the effects of dopamine and dopamine receptor agonists were tested on the capsaicin-activated current recorded from acutely dissociated small diameter (<27 μm) dorsal root ganglia (DRG) neurons. Dopamine or SKF 81297 (an agonist at D1/D5 receptors), caused inhibition of both inward and outward currents by ∼60% and ∼48%, respectively. The effect of SKF 81297 was reversed by SCH 23390 (an antagonist at D1/D5 receptors), confirming that it was mediated by activation of D1/D5 dopamine receptors. In contrast, quinpirole (an agonist at D2 receptors) had no significant effect on the capsaicin-activated current. Inhibition of the capsaicin-activated current by SKF 81297 was mediated by G protein coupled receptors (GPCRs), and highly dependent on external calcium. The inhibitory effect of SKF 81297 on the capsaicin-activated current was not affected when the protein kinase A (PKA) activity was blocked with H89, or when the protein kinase C (PKC) activity was blocked with bisindolylmaleimide II (BIM). In contrast, when the calcium-calmodulin-dependent protein kinase II (CaMKII) was blocked with KN-93, the inhibitory effect of SKF 81297 on the capsaicin-activated current was greatly reduced, suggesting that activation of D1/D5 dopamine receptors may be preferentially linked to CaMKII activity. We suggest that modulation of TRPV1 channels by dopamine in nociceptive neurons may represent a way for dopamine to modulate incoming noxious stimuli. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

PubMed Central

Frank, Guido K. W.

2014-01-01

Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

Diagnosis, assessment and management of delusional jealousy in Parkinson's disease with and without dementia.

PubMed

Perugi, Giulio; Poletti, Michele; Logi, Chiara; Berti, Caterina; Romano, Anna; Del Dotto, Paolo; Lucetti, Claudio; Ceravolo, Roberto; Dell'Osso, Liliana; Bonuccelli, Ubaldo

2013-09-01

Patients with Parkinson's disease (PD) may present delusional jealousy (DJ). In a previous cross-sectional prevalence study we identified 15 cognitively preserved and five demented PD patients with DJ. The current study aimed at evaluating their clinical (motor and non-motor) characteristics and the pharmacological treatments associated with DJ, and its subsequent pharmacological management. Patients were assessed by neurologists and psychiatrists using the Hoehn and Yahr scale, the Unified Parkinson's Disease Rating Scale, the Brief Psychiatric Rating Scale, the Beck Depression Inventory, the Hamilton Anxiety Scale and the Neuropsychiatric Inventory. Efficacy of DJ management was evaluated in follow-up visits. All patients were in therapy with dopamine agonists. A subgroup of five cognitively preserved patients developed DJ after a short period of treatment of therapy with dopamine agonists, while other patients developed DJ after a longer period of dopaminergic treatment. Psychiatric comorbidities were common in cognitively preserved and in demented patients. The pharmacological management included the interruption of dopamine agonists in two patients and the reduction of dopamine agonist dose plus the use of antipsychotics in other patients. These clinical data suggest that the management of medicated PD patients should include investigation for the presence of DJ and the evaluation of clinical characteristics potentially relevant to the prevention or the early recognition of delusions.

Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer

PubMed Central

Bonaventura, Jordi; Navarro, Gemma; Casadó-Anguera, Verònica; Azdad, Karima; Rea, William; Moreno, Estefanía; Brugarolas, Marc; Mallol, Josefa; Canela, Enric I.; Lluís, Carme; Cortés, Antoni; Volkow, Nora D.; Schiffmann, Serge N.; Ferré, Sergi; Casadó, Vicent

2015-01-01

Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain. PMID:26100888

Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer.

PubMed

Bonaventura, Jordi; Navarro, Gemma; Casadó-Anguera, Verònica; Azdad, Karima; Rea, William; Moreno, Estefanía; Brugarolas, Marc; Mallol, Josefa; Canela, Enric I; Lluís, Carme; Cortés, Antoni; Volkow, Nora D; Schiffmann, Serge N; Ferré, Sergi; Casadó, Vicent

2015-07-07

Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain.

Guanine nucleotide regulatory protein co-purifies with the D/sub 2/-dopamine receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Senogles, S.E.; Caron, M.G.

1986-05-01

The D/sub 2/-dopamine receptor from bovine anterior pituitary was purified approx.1000 fold by affinity chromatography on CMOS-Sepharose. Reconstitution of the affinity-purified receptor into phospholipid vesicles revealed the presence of high and low affinity agonist sites as detected by N-n-propylnorapomorphine (NPA) competition experiments with /sup 3/H-spiperone. High affinity agonist binding could be converted to the low affinity form by guanine nucleotides, indicating the presence of an endogenous guanine nucleotide binding protein (N protein) in the affinity-purified D/sub 2/ receptor preparations. Furthermore, this preparation contained an agonist-sensitive GTPase activity which was stimulated 2-3 fold over basal by 10 ..mu..M NPA. /sup 35/S-GTP..gamma..Smore » binding to these preparations revealed a stoichiometry of 0.4-0.7 mole N protein/mole receptor, suggesting the N protein may be specifically coupled with the purified D/sub 2/-dopamine receptor and not present as a contaminant. Pertussis toxin treatment of the affinity purified receptor preparations prevented high affinity agonist binding, as well as agonist stimulation of the GTPase activity, presumably by inactivating the associated N protein. Pertussis toxin lead to the ADP-ribosylation of a protein of 39-40K on SDS-PAGE. These findings indicate that an endogenous N protein, N/sub i/ or N/sub o/, co-purifies with the D/sub 2/-dopamine receptor which may reflect a precoupling of this receptor with an N protein within the membranes.« less

Repeated stimulation of D1 dopamine receptors enhances (-)-11-hydroxy-delta 8-tetrahydrocannabinol-dimethyl-heptyl-induced catalepsy in male rats.

PubMed

Rodríguez de Fonseca, F; Martín Calderón, J L; Mechoulam, R; Navarro, M

1994-03-21

Dopaminergic and cannabinoid receptors are localized in the outflow nuclei of the basal ganglia. We have investigated the possible interrelation of these receptors in the regulation of motor activity in male rats. To this end we have first studied the behavioural effects of the highly potent cannabinoid receptor agonist (-)11-hydroxy-delta 8-tetrahydrocannabinol-dimethylheptyl (HU-210, 20 micrograms mg) after chronic stimulation of dopamine D1 and D2 receptors. The catalepsy induced by the synthetic cannabinoid, measured as the descent latency in the bar test, was enhanced in male rats chronically treated with the dopamine D1 receptor agonist SKF38393 (8 mg kg-1, twice a day during 21 days). However, animals exposed to the dopamine D2 agonist quinpirole (1 mg kg-1 daily during 21 days) displayed the same degree of catalepsy as those exposed to HU-210 alone. Although a possible involvement of D2 receptors cannot be excluded, this finding suggests a predominant role for dopamine D1 receptors in the regulation of the cataleptic response to cannabinoids. The possible cross-talk between dopamine D1 and cannabinoid receptors is further supported by the decreased responsiveness to the acute behavioural effects of SKF38393 (8 mg kg-1) observed in animals chronically exposed to HU-210 (20 micrograms kg-1 daily during 14 days).

Stimulants as Specific Inducers of Dopamine-Independent σ Agonist Self-Administration in Rats

PubMed Central

Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi; Kopajtic, Theresa A.

2013-01-01

A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of σ agonists mediated by their selective actions at σ1 receptors (σ1Rs), which are intracellularly mobile chaperone proteins implicated in abuse-related effects of stimulants. The present study assessed whether the induction was specific to self-administration of cocaine. Rats were trained to self-administer the dopamine releaser, d-methamphetamine (0.01–0.32 mg/kg per injection), the μ-opioid receptor agonist, heroin (0.001–0.032 mg/kg per injection), and the noncompetitive N-methyl-d-aspartate receptor/channel antagonist ketamine (0.032–1.0 mg/kg per injection). As with cocaine, self-administration of d-methamphetamine induced reinforcing effects of the selective σ1R agonists PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate hydrochloride] and (+)-pentazocine (0.032–1.0 mg/kg per injection, each). In contrast, neither self-administration of heroin nor ketamine induced PRE-084 or (+)-pentazocine (0.032–10 mg/kg per injection, each) self-administration. Although the σ1R agonists did not maintain responding in subjects with histories of heroin or ketamine self-administration, substitution for those drugs was obtained with appropriate agonists (e.g., remifentanil, 0.1–3.2 µg/kg per injection, for heroin and (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+)-MK 801; dizocilpine), 0.32–10.0 µg/kg per injection, for ketamine). The σR antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008; 1.0–10 mg/kg) dose-dependently blocked PRE-084 self-administration but was inactive against d-methamphetamine, heroin, and ketamine. In contrast, PRE-084 self-administration was affected neither by the dopamine receptor antagonist (+)-butaclamol (10–100 μg/kg) nor by the opioid antagonist (−)-naltrexone (1.0–10 mg/kg), whereas these antagonists were active against d-methamphetamine and heroin self-administration, respectively. The results indicate that experience specifically with indirect-acting dopamine agonists induces reinforcing effects of previously inactive σ1R agonists. It is further suggested that induced σ1R reinforcing mechanisms may play an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for its treatment. PMID:23908387

Stimulants as specific inducers of dopamine-independent σ agonist self-administration in rats.

PubMed

Hiranita, Takato; Soto, Paul L; Tanda, Gianluigi; Kopajtic, Theresa A; Katz, Jonathan L

2013-10-01

A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of σ agonists mediated by their selective actions at σ1 receptors (σ1Rs), which are intracellularly mobile chaperone proteins implicated in abuse-related effects of stimulants. The present study assessed whether the induction was specific to self-administration of cocaine. Rats were trained to self-administer the dopamine releaser, d-methamphetamine (0.01-0.32 mg/kg per injection), the μ-opioid receptor agonist, heroin (0.001-0.032 mg/kg per injection), and the noncompetitive N-methyl-d-aspartate receptor/channel antagonist ketamine (0.032-1.0 mg/kg per injection). As with cocaine, self-administration of d-methamphetamine induced reinforcing effects of the selective σ1R agonists PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate hydrochloride] and (+)-pentazocine (0.032-1.0 mg/kg per injection, each). In contrast, neither self-administration of heroin nor ketamine induced PRE-084 or (+)-pentazocine (0.032-10 mg/kg per injection, each) self-administration. Although the σ1R agonists did not maintain responding in subjects with histories of heroin or ketamine self-administration, substitution for those drugs was obtained with appropriate agonists (e.g., remifentanil, 0.1-3.2 µg/kg per injection, for heroin and (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+)-MK 801; dizocilpine), 0.32-10.0 µg/kg per injection, for ketamine). The σR antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008; 1.0-10 mg/kg) dose-dependently blocked PRE-084 self-administration but was inactive against d-methamphetamine, heroin, and ketamine. In contrast, PRE-084 self-administration was affected neither by the dopamine receptor antagonist (+)-butaclamol (10-100 μg/kg) nor by the opioid antagonist (-)-naltrexone (1.0-10 mg/kg), whereas these antagonists were active against d-methamphetamine and heroin self-administration, respectively. The results indicate that experience specifically with indirect-acting dopamine agonists induces reinforcing effects of previously inactive σ1R agonists. It is further suggested that induced σ1R reinforcing mechanisms may play an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for its treatment.

Neuropsychiatric and metabolic aspects of dopaminergic therapy: perspectives from an endocrinologist and a psychiatrist

PubMed Central

Athanasoulia-Kaspar, Anastasia P; Popp, Kathrin H; Stalla, Gunter Karl

2018-01-01

The dopaminergic treatment represents the primary treatment in prolactinomas, which are the most common pituitary adenomas and account for about 40% of all pituitary tumours with an annual incidence of six to ten cases per million population. The dopaminergic treatment includes ergot and non-ergot derivatives with high affinity for the dopamine receptors D1 or/and D2. Through the activation of the dopaminergic pathway on pituitary lactotrophs, the dopamine agonists inhibit the prolactin synthesis and secretion, therefore normalizing the prolactin levels and restoring eugonadism, but they also lead to tumour shrinkage. Treatment with dopamine agonists has been associated – apart from the common side effects such as gastrointestinal symptoms, dizziness and hypotension – with neuropsychiatric side effects such as impulse control disorders (e.g. pathological gambling, compulsive shopping, hypersexuality and binge eating) and also with behavioral changes from low mood, irritability and verbal aggressiveness up to psychotic and manic symptoms and paranoid delusions not only in patients with prolactinomas but also in patients with Parkinson’s disease and restless leg syndrome. They usually have de novo onset after initiation of the dopaminergic treatment and have been mainly reported in patients with Parkinson’s disease, who are being treated with higher doses of dopamine agonists. Moreover, dopamine and prolactin seem to play an essential role in the metabolic pathway. Patients with hyperprolactinemia tend to have increased body weight and an altered metabolic profile with hyperinsulinemia and increased prevalence of diabetes mellitus in comparison to healthy individuals and patients with non-functioning pituitary adenomas. Treatment with dopamine agonists in these patients in short-term studies seems to lead to weight loss and amelioration of the metabolic changes. Together these observations provide evidence that dopamine and prolactin have a crucial role both in the regard and metabolic system, findings that merit further investigation in long-term studies. PMID:29378769

Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson s disease patients with motor complications.

PubMed

Stowe, Rebecca; Ives, Natalie; Clarke, Carl E; Deane, Katherine; Wheatley, Keith; Gray, Richard; Handley, Kelly; Furmston, Alex

2010-07-07

One of the complications of long-term treatment of Parkinson's disease (PD) with levodopa is the development of motor complications. Generally, when motor complications develop, clinicians add in an additional drug (to the levodopa regimen) from one of three other classes of anti-Parkinsonian treatments (dopamine agonists, catechol-O-methyl transferase inhibitors (COMTIs) or monoamine oxidase type B inhibitors (MAOBIs)). However, despite trials having shown that these drugs are beneficial compared to placebo, it remains unclear as to the best way to treat patients experiencing motor complications and whether one class of drug is more effective than another. This meta-analysis aims to assess more reliably the benefits and risks of the three classes of drugs (dopamine agonists, COMTIs and MAOBIs) currently used as adjuvant treatment to levodopa in PD patients suffering from motor complications. The three drug classes were compared with the aim of determining whether one class of drug provides better symptomatic control than another. We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications. Randomised trials comparing an orally administered dopamine agonist, COMTI or MAOBI versus placebo, both on a background of levodopa therapy, in PD patients experiencing motor complications. Two authors independently extracted data on off-time, levodopa dose, motor complications, side-effects, treatment concordance, clinician-rated disability, mortality, quality of life and health economic data. Forty-four eligible trials, involving 8436 participants were identified. Compared to placebo, adjuvant therapy significantly reduced off-time (-1.05 hours/day, 95% confidence interval (CI) -1.19 to -0.90; P<0.00001), the required levodopa dose (-55.65 mg/day, CI -62.67 to -48.62; P<0.00001) and improved UPDRS scores (UPDRS ADL score: -1.31 points, CI -1.62 to -0.99; P<0.00001; UPDRS motor score: -2.84 points, CI -3.36 to -2.32; P<0.00001; UPDRS total score: -3.26 points, CI -4.52 to -2.00; P<0.00001). However, dyskinesia (odds ratio (OR) 2.50, CI 2.21 to 2.84; P<0.00001) and side-effects including constipation (OR 3.19, CI 2.17 to 4.68; P<0.00001), dizziness (OR 1.57, CI 1.30 to 1.90; P<0.00001), dry mouth (OR 2.33, CI 1.22 to 4.47; P=0.01), hallucinations (OR 2.16, CI 1.70 to 2.74; P<0.00001), hypotension (OR 1.47, CI 1.18 to 1.83; P=0.0007), insomnia (OR 1.38, CI 1.09 to 1.74; P=0.007), nausea (OR 1.78, CI 1.53 to 2.07; P<0.00001), somnolence (OR 1.87, CI 1.40 to 2.51; P<0.0001) and vomiting (OR 2.56, CI 1.67 to 3.93; P<0.0001) were all increased with adjuvant therapy.Indirect comparisons of the three drug classes suggested that dopamine agonists were more efficacious in reducing off-time (dopamine agonist: -1.54 hours/day; COMTI: -0.83 hours/day; MAOBI: -0.93 hours/day; test for heterogeneity between drug classes P=0.0003) and levodopa dose (dopamine agonist: -116 mg/day; COMTI: -52 mg/day; MAOBI: -29 mg/day; test for heterogeneity between drug classes P<0.00001). UPDRS scores also improved more with dopamine agonists than with COMTI or MAOBI (UPDRS total scores - dopamine agonist: -10.01 points versus COMTI: -1.46 points versus MAOBI: -2.20 points; test for heterogeneity between drug classes P<0.00001), although more dyskinesia were seen with dopamine agonists (OR 2.70) and COMTI (OR 2.50) than with MAOBI (OR 0.94) (test for heterogeneity between drug classes P=0.009). Although the increase in the overall incidence of side-effects was generally more marked with dopamine agonists (OR 1.52) and COMTI (OR 2.0) than with MAOBI (OR 1.32), heterogeneity between drug classes was only of borderline significance (P=0.07). Compared to placebo, adjuvant therapy reduces off-time, levodopa dose, and improves UPDRS scores in PD patients who develop motor complications on levodopa therapy. However, this is at the expense of increased dyskinesia and numerous other side-effects. Indirect comparisons suggest that dopamine agonist therapy may be more effective than COMTI and MAOBI therapy, which have comparable efficacy. However, as indirect comparisons should be interpreted with caution, direct head-to-head randomised trials assessing the impact of these different drug classes on overall patient-rated quality of life are needed.

TAAR1 in Addiction: Looking Beyond the Tip of the Iceberg

PubMed Central

Liu, Jian-Feng; Li, Jun-Xu

2018-01-01

Trace-amine associated receptor 1 (TAAR1) is the best-characterized member of the family of TAARs. TAAR1 is broadly expressed in the brain, especially within the monoaminergic systems. Evidence from electrophysiological and neurochemical studies evaluating the effects of genetic and pharmacological interventions on TAAR1 revealed that TAAR1 modulates transmission of monoamines, especially dopamine. TAAR1 agonists dampened drugs of abuse-induced dopamine accumulation. In general, TAAR1 agonists specifically inhibited the rewarding and reinforcing effects of drugs of abuse and drug-abuse related behaviors. Details of the mechanism of TAAR1 remain elusive; however, it is thought to be regulated by its interactions with D2 receptors. In addition, the alternative cellular mechanism such as an interaction between TAAR1 and D3 may also participate in the action of TAAR1 agonists. Further studies are required to investigate the role of TAAR1 in other drugs of abuse-related behaviors and the underlying neural mechanisms. Collectively, TAAR1 negatively modulates dopaminergic systems and dopamine-related behaviors and TAAR1 agonists are promising pharmacotherapy to treat drug addiction and relapse. PMID:29636691

Stimulation of accumbal GABAA receptors inhibits delta2-, but not delta1-, opioid receptor-mediated dopamine efflux in the nucleus accumbens of freely moving rats.

PubMed

Aono, Yuri; Kiguchi, Yuri; Watanabe, Yuriko; Waddington, John L; Saigusa, Tadashi

2017-11-15

The nucleus accumbens contains delta-opioid receptors that may reduce inhibitory neurotransmission. Reduction in GABA A receptor-mediated inhibition of accumbal dopamine release due to delta-opioid receptor activation should be suppressed by stimulating accumbal GABA A receptors. As delta-opioid receptors are divided into delta2- and delta1-opioid receptors, we analysed the effects of the GABA A receptor agonist muscimol on delta2- and delta1-opioid receptor-mediated accumbal dopamine efflux in freely moving rats using in vivo microdialysis. Drugs were administered intracerebrally through the dialysis probe. Doses of compounds indicate total amount administered (mol) during 25-50min infusions. The delta2-opioid receptor agonist deltorphin II (25.0nmol)- and delta1-opioid receptor agonist DPDPE (5.0nmol)-induced increases in dopamine efflux were inhibited by the delta2-opioid receptor antagonist naltriben (1.5nmol) and the delta1-opioid receptor antagonist BNTX (150.0pmol), respectively. Muscimol (250.0pmol) inhibited deltorphin II (25.0nmol)-induced dopamine efflux. The GABA A receptor antagonist bicuculline (50.0pmol), which failed to affect deltorphin II (25.0nmol)-induced dopamine efflux, counteracted the inhibitory effect of muscimol on deltorphin II-induced dopamine efflux. Neither muscimol (250.0pmol) nor bicuculline (50.0 and 500.0pmol) altered DPDPE (5.0nmol)-induced dopamine efflux. The present results show that reduction in accumbal GABA A receptor-mediated inhibition of dopaminergic activity is necessary to produce delta2-opioid receptor-induced increase in accumbal dopamine efflux. This study indicates that activation of delta2- but not delta1-opioid receptors on the cell bodies and/or terminals of accumbal GABAergic interneurons inhibits GABA release and, accordingly, decreases GABA A receptor-mediated inhibition of dopaminergic terminals, resulting in enhanced accumbal dopamine efflux. Copyright © 2017 Elsevier B.V. All rights reserved.

Modern treatment in Parkinson's disease, a personal approach.

PubMed

Reichmann, Heinz

2016-01-01

There are many guidelines available concerning the treatment of Parkinson's disease. Most of these advocate treating young-onset patients with a dopamine agonist and older patients with levodopa. The rationale behind this recommendation has its origins in the side effects associated with each of these drug classes: whilst levodopa leads to dyskinesia, which may not be relevant for patients with a limited life-expectancy, dopamine agonists have a much longer plasma half life which probably leads to more continuous dopamine receptor stimulation and thus decreases the occurrence and severity of dyskinesia. However, the side effects associated with the use of dopamine agonists, such as sleepiness, orthostatic problems, hallucinations and impulse control disorders are a drawback. In this overview, the hypothesis will be put forward that perhaps such a strict distinction is no longer needed. A new idea may be the early combination of levodopa with a dopamine agonist which would provide good clinical efficacy and, because of the relatively low doses involved, would reduce the side effects associated with both substances. MAO-B inhibitors may be a good option for early treatment and especially for patients who experience first motor fluctuations. Similarly, and particularly if a wearing-off symptom is present, COMT inhibitors smoothen and prolong the action of levodopa. More invasive escalation therapy comes into play when patients reach the advanced stages with problems of insufficient motor control, such as bradykinesia, rigidity and resting tremor, combined with on-time dyskinesia. The use of all oral and invasive treatment has to be individualized to gain a good motor and non-motor control and especially a good quality of life.

Management of prolactinomas.

PubMed

Molitch, M E

1989-01-01

Prolactinomas are the most common of the hormone-secreting pituitary tumors and must be distinguished from nonsecreting tumors causing hyperprolactinemia by hypothalamic or stalk dysfunction. For both micro- and macroadenomas, dopamine agonists appear to be the treatment of choice, transsphenoidal surgery being reserved for nonresponders. For women desiring pregnancy, dopamine agonists are safe when there is a microadenoma or an intrasellar macroadenoma. However, in women with large macroadenomas desiring pregnancy, limited transsphenoidal decompression followed by bromocriptine appears to be the safest mode of treatment.

Hyperactivity and impaired response habituation in hyperdopaminergic mice

PubMed Central

Zhuang, Xiaoxi; Oosting, Ronald S.; Jones, Sara R.; Gainetdinov, Raul R.; Miller, Gary W.; Caron, Marc G.; Hen, René

2001-01-01

Abnormal dopaminergic transmission is implicated in schizophrenia, attention deficit hyperactivity disorder, and drug addiction. In an attempt to model aspects of these disorders, we have generated hyperdopaminergic mutant mice by reducing expression of the dopamine transporter (DAT) to 10% of wild-type levels (DAT knockdown). Fast-scan cyclic voltammetry and in vivo microdialysis revealed that released dopamine was cleared at a slow rate in knockdown mice, which resulted in a higher extracellular dopamine concentration. Unlike the DAT knockout mice, the DAT knockdown mice do not display a growth retardation phenotype. They have normal home cage activity but display hyperactivity and impaired response habituation in novel environments. In addition, we show that both the indirect dopamine receptor agonist amphetamine and the direct agonists apomorphine and quinpirole inhibit locomotor activity in the DAT knockdown mice, leading to the hypothesis that a shift in the balance between dopamine auto and heteroreceptor function may contribute to the therapeutic effect of psychostimulants in attention deficit hyperactivity disorder. PMID:11172062

Dopamine alters glutamate receptor desensitization in retinal horizontal cells of the perch (Perca fluviatilis).

PubMed Central

Schmidt, K F; Kruse, M; Hatt, H

1994-01-01

The patch-clamp technique in combination with a fast liquid filament application system was used to study the effect of dopamine on the glutamate receptor desensitization in horizontal cells of the perch (Perca fluviatilis). Kinetics of ligand-gated ion channels in fish horizontal cells are modulated by dopamine. This modulation is presumably mediated by a cAMP-dependent protein phosphorylation. Before incubation with dopamine, the glutamate receptors of horizontal cells activate and desensitize with fast time constants. In the whole-cell recording mode, fast application of the agonists L-glutamate, quisqualate, or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid prior to the dopamine incubation gives rise to fast transient currents with peak values of about 200 pA that desensitize within 100 ms. Kainate as agonist produced higher steady-state currents but no transient currents. After incubation of the cells with dopamine for 3 min, the desensitization was significantly reduced and the agonists L-glutamate, quisqualate, or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid induced steady-state currents with amplitudes that were similar to the previously observed transient currents. Kainate-induced currents were only slightly affected. Fast desensitizing currents upon fast application of L-glutamate were also recorded from outside-out patches that were excised from horizontal cells before incubation with dopamine. The currents from excised patches desensitized to a steady-state level of about 0.2 of the peak amplitude with time constants of less than 2 ms. When the outside-out patches were excised from cells after dopamine incubation, steady-state currents were enhanced and no transient currents were observed. The results may indicate that the dopamine-dependent modulation of glutamate-induced currents, which is presumably mediated by a protein phosphorylation, is due to an alteration of the desensitization of the glutamate receptors. PMID:7520178

Transmembrane Segment Five Serines of the D4 Dopamine Receptor Uniquely Influence the Interactions of Dopamine, Norepinephrine, and Ro10-4548

PubMed Central

Cummings, David F.; Ericksen, Spencer S.; Goetz, Angela

2010-01-01

Conserved serines of transmembrane segment (TM) five (TM5) are critical for the interactions of endogenous catecholamines with α1- and α2-adrenergic, β2-adrenergic, and D1, D2, and D3 dopamine receptors. The unique high-affinity interaction of the D4 dopamine receptor subtype with both norepinephrine and dopamine, and the fact that TM5 serine interactions have never been studied for this receptor subtype, led us to investigate the interactions of ligands with D4 receptor TM5 serines. Serine-to-alanine mutations at positions 5.42 and 5.46 drastically decreased affinities of dopamine and norepinephrine for the D4 receptor. The D4-S5.43A receptor mutant had substantially reduced affinity for norepinephrine, but a modest loss of affinity for dopamine. In functional assays of cAMP accumulation, norephinephrine was unable to activate any of the mutant receptors, even though the agonist quinpirole displayed wild-type functional properties for all of them. Dopamine was unable to activate the S5.46A mutant and had reduced potency for the S5.43A mutant and reduced potency and efficacy for the S5.42A mutant. In contrast, Ro10-4548 [RAC-2′-2-hydroxy-3-4-(4-hydroxy-2-methoxyphenyl)-1-piperazinyl-propoxy-acetanilide], a catechol-like antagonist of the wild-type receptor unexpectedly functions as an agonist of the S5.43A mutant. Other noncatechol ligands had similar properties for mutant and wild-type receptors. This is the first example of a dopamine receptor point mutation selectively changing the receptor's interaction with a specific antagonist to that of an agonist, and together with other data, provides evidence, supported by molecular modeling, that catecholamine-type agonism is induced by different ligand-specific configurations of intermolecular H-bonds with the TM5 conserved serines. PMID:20215412

[Are there innovations in the treatment of Parkinson's disease?].

PubMed

Ludin, H P

2004-11-03

In the group of medication acting on the dopaminergic system the transdermal application of a dopamine agonist (Rotigotine) and a new MAO B inhibitor (Rasigiline) are receiving most attention. With some concern we had to learn that pergolide, a potent dopamine agonist, may be the cause of clinically relevant valvulopathies. Our possibilities to act on non-dopaminergic deficits is still very limited. The studies demonstrating a positive effect of cholinesterase inhibitors on cognitive decline are at least a positive signal.

Mesolimbic and Nigrostriatal Dopaminergic Systems: Behavioral Neuropharmacology.

DTIC Science & Technology

1985-08-01

presented in Table Table III List of drugs D ru gVeh i c l e Intracerebral infusions Dopamine agonist~s Apomorphine hydrochloride 0.1% Na metabisulfite...saline GABA 0.9% saline Picrotoxin 0 .9%saline Systemic injections Dopamine agents d-Amphetamine sulfate 0.9% saline Aponiorphine hydrochloride 0.9...3H)methionine (15 Ci/mmole, lmCi/ml. 16 Amersham), 122 ul of freshly prepared pargyline hydrochloride (10.2 mM), 326 ul of I M Tris pH 10.8, 246 ul

The role of dopamine in risk taking: a specific look at Parkinson’s disease and gambling

PubMed Central

Clark, Crystal A.; Dagher, Alain

2014-01-01

An influential model suggests that dopamine signals the difference between predicted and experienced reward. In this way, dopamine can act as a learning signal that can shape behaviors to maximize rewards and avoid punishments. Dopamine is also thought to invigorate reward seeking behavior. Loss of dopamine signaling is the major abnormality in Parkinson’s disease. Dopamine agonists have been implicated in the occurrence of impulse control disorders in Parkinson’s disease patients, the most common being pathological gambling, compulsive sexual behavior, and compulsive buying. Recently, a number of functional imaging studies investigating impulse control disorders in Parkinson’s disease have been published. Here we review this literature, and attempt to place it within a decision-making framework in which potential gains and losses are evaluated to arrive at optimum choices. We also provide a hypothetical but still incomplete model on the effect of dopamine agonist treatment on these value and risk assessments. Two of the main brain structures thought to be involved in computing aspects of reward and loss are the ventral striatum (VStr) and the insula, both dopamine projection sites. Both structures are consistently implicated in functional brain imaging studies of pathological gambling in Parkinson’s disease. PMID:24910600

Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial.

PubMed

Gray, Richard; Ives, Natalie; Rick, Caroline; Patel, Smitaa; Gray, Alastair; Jenkinson, Crispin; McIntosh, Emma; Wheatley, Keith; Williams, Adrian; Clarke, Carl E

2014-09-27

Whether initial treatment for Parkinson's disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson's disease. In this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson's disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale (range 0-100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, number ISRCTN69812316. Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1·8 points (95% CI 0·5-3·0, p=0·005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years' observation. PDQ-39 mobility scores were 1·4 points (95% CI 0·0-2·9, p=0·05) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0·03 (95% CI 0·01-0·05; p=0·0002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio [HR] 0·81, 95% CI 0·61-1·08, p=0·14), admissions to institutions (0·86, 0·63-1·18; p=0·4), and death (0·85, 0·69-1·06, p=0·17) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p<0·0001). Very small but persistent benefits are shown for patient-rated mobility scores when treatment is initiated with levodopa compared with levodopa-sparing therapy. MAOBI as initial levodopa-sparing therapy was at least as effective as dopamine agonists. UK National Institute for Health Research Health Technology Assessment Programme and UK Department of Health. Copyright © 2014 Elsevier Ltd. All rights reserved.

Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism.

PubMed

Kivell, Bronwyn; Uzelac, Zeljko; Sundaramurthy, Santhanalakshmi; Rajamanickam, Jeyaganesh; Ewald, Amy; Chefer, Vladimir; Jaligam, Vanaja; Bolan, Elizabeth; Simonson, Bridget; Annamalai, Balasubramaniam; Mannangatti, Padmanabhan; Prisinzano, Thomas E; Gomes, Ivone; Devi, Lakshmi A; Jayanthi, Lankupalle D; Sitte, Harald H; Ramamoorthy, Sammanda; Shippenberg, Toni S

2014-11-01

Salvinorin A (SalA), a selective κ-opioid receptor (KOR) agonist, produces dysphoria and pro-depressant like effects. These actions have been attributed to inhibition of striatal dopamine release. The dopamine transporter (DAT) regulates dopamine transmission via uptake of released neurotransmitter. KORs are apposed to DAT in dopamine nerve terminals suggesting an additional target by which SalA modulates dopamine transmission. SalA produced a concentration-dependent, nor-binaltorphimine (BNI)- and pertussis toxin-sensitive increase of ASP(+) accumulation in EM4 cells coexpressing myc-KOR and YFP-DAT, using live cell imaging and the fluorescent monoamine transporter substrate, trans 4-(4-(dimethylamino)-styryl)-N-methylpyridinium) (ASP(+)). Other KOR agonists also increased DAT activity that was abolished by BNI pretreatment. While SalA increased DAT activity, SalA treatment decreased serotonin transporter (SERT) activity and had no effect on norepinephrine transporter (NET) activity. In striatum, SalA increased the Vmax for DAT mediated DA transport and DAT surface expression. SalA up-regulation of DAT function is mediated by KOR activation and the KOR-linked extracellular signal regulated kinase-½ (ERK1/2) pathway. Co-immunoprecipitation and BRET studies revealed that DAT and KOR exist in a complex. In live cells, DAT and KOR exhibited robust FRET signals under basal conditions. SalA exposure caused a rapid and significant increase of the FRET signal. This suggests that the formation of KOR and DAT complexes is promoted in response to KOR activation. Together, these data suggest that enhanced DA transport and decreased DA release resulting in decreased dopamine signalling may contribute to the dysphoric and pro-depressant like effects of SalA and other KOR agonists. Copyright © 2014 Elsevier Ltd. All rights reserved.

Treatment of early Parkinson's disease.

PubMed

Pahwa, Rajesh; Lyons, Kelly E

2014-08-01

This review summarizes currently available treatment options and treatment strategies, investigational treatments, and the importance of exercise for early Parkinson's disease. The available treatment options for early Parkinson's disease have changed little in the past decade and include carbidopa/levodopa, dopamine agonists, and monoamine oxidase type B (MAO-B) inhibitors. However, we discuss changes in treatment strategies, including dosing and the use of combination therapy used in an attempt to reduce or delay the appearance of motor complications and other adverse events. We will also review several investigational treatments that have shown promise for the treatment of early Parkinson's disease, including a new extended release formulation of carbidopa/levodopa (IPX066), safinamide which inhibits MAO-B, dopamine uptake and glutamate and pardoprunox which is a 5HT-1A agonist and a partial dopamine agonist. Finally, we discuss recent studies focusing on exercise as an important component in the management of early Parkinson's disease. Advances in the management of early Parkinson's disease include evolving treatment strategies, new investigational treatments, and earlier implementation of various forms of exercise.

Dopamine agonists and delusional jealousy in Parkinson's disease: a cross-sectional prevalence study.

PubMed

Poletti, Michele; Perugi, Giulio; Logi, Chiara; Romano, Anna; Del Dotto, Paolo; Ceravolo, Roberto; Rossi, Giuseppe; Pepe, Pasquale; Dell'Osso, Liliana; Bonuccelli, Ubaldo

2012-11-01

Delusional jealousy (DJ) has been described in patients with Parkinson's disease (PD) on dopaminergic therapy, but a role for dopaminergic therapy in DJ has not been established. The current cross-sectional study on DJ investigated its association with dopaminergic therapies compared with their associations with hallucinations and its prevalence in PD patients. Eight hundred five consecutive patients with PD were enrolled between January 2009 and June 2010. DJ was identified in 20 patients (2.48%) and hallucinations in 193 patients (23.98%). In the multivariate logistic regression analyses, dopamine agonists were significantly associated with DJ (odds ratio, 18.1; 95% CI, 3.0-infinity; P = .0002) but not with hallucinations (odds ratio, 0.73; 95% CI, 0.49-1.10; P = .133). These findings suggest that dopamine agonist treatment represents a risk factor for DJ in PD independent of the presence of a dementing disorder, and the presence of this additional nonmotor side effect should be investigated in this clinical population. Copyright © 2012 Movement Disorder Society.

The effects of dopamine receptor 1 and 2 agonists and antagonists on sexual and aggressive behaviors in male green anoles.

PubMed

Smith, Alexandra N; Kabelik, David

2017-01-01

The propensity to exhibit social behaviors during interactions with same-sex and opposite-sex conspecifics is modulated by various neurotransmitters, including dopamine. Dopamine is a conserved neurotransmitter among vertebrates and dopaminergic receptors are also highly conserved among taxa. Activation of D1 and D2 dopamine receptor subtypes has been shown to modulate social behaviors, especially in mammalian and avian studies. However, the specific behavioral functions of these receptors vary across taxa. In reptiles there have been few studies examining the relationship between dopaminergic receptors and social behaviors. We therefore examined the effects of D1 and D2 agonists and antagonists on sexual and aggressive behaviors in the male green anole lizard (Anolis carolinensis). Treatment with high doses of both D1 and D2 agonists was found to impair both sexual and aggressive behaviors. However, the D1 agonist treatment was also found to impair motor function, suggesting that those effects were likely nonspecific. Lower doses of both agonists and antagonists failed to affect social behaviors. These findings provide some evidence for D2 receptor regulation of social behaviors, but in contrast with previous research, these effects are all inhibitory and no effects were found for manipulations of D1 receptors. A potential reason for the lack of more widespread effects on social behaviors using moderate or low drug doses is that systemic injection of drugs resulted in effects throughout the whole brain, thus affecting counteracting circuits which negated one another, making measurable changes in behavioral output difficult to detect. Future studies should administer drugs directly into brain regions known to regulate sexual and aggressive behaviors.

Interactions of ligands with active and inactive conformations of the dopamine D2 receptor.

PubMed

Malmberg, A; Mohell, N; Backlund Höök, B; Johansson, A M; Hacksell, U; Nordvall, G

1998-04-10

The affinities of 19 pharmacologically diverse dopamine D2 receptor ligands were determined for the active and inactive conformations of cloned human dopamine D2 receptors expressed in Ltk cells. The agonist [3H]quinpirole was used to selectively label the guanine nucleotide-binding protein-coupled, active receptor conformation. The antagonist [3H]raclopride, in the presence of the non-hydrolysable GTP-analogue Gpp(NH)p and sodium ions and in the absence of magnesium ions, was used to label the free inactive receptor conformation. The intrinsic activities of the ligands were determined in a forskolin-stimulated cyclic AMP assay using the same cells. An excellent correlation was shown between the affinity ratios (KR/KRG) of the ligands for the two receptor conformations and their intrinsic activity (r=0.96). The ligands included eight structurally related and enantiopure 2-aminotetralin derivatives; the enantiomers of 5-hydroxy-2-(dipropylamino)tetralin, 5-methoxy-2-(dipropylamino)tetralin, 5-fluoro-2-(dipropylamino)tetralin and 2-(dipropylamino)tetralin. The (S)-enantiomers behaved as full agonists in the cyclic AMP assay and displayed a large KR/KRG ratio. The (R)-enantiomers were classified as partial agonists and had lower ratios. The structure-affinity relationships of these compounds at the active and the inactive receptor conformations were analysed separately, and used in conjunction with a homology based receptor model of the dopamine D2 receptor. This led to proposed binding modes for agonists, antagonists and partial agonists in the 2-aminotetralin series. The concepts used in this study should be of value in the design of ligands with predetermined affinity and intrinsic activity.

Successful Improvement of Metabolic Disorders, Including Osteopenia, by a Dopamine Agonist in a Male Patient with Macro-Prolactinoma.

PubMed

Takeno, Ayumu; Yamamoto, Masahiro; Okazaki, Kyoko; Yamaguchi, Toru; Sugimoto, Toshitsugu

2016-03-13

Bone metabolic disorders in patients with prolactinoma have not been fully characterized. The case presented herein illustrates potential causal associations between prolactinoma and osteopenia, with a reversal of the disorder by treatment with a dopamine agonist. A 43-year-old male with macro-prolactinoma [PRL 7770 ng/mL] was referred to our hospital. He suffered was overweight [body mass index (BMI) 29.4 kg/m2] and had impaired glucose tolerance, hypertriglyceridemia, and osteopenia. The patient was administered cabergoline, a dopamine D2 receptor agonist, and the dose was gradually increased up to 9 mg/week over the period of 1 year. One year later, the patient's serum PRL levels decreased to within the normal range (19.1 ng/mL), and his pituitary tumor mass decreased to 1/4 of its initial size. His weight, dyslipidemia, and impaired glucose tolerance improved within 1 year. A marked increase in the bone mineral density (BMD) at the second to fourth lumbar spine (from 0.801 g/cm2 to 0.870 g/cm2, +8.6%) and at the femoral neck (from 0.785 g/cm2 to 0.864 g/cm2, +10.1%) were observed despite the presence of unresolved hypogonadism. Treatments with dopamine agonists represent a beneficial strategy for patients with prolactinoma accompanied with bone loss, in addition to their established efficacy in shrinkage of the size of pituitary tumors, normalization of PRL levels, and improvement of metabolic disorders.

Effects of dopamine agonist dose and gender on the prognosis of impulse control disorders in Parkinson's disease.

PubMed

Joutsa, Juho; Martikainen, Kirsti; Vahlberg, Tero; Kaasinen, Valtteri

2012-12-01

Cross-sectional studies have demonstrated that Parkinson's disease patients have an increased risk of impulse control disorders, and that the disorders frequently co-exist with depressive symptoms. There have been no previous large-scale prospective studies investigating predictive and prognostic factors of these disorders. A population of 290 Parkinson's disease patients was studied at baseline and approximately 15 months later. The same screening methodology was used at both time-points (demographic and medication data together with the Questionnaire for Impulsive-compulsive Disorders in Parkinson's disease and the Beck Depression Inventory). The data was analyzed separating patients with and without impulse control disorders at baseline to obtain clinically useful prognostic factors. In patients who had impulse control disorders at baseline (n = 119), high dopamine agonist dose was associated with the presence of disorders at follow-up. Dopamine agonist levodopa equivalent daily dose over 160 mg was significantly associated with impulse control disorders with a positive predictive value of 92.5% (95% confidence interval 79.6%-98.4%). In addition, females had a better prognosis of impulse control disorders compared to males. The development of novel impulse control disorders (no disorder at baseline, disorder at follow-up) was associated with a concurrent increase in depression scores. The results suggest that dopamine agonist dose and gender are associated with the prognosis of impulse control disorders. Symptoms of depression emerge together with novel impulse control disorders in Parkinson's disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

A Role for Sigma Receptors in Stimulant Self Administration and Addiction

PubMed Central

Katz, Jonathan L.; Su, Tsung-Ping; Hiranita, Takato; Hayashi, Teruo; Tanda, Gianluigi; Kopajtic, Theresa; Tsai, Shang-Yi

2011-01-01

Sigma1 receptors (σ1Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs. Although the effects of the σR agonist, DTG, on dopamine were obtained at doses that approximated those that maintained self administration behavior those of another agonist, PRE-084 required higher doses. The effects of DTG were antagonized by non-selective or a preferential σ2R antagonist but not by a preferential σ1R antagonist. The effects of PRE-084 on dopamine were insensitive to σR antagonists. The data suggest that the self administration of σR agonists is independent of dopamine and the findings are discussed in light of a hypothesis that cocaine has both intracellular actions mediated by σRs, as well as extracellular actions mediated through conventionally studied mechanisms. The co-activation and potential interactions among these mechanisms, in particular those involving the intracellular chaperone σRs, may lead to the pernicious addictive effects of stimulant drugs. PMID:21904468

A Role for Sigma Receptors in Stimulant Self Administration and Addiction.

PubMed

Katz, Jonathan L; Su, Tsung-Ping; Hiranita, Takato; Hayashi, Teruo; Tanda, Gianluigi; Kopajtic, Theresa; Tsai, Shang-Yi

2011-01-01

Sigma(1) receptors (σ(1)Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ(1)Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs. Although the effects of the σR agonist, DTG, on dopamine were obtained at doses that approximated those that maintained self administration behavior those of another agonist, PRE-084 required higher doses. The effects of DTG were antagonized by non-selective or a preferential σ(2)R antagonist but not by a preferential σ(1)R antagonist. The effects of PRE-084 on dopamine were insensitive to σR antagonists. The data suggest that the self administration of σR agonists is independent of dopamine and the findings are discussed in light of a hypothesis that cocaine has both intracellular actions mediated by σRs, as well as extracellular actions mediated through conventionally studied mechanisms. The co-activation and potential interactions among these mechanisms, in particular those involving the intracellular chaperone σRs, may lead to the pernicious addictive effects of stimulant drugs.

Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor.

PubMed

Gray, David L; Allen, John A; Mente, Scot; O'Connor, Rebecca E; DeMarco, George J; Efremov, Ivan; Tierney, Patrick; Volfson, Dmitri; Davoren, Jennifer; Guilmette, Edward; Salafia, Michelle; Kozak, Rouba; Ehlers, Michael D

2018-02-14

Selective activation of dopamine D1 receptors (D1Rs) has been pursued for 40 years as a therapeutic strategy for neurologic and psychiatric diseases due to the fundamental role of D1Rs in motor function, reward processing, and cognition. All known D1R-selective agonists are catechols, which are rapidly metabolized and desensitize the D1R after prolonged exposure, reducing agonist response. As such, drug-like selective D1R agonists have remained elusive. Here we report a novel series of selective, potent non-catechol D1R agonists with promising in vivo pharmacokinetic properties. These ligands stimulate adenylyl cyclase signaling and are efficacious in a rodent model of Parkinson's disease after oral administration. They exhibit distinct binding to the D1R orthosteric site and a novel functional profile including minimal receptor desensitization, reduced recruitment of β-arrestin, and sustained in vivo efficacy. These results reveal a novel class of D1 agonists with favorable drug-like properties, and define the molecular basis for catechol-specific recruitment of β-arrestin to D1Rs.

Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.

PubMed

Weichert, Dietmar; Stanek, Markus; Hübner, Harald; Gmeiner, Peter

2016-06-15

Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors.

PubMed

Abraham, Antony D; Neve, Kim A; Lattal, K Matthew

2016-07-01

Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.

Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure

PubMed Central

Rose, Jamie H.; Karkhanis, Anushree N.; Steiniger-Brach, Björn; Jones, Sara R.

2016-01-01

The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc) κ opioid receptors (KOR) in chronic intermittent ethanol (CIE) exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood. We investigated the effects of nalmefene on dopamine transmission and KORs using fast scan cyclic voltammetry in NAc brain slices from male C57BL/6J mice following five weeks of CIE or air exposure. Nalmefene concentration-dependently reduced dopamine release similarly in air and CIE groups, suggesting that dynorphin tone may not be present in brain slices. Further, nalmefene attenuated dopamine uptake rates to a greater extent in brain slices from CIE-exposed mice, suggesting that dopamine transporter-KOR interactions may be fundamentally altered following CIE. Additionally, nalmefene reversed the dopamine-decreasing effects of a maximal concentration of a KOR agonist selectively in brain slices of CIE-exposed mice. It is possible that nalmefene may attenuate withdrawal-induced increases in ethanol consumption by modulation of dopamine transmission through KORs. PMID:27472317

Molecular Genetic Testing in Reward Deficiency Syndrome (RDS): Facts and Fiction.

PubMed

Blum, Kenneth; Badgaiyan, Rajendra D; Agan, Gozde; Fratantonio, James; Simpatico, Thomas; Febo, Marcelo; Haberstick, Brett C; Smolen, Andrew; Gold, Mark S

The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors or RDS, which was coined to define addictive behaviors and their genetic components. To carry out this review we searched a number of important databases including: Filtered: Cochrane Systematic reviews; DARE; Pubmed Central Clinical Quaries; National Guideline Clearinghouse and unfiltered resources: PsychINFO; ACP PIER; PsychSage; Pubmed/Medline. The major search terms included: dopamine agonist therapy for Addiction; dopamine agonist therapy for Reward dependence; dopamine antagonistic therapy for addiction; dopamine antagonistic therapy for reward dependence and neurogenetics of RDS. While there are many studies claiming a genetic association with RDS behavior, not all are scientifically accurate. Albeit our bias, this Clinical Pearl discusses the facts and fictions behind molecular genetic testing in RDS and the significance behind the development of the Genetic Addiction Risk Score (GARS PREDX ™), the first test to accurately predict one's genetic risk for RDS.

The effect of prolonged treatment with imipramine on the biosynthesis and functional characteristics of D2 dopamine receptors in the rat caudate putamen

PubMed Central

Dziedzicka-Wasylewska, Marta; Rogoż, Renata

1998-01-01

The present study shows the effects of imipramine in a single dose (10 mg kg−1, p.o.) or following repeated (14 days, twice a day) treatment on the level of mRNA coding for D2 dopamine receptors in the rat caudate putamen (CP). Repeated administration of imipramine resulted in the increase of the level of mRNA coding for D2 dopamine receptors. Radioligand binding studies with the D2 receptor agonist, [3H]-N-0437, indicated, that following imipramine administration, the affinity of the agonist for the D2 dopamine receptor significantly increased, though without any alterations in the Bmax. Pharmacological manipulations (by use of forskolin, GppNHp and quinpirole) of the cyclic AMP generating system, ex vivo following administration of imipramine indicated that an up-regulation of factors inhibiting cyclic GMP formation takes place. Most probably it is the D2 dopamine receptor which undergoes functional up-regulation, resulting from the enhancement of its biosynthesis. PMID:9535010

Parkinson's disease (PD) with dementia and falls is improved by AChEI? A preliminary study report.

PubMed

Lauretani, Fulvio; Galuppo, Laura; Costantino, Cosimo; Ticinesi, Andrea; Ceda, Gianpaolo; Ruffini, Livio; Nardelli, Anna; Maggio, Marcello

2016-06-01

Advanced PD is often associated with cognitive impairment and frequent falls. We describe a suggestive case report of PD associated with mild cognitive impairment (MCI) and falls. The aim of our study was to test alteration in balance potentially related to use of acetylcholinesterase inhibitor (AchEI). We address this hypothesis after keeping the patient in stable dosage of dopamine agonist. We describe an initial pharmacological management in a 78-year-old man affected by Parkinson disease (PD) associated with mild cognitive impairment (MCI) and history of falls. The diagnosis of PD was also confirmed by SPECT with DATSCAN, after CT-brain exclusion of potential other causes of the symptoms. Cognitive and motor performances of the patient were initially evaluated by Mini Mental Examination State Examination (MMSE), Short Physical Performance Battery (SPPB) and Romberg test. We also recorded gait parameters using an accelerometer, while balance and stability were assessed by stabilometric platform with open and closed eyes. We repeated cognitive and motor tests and gait and balance evaluation after stable dosage of dopamine agonist before and after introduction of AchEI. After starting dopamine agonist therapy, there was a significant improvement in gait parameters (speed, stride/min, stride length, swing duration, and decrease in gait cycle duration and rolling duration). When stable dosage of dopamine agonist was reached, AchEI was introduced obtaining not only a significant improvement of cognitive performance, but also a significant positive change in balance. We hypothesize that AchEI could improve stability, balance and postural instability in addition to cognitive performance in PD with MCI and balance deficits.

Dopamine depresses excitatory synaptic transmission onto rat subicular neurons via presynaptic D1-like dopamine receptors.

PubMed

Behr, J; Gloveli, T; Schmitz, D; Heinemann, U

2000-07-01

Schizophrenia is considered to be associated with an abnormal functioning of the hippocampal output. The high clinical potency of antipsychotics that act as antagonists at dopamine (DA) receptors indicate a hyperfunction of the dopaminergic system. The subiculum obtains information from area CA1 and the entorhinal cortex and represents the major output region of the hippocampal complex. To clarify whether an enhanced dopaminergic activity alters the hippocampal output, the effect of DA on alveus- and perforant path-evoked excitatory postsynaptic currents (EPSCs) in subicular neurons was examined using conventional intracellular and whole cell voltage-clamp recordings. Dopamine (100 microM) depressed alveus-elicited (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated EPSCs to 56 +/- 8% of control while perforant path-evoked EPSCs were attenuated to only 76 +/- 7% of control. Dopamine had no effect on the EPSC kinetics. Dopamine reduced the frequency of spontaneous miniature EPSCs without affecting their amplitudes. The sensitivity of subicular neurons to the glutamate receptor agonist (S)-alpha-amino-3-hydoxy-5-methyl-4-isoxazolepropionic acid was unchanged by DA pretreatment, excluding a postsynaptic mechanism for the observed reduction of excitatory synaptic transmission. The effect of DA on evoked EPSCs was mimicked by the D1 receptor agonist SFK 38393 and partially antagonized by the D1 receptor antagonist SCH 23390. While the D2 receptor agonist quinelorane failed to reduce the EPSCs, the D2 receptor antagonist sulpiride did not block the action of DA. The results indicate that DA strongly depresses the hippocampal and the entorhinal excitatory input onto subicular neurons by decreasing the glutamate release following activation of presynaptic D1-like DA receptors.

The effects of early-life stress on dopamine system function in adolescent female rats.

PubMed

Majcher-Maślanka, Iwona; Solarz, Anna; Wędzony, Krzysztof; Chocyk, Agnieszka

2017-04-01

During adolescence, many neural systems, including the dopamine system, undergo essential remodeling and maturation. It is well known that early-life stress (ELS) increases the risk for many psychopathologies during adolescence and adulthood. It is hypothesized that ELS interferes with the maturation of the dopamine system. There is a sex bias in the prevalence of stress-related mental disorders. Information regarding the effects of ELS on brain functioning in females is very limited. In the current study, maternal separation (MS) procedures were carried out to study the effects of ELS on dopamine system functioning in adolescent female rats. Our study showed that MS increased the density of tyrosine hydroxylase immunoreactive fibers in the prelimbic cortex (PLC) and nucleus accumbens (Acb). These changes were accompanied by a decrease in the level of D5 receptor mRNA and an increase in D2 receptor mRNA expression in the PLC of MS females. Conversely, D1 and D5 receptor mRNA levels were augmented in the caudate putamen (CPu), while the expression of the D3 dopamine receptor transcript was reduced in MS females. Additionally, in the Acb, MS elicited a decrease in D2 receptor mRNA expression. At the behavioral level, MS increased apomorphine-induced locomotion; however, it did not change locomotor responses to selective D1/D5 receptor agonist and attenuated D2/D3 receptor agonist-triggered locomotion. Moreover, MS decreased D1/D5 receptor agonist-induced grooming behavior. These results indicate that ELS disrupts dopamine receptor function in the PLC and basal ganglia during adolescence in females and may predispose them to psychopathologies during adolescence and adulthood. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Peripartum Cardiomyopathy Treatment with Dopamine Agonist and Subsequent Pregnancy with a Satisfactory Outcome.

PubMed

Melo, Maria Adélia Medeiros E; Carvalho, Jordão Sousa; Feitosa, Francisco Edson de Lucena; Araujo Júnior, Edward; Peixoto, Alberto Borges; Costa Carvalho, Francisco Herlânio; Carvalho, Regina Coeli Marques

2016-06-01

Pathophysiological mechanisms of peripartum cardiomyopathy are not yet completely defined, although there is a strong association with various factors that are already known, including pre-eclampsia. Peripartum cardiomyopathy treatment follows the same recommendations as heart failure with systolic dysfunction. Clinical and experimental studies suggest that products of prolactin degradation can induce this cardiomyopathy. The pharmacological suppression of prolactin production by D2 dopamine receptor agonists bromocriptine and cabergoline has demonstrated satisfactory results in the therapeutic response to the treatment. Here we present a case of an adolescent patient in her first gestation with peripartum cardiomyopathy that evolved to the normalized left ventricular function after cabergoline administration, which was used as an adjuvant in cardiac dysfunction treatment. Subsequently, despite a short interval between pregnancies, the patient exhibited satisfactory progress throughout the entire gestation or puerperium in a new pregnancy without any cardiac alterations. Dopamine agonists that are orally used and are affordable in most tertiary centers, particularly in developing countries, should be considered when treating peripartum cardiomyopathy cases. Thieme Publicações Ltda Rio de Janeiro, Brazil.

Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study.

PubMed

Newman-Tancredi, A; Gavaudan, S; Conte, C; Chaput, C; Touzard, M; Verrièle, L; Audinot, V; Millan, M J

1998-08-21

Recombinant human (h) 5-HT1A receptor-mediated G-protein activation was characterised in membranes of transfected Chinese hamster ovary (CHO) cells by use of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS binding). The potency and efficacy of 21 5-HT receptor agonists and antagonists was determined. The agonists, 5-CT (carboxamidotryptamine) and flesinoxan displayed high affinity (subnanomolar Ki values) and high efficacy (Emax > 90%, relative to 5-HT = 100%). In contrast, ipsapirone, zalospirone and buspirone displayed partial agonist activity. EC50s for agonist stimulation of [35S]GTPgammaS binding correlated well with Ki values from competition binding (r = +0.99). Among the compounds tested for antagonist activity, methiothepin and (+)butaclamol exhibited 'inverse agonist' behaviour, inhibiting basal [35S]GTPgammaS binding. The actions of 17 antipsychotic agents were investigated. Clozapine and several putatively 'atypical' antipsychotic agents, including ziprasidone, quetiapine and tiospirone, exhibited partial agonist activity and marked affinity at h5-HT1A receptors, similar to their affinity at hD2 dopamine receptors. In contrast, risperidone and sertindole displayed low affinity at h5-HT1A receptors and behaved as 'neutral' antagonists, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Likewise the 'typical' neuroleptics, haloperidol, pimozide, raclopride and chlorpromazine exhibited relatively low affinity and 'neutral' antagonist activity at h5-HT1A receptors with Ki values which correlated with their respective Kb values. The present data show that (i) [35S]GTPgammaS binding is an effective method to evaluate the efficacy and potency of agonists and antagonists at recombinant human 5-HT1A receptors. (ii) Like clozapine, several putatively 'atypical' antipsychotic drugs display balanced serotonin h5-HT1A/dopamine hD2 receptor affinity and partial agonist activity at h5-HT1A receptors. (iii) Several 'typical' and some putatively 'atypical' antipsychotic agents displayed antagonist properties at h5-HT1A sites with generally much lower affinity than at hD2 dopamine receptors. It is suggested that agonist activity at 5-HT1A receptors may be of utility for certain antipsychotic agents.

CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist.

PubMed

Chen, Jianyong; Collins, Gregory T; Levant, Beth; Woods, James; Deschamps, Jeffrey R; Wang, Shaomeng

2011-08-11

We have identified several ligands with high binding affinities to the dopamine D3 receptor and excellent selectivity over the D2 and D1 receptors. CJ-1639 (17) binds to the D3 receptor with a K(i) value of 0.50 nM and displays a selectivity of >5,000 times over D2 and D1 receptors in binding assays using dopamine receptors expressed in the native rat brain tissues. CJ-1639 binds to human D3 receptor with a K(i) value of 3.61 nM and displays over >1000-fold selectivity over human D1 and D2 receptors. CJ-1639 is active at 0.01 mg/kg at the dopamine D3 receptor in the rat and only starts to show a modest D2 activity at doses as high as 10 mg/kg. CJ-1639 is the most potent and selective D3 full agonist reported to date.

Heterogeneity of D2 dopamine receptors in different brain regions.

PubMed Central

Leonard, M N; Macey, C A; Strange, P G

1987-01-01

The binding of [3H]spiperone has been examined in membranes derived from different regions of bovine brain. In caudate nucleus, nucleus accumbens, olfactory tubercle and putamen binding is to D2 dopamine and 5HT2 serotonin receptors, whereas in cingulate cortex only serotonin 5HT2 receptor binding can be detected. D2 dopamine receptors were examined in detail in caudate nucleus, olfactory tubercle and putamen using [3H]spiperone binding in the presence of 0.3 microM-mianserin (to block 5HT2 serotonin receptors). No evidence for heterogeneity among D2 dopamine receptors either between brain regions or within a brain region was found from the displacements of [3H]spiperone binding by a range of antagonists, including dibenzazepines and substituted benzamides. Regulation of agonist binding by guanine nucleotides did, however, differ between regions. In caudate nucleus a population of agonist binding sites appeared resistant to guanine nucleotide regulation, whereas this was not the case in olfactory tubercle and putamen. PMID:2963621

Dopamine-Independent Locomotor Actions of Amphetamines in a Novel Acute Mouse Model of Parkinson Disease

PubMed Central

Sotnikova, Tatyana D; Beaulieu, Jean-Martin; Barak, Larry S; Wetsel, William C; Gainetdinov, Raul R

2005-01-01

Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs. PMID:16050778

Ventral tegmental ionotropic glutamate receptor stimulation of nucleus accumbens tonic dopamine efflux blunts hindbrain-evoked phasic neurotransmission: implications for dopamine dysregulation disorders.

PubMed

Tye, S J; Miller, A D; Blaha, C D

2013-11-12

Activation of glutamate receptors within the ventral tegmental area (VTA) stimulates extrasynaptic (basal) dopamine release in terminal regions, including the nucleus accumbens (NAc). Hindbrain inputs from the laterodorsal tegmental nucleus (LDT) are critical for elicitation of phasic VTA dopamine cell activity and consequent transient dopamine release. This study investigated the role of VTA ionotropic glutamate receptor (iGluR) stimulation on both basal and LDT electrical stimulation-evoked dopamine efflux in the NAc using in vivo chronoamperometry and fixed potential amperometry in combination with stearate-graphite paste and carbon fiber electrodes, respectively. Intra-VTA infusion of the iGluR agonists (±)-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; 1 μg/μl) or N-methyl-d-aspartic acid (NMDA; 2 μg/μl) enhanced basal NAc dopamine efflux. This iGluR-mediated potentiation of basal dopamine efflux was paralleled by an attenuation of LDT-evoked transient NAc dopamine efflux, suggesting that excitation of basal activity effectively inhibited the capacity of hindbrain afferents to elicit transient dopamine efflux. In line with this, post-NMDA infusion of the dopamine D2 autoreceptor (D2R) agonist quinpirole (1 μg/μl; intra-VTA) partially recovered NMDA-mediated attenuation of LDT-evoked NAc dopamine, while concurrently attenuating NMDA-mediated potentiation of basal dopamine efflux. Post-NMDA infusion of quinpirole (1 μg/μl) alone attenuated basal and LDT-evoked dopamine efflux. Taken together, these data reveal that hyperstimulation of basal dopamine transmission can stunt hindbrain burst-like stimulation-evoked dopamine efflux. Inhibitory autoreceptor mechanisms within the VTA help to partially recover the magnitude of phasic dopamine efflux, highlighting the importance of both iGluRs and D2 autoreceptors in maintaining the functional balance of tonic and phasic dopamine neurotransmission. Dysregulation of this balance may have important implications for disorders of dopamine dysregulation such as attention deficit hyperactivity disorder. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Cocaine Self-Administration Produces a Persistent Increase in Dopamine D2High Receptors

PubMed Central

Briand, Lisa A.; Flagel, Shelly B.; Seeman, Philip; Robinson, Terry E.

2008-01-01

Cocaine addicts are reported to have decreased numbers of striatal dopamine D2 receptors. However, in rodents, repeated cocaine administration consistently produces hypersensitivity to the psychomotor activating effects of both indirect dopamine agonists, such as cocaine itself, and importantly, to direct-acting D2 receptor agonists. The current study reports a possible resolution to this long-standing paradox. The dopamine D2 receptor exists in both a low and a high affinity state, and dopamine exerts its effects via the more functionally relevant high-affinity D2 receptor (D2High). We report here that cocaine self-administration experience produces a large (approximately 150%) increase in the proportion of D2High receptors in the striatum with no change in the total number of D2 receptors, and this effect is evident both 3 and 30 days after the discontinuation of cocaine self-administration. Changes in D2High receptors would not be evident with the probes used in human (and non-human primate) imaging studies. We suggest, therefore, that cocaine addicts and animals previously treated with cocaine may be hyper-responsive to dopaminergic drugs in part because an increase in D2High receptors results in dopamine supersensitivity. This may also help explain why stimuli that increase dopamine neurotransmission, including drugs themselves, are so effective in producing relapse in individuals with a history of exposure to cocaine. PMID:18284941

Blonanserin Ameliorates Phencyclidine-Induced Visual-Recognition Memory Deficits: the Complex Mechanism of Blonanserin Action Involving D3-5-HT2A and D1-NMDA Receptors in the mPFC

PubMed Central

Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2015-01-01

Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr197 and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser897 by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser896 by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC. PMID:25120077

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

PubMed Central

Politis, Marios; Wu, Kit; Loane, Clare; Brooks, David J.; Kiferle, Lorenzo; Turkheimer, Federico E.; Bain, Peter; Molloy, Sophie; Piccini, Paola

2014-01-01

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson’s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD. PMID:24531549

In vivo dopamine agonist properties of rotigotine: Role of D1 and D2 receptors.

PubMed

Fenu, Sandro; Espa, Elena; Pisanu, Augusta; Di Chiara, Gaetano

2016-10-05

Rotigotine acts in vitro as a full agonist of dopamine D1 receptors at concentrations almost superimposable to those at which it acts on D2 receptors. However in vivo evidence of the differences between the agonist activity of rotigotine at D1 receptors from that on the D2 receptors has not been provided yet. In order to test the ability of rotigotine to stimulate dopamine D1 and D2 receptors in vivo, we studied the effect of SCH39166 and eticlopride, selective dopamine D1 and D2/D3 receptor antagonists respectively, on rotigotine-induced contralateral turning behavior in 6-hydroxydopamine lesioned rats. Furthermore, the expression of the immediate-early gene c-fos in the caudate-putamen, was evaluated. As a comparison, we tested the D2/D3 agonist pramipexole. In primed rats, rotigotine (0.035, 0.1 and 0.35mg/kg) induced dose-dependent contralateral turning. Turning induced by 0.1mg/kg of rotigotine was reduced by pretreatment with the D1 antagonist SCH39166 and the D2 antagonist eticlopride. In drug-naive rats, rotigotine was less effective in eliciting turning but SCH39166 still reduced turning induced by rotigotine (0.35mg/kg). Pramipexole induced contralateral turning only in primed rats. SCH39166 potentiated and eticlopride abolished pramipexole-induced turning. Rotigotine induced Fos expression in the caudate-putamen and SCH39166 completely blocked it. Pramipexole failed to induce Fos. These results indicate that rotigotine acts in vivo as an agonist of D1 and D2 receptors while pramipexole is devoid of D1 activity in vivo. Given their differing DA receptor profiles, rotigotine and pramipexole might differ in their spectrum of application to the therapy of Parkinson's disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Dopaminergic system and dream recall: An MRI study in Parkinson's disease patients.

PubMed

De Gennaro, Luigi; Lanteri, Olimpia; Piras, Fabrizio; Scarpelli, Serena; Assogna, Francesca; Ferrara, Michele; Caltagirone, Carlo; Spalletta, Gianfranco

2016-03-01

We investigated the role of the dopamine system [i.e., subcortical-medial prefrontal cortex (mPFC) network] in dreaming, by studying patients with Parkinson's Disease (PD) as a model of altered dopaminergic transmission. Subcortical volumes and cortical thickness were extracted by 3T-MR images of 27 PD patients and 27 age-matched controls, who were asked to fill out a dream diary upon morning awakening for one week. PD patients do not substantially differ from healthy controls with respect to the sleep, dream, and neuroanatomical measures. Multivariate correlational analyses in PD patients show that dopamine agonist dosage is associated to qualitatively impoverished dreams, as expressed by lower bizarreness and lower emotional load values. Visual vividness (VV) of their dream reports positively correlates with volumes of both the amygdalae and with thickness of the left mPFC. Emotional load also positively correlates with hippocampal volume. Beside the replication of our previous finding on the role of subcortical nuclei in dreaming experience of healthy subjects, this represents the first evidence of a specific role of the amygdala-mPFC dopaminergic network system in dream recall. The association in PD patients between higher dopamine agonist dosages and impoverished dream reports, however, and the significant correlations between VV and mesolimbic regions, however, provide an empirical support to the hypothesis that a dopamine network plays a key role in dream generation. The causal relation is however precluded by the intrinsic limitation of assuming the dopamine agonist dosage as a measure of the hypodopaminergic state in PD. Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Recommendations for the Treatment of Patients With Parkinson Disease During Ramadan.

PubMed

Damier, Philippe; Al-Hashel, Jasem

2017-02-01

Every year, Ramadan fasting is practiced by many Muslim individuals. In cases of chronic disease, religious texts allow fasting to be broken. However, many believers still want to fast even at the risk of damaging their health. To our knowledge, there are no published recommendations on the medical management of Parkinson disease (PD) during Ramadan. Effective treatments exist in PD and usually require several daily drug intakes. Apart from worsening symptoms, interrupting PD treatment might lead to a severe withdrawal syndrome. Although no specific studies on this topic have led to formal recommendations, we suggest some options for adapting the treatment for patients who fast during Ramadan. The general principle is based on switching the patient's treatment to an equivalent dosage of a dopamine agonist that can be administered once daily or by transdermal patch. However, such an option is only feasible for patients who require a moderate amount of PD treatment and can tolerate dopamine agonist therapy. Because many patients with PD require regular multiple daily administration of dopamine-replacement medication, the management of Ramadan fasting is not easy. Switching the patient's treatment to an equivalent dosage of a dopamine agonist that can be administered once daily or by transdermal patch seems to be a reasonable option to consider for patients treated with a low-to-moderate amount of PD medication.

Dopamine D2 receptors photolabeled by iodo-azido-clebopride.

PubMed

Niznik, H B; Dumbrille-Ross, A; Guan, J H; Neumeyer, J L; Seeman, P

1985-04-19

Iodo-azido-clebopride, a photoaffinity compound for dopamine D2 receptors, had high affinity for canine brain striatal dopamine D2 receptors with a dissociation constant (Kd) of 14 nM. Irradiation of striatal homogenate with iodo-azido-clebopride irreversibly inactivated 50% of dopamine D2 receptors at 20 nM (as indicated by subsequent [3H]spiperone binding). Dopamine agonists and antagonists prevented this photo-inactivation with the appropriate rank-order of potency. Striatal dopamine D1, serotonin (S2), alpha 1- and beta-adrenoceptors were not significantly inactivated following irradiation with iodo-azido-clebopride. Thus, iodo-azido-clebopride is a selective photoaffinity probe for dopamine D2 receptors, the radiolabelled form of which may aid in the molecular characterization of these proteins.

Current and experimental treatments of Parkinson disease: A guide for neuroscientists.

PubMed

Oertel, Wolfgang; Schulz, Jörg B

2016-10-01

Over a period of more than 50 years, the symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been optimized using pharmacotherapy, deep brain stimulation, and physiotherapy. The arsenal of pharmacotherapies includes L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine. In the later course of the disease, motor complications occur, at which stage different oral formulations of L-Dopa or dopamine agonists with long half-life, a transdermal application or parenteral pumps for continuous drug supply can be subscribed. Alternatively, the patient is offered deep brain stimulation of the subthalamic nucleus (STN) or the internal part of the globus pallidus (GPi). For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials, and some of them already yielding positive results in phase 3 trials. In addition, non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia, including adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) and modulators of the metabolic glutamate receptor 5 (mGluR5 - mavoglurant) and serotonin (eltoprazine) receptors. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, inosine (a precursor of urate), and isradipine (a dihydropyridine calcium channel blocker), as well as active and passive immunization against α-synuclein and inhibitors or modulators of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available. We here review the current status of treatment options for motor and non-motor symptoms, and discuss current investigative strategies for disease modification. This review provides basic insights, mainly addressing basic scientists and non-specialists. It stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials. Non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, and isradipine - a dihydropyridine calcium channel blocker - as well as active and passive immunization against α-synuclein and inhibitors of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available for PD. We here review the current status of treatment options and investigative strategies for both motor and non-motor symptoms. This review stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. This article is part of a special issue on Parkinson disease. © 2016 International Society for Neurochemistry.

Mechanisms of inverse agonist action at D2 dopamine receptors

PubMed Central

Roberts, David J; Strange, Philip G

2005-01-01

Mechanisms of inverse agonist action at the D2(short) dopamine receptor have been examined. Discrimination of G-protein-coupled and -uncoupled forms of the receptor by inverse agonists was examined in competition ligand-binding studies versus the agonist [3H]NPA at a concentration labelling both G-protein-coupled and -uncoupled receptors. Competition of inverse agonists versus [3H]NPA gave data that were fitted best by a two-binding site model in the absence of GTP but by a one-binding site model in the presence of GTP. Ki values were derived from the competition data for binding of the inverse agonists to G-protein-uncoupled and -coupled receptors. Kcoupled and Kuncoupled were statistically different for the set of compounds tested (ANOVA) but the individual values were different in a post hoc test only for (+)-butaclamol. These observations were supported by simulations of these competition experiments according to the extended ternary complex model. Inverse agonist efficacy of the ligands was assessed from their ability to reduce agonist-independent [35S]GTPγS binding to varying degrees in concentration–response curves. Inverse agonism by (+)-butaclamol and spiperone occurred at higher potency when GDP was added to assays, whereas the potency of (−)-sulpiride was unaffected. These data show that some inverse agonists ((+)-butaclamol, spiperone) achieve inverse agonism by stabilising the uncoupled form of the receptor at the expense of the coupled form. For other compounds tested, we were unable to define the mechanism. PMID:15735658

Effects of Serotonin 2C Receptor Agonists on the Behavioral and Neurochemical Effects of Cocaine in Squirrel Monkeys

PubMed Central

Manvich, Daniel F.; Kimmel, Heather L.

2012-01-01

Accumulating evidence indicates that the serotonin system modulates the behavioral and neurochemical effects of cocaine, but the receptor subtypes mediating these effects remain unknown. Recent studies have demonstrated that pharmacological activation of the serotonin 2C receptor (5-HT2CR) attenuates the behavioral and neurochemical effects of cocaine in rodents, but such compounds have not been systematically evaluated in nonhuman primates. The present experiments sought to determine the impact of pretreatment with the preferential 5-HT2CR agonist m-chlorophenylpiperazine (mCPP) and the selective 5-HT2CR agonist Ro 60-0175 [(α-S)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine fumarate] on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press according to a 300-s fixed-interval schedule of stimulus termination, pretreatment with either 5-HT2CR agonist dose-dependently and insurmountably attenuated the behavioral stimulant effects of cocaine. In subjects trained to self-administer cocaine, both compounds dose-dependently and insurmountably attenuated cocaine-induced reinstatement of previously extinguished responding in an antagonist-reversible manner, and the selective agonist Ro 60-0175 also attenuated the reinforcing effects of cocaine during ongoing cocaine self-administration. It is noteworthy that the selective agonist Ro 60-0175 exhibited behavioral specificity because it did not significantly alter nondrug-maintained responding. Finally, in vivo microdialysis studies revealed that pretreatment with Ro 60-0175 caused a reduction of cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus. These results suggest that 5-HT2CR agonists functionally antagonize the behavioral effects of cocaine in nonhuman primates, possibly via a selective modulation of cocaine-induced dopamine increases within the mesolimbic dopamine system and may therefore represent a novel class of pharmacotherapeutics for the treatment of cocaine abuse. PMID:22328576

alpha7 and non-alpha7 nicotinic acetylcholine receptors modulate dopamine release in vitro and in vivo in the rat prefrontal cortex.

PubMed

Livingstone, Phil D; Srinivasan, Jayaraman; Kew, James N C; Dawson, Lee A; Gotti, Cecilia; Moretti, Milena; Shoaib, Mohammed; Wonnacott, Susan

2009-02-01

Nicotine enhances attentional and working memory aspects of executive function in the prefrontal cortex (PFC) where dopamine plays a major role. Here, we have determined the nicotinic acetylcholine receptor (nAChR) subtypes that can modulate dopamine release in rat PFC using subtype-selective drugs. Nicotine and 5-Iodo-A-85380 (beta2* selective) elicited [(3)H]dopamine release from both PFC and striatal prisms in vitro and dopamine overflow from medial PFC in vivo. Blockade by dihydro-beta-erythroidine supports the participation of beta2* nAChRs. However, insensitivity of nicotine-evoked [(3)H]dopamine release to alpha-conotoxin-MII in PFC prisms suggests no involvement of alpha6beta2* nAChRs, in contrast to the striatum, and this distinction is supported by immunoprecipitation of nAChR subunits from these tissues. The alpha7 nAChR-selective agonists choline and Compound A also promoted dopamine release from PFC in vitro and in vivo, and their effects were enhanced by the alpha7 nAChR-selective allosteric potentiator PNU-120596 and blocked by specific antagonists. DNQX and MK801 inhibited [(3)H]dopamine release evoked by choline and PNU-120596, suggesting crosstalk between alpha7 nAChRs, glutamate and dopamine in the PFC. In vivo, systemic (but not local) administration of PNU-120596, in the absence of agonist, facilitated dopamine overflow in the medial PFC, consistent with the activation of extracortical alpha7 nAChRs by endogenous acetylcholine or choline. These data establish that both beta2* and alpha7 nAChRs can modulate dopamine release in the PFC in vitro and in vivo. Through their distinct actions on dopamine release, these nAChR subtypes could contribute to executive function, making them specific therapeutic targets for conditions such as schizophrenia and attention deficit hyperactivity disorder.

[Stealing as an Impulse Control Disorder Associated with Pramipexole - A Case Report from Forensic Psychiatric Practice].

PubMed

Clemm von Hohenberg, Christian; Dreßing, Harald

2017-04-01

We report the case of a 48-year-old female whom we examined for legal culpability. The proband was taking the dopamine agonist pramipexole as a treatment for Parkinson's disease. In temporal association, she had committed numerous shoplifting offences.While pathological gambling, excessive shopping and hypersexuality have often been described as adverse effects of dopamine agonists, there are only few reports about impulsive stealing in this context.We discuss the synergy of the pharmacological effects with familial, biographic and social factors, suggesting a bio-psycho-social etiology. © Georg Thieme Verlag KG Stuttgart · New York.

Current Challenges in the Management of Prolactinomas.

PubMed

Maiter, Dominique

2015-04-01

Although the diagnosis of prolactinoma is often straightforward and the treatment strategy has been well defined in recent guidelines, several challenging issues persist in their management. The differential diagnosis of a large pituitary tumour with moderately elevated prolactin (PRL) concentrations is sometimes difficult, and prolonged treatment with a dopamine agonist may be inappropriate when the diagnosis of a prolactinoma is not sufficiently well substantiated. Also, timely withdrawal of dopamine agonist treatment and the remaining indications of transsphenoidal surgery are still matters of debate. Last but not least, the management of resistant or aggressive prolactinomas remains a challenge for the clinician, especially when they occur in young patients.

Current Challenges in the Management of Prolactinomas

PubMed Central

2015-01-01

Summary Although the diagnosis of prolactinoma is often straightforward and the treatment strategy has been well defined in recent guidelines, several challenging issues persist in their management. The differential diagnosis of a large pituitary tumour with moderately elevated prolactin (PRL) concentrations is sometimes difficult, and prolonged treatment with a dopamine agonist may be inappropriate when the diagnosis of a prolactinoma is not sufficiently well substantiated. Also, timely withdrawal of dopamine agonist treatment and the remaining indications of transsphenoidal surgery are still matters of debate. Last but not least, the management of resistant or aggressive prolactinomas remains a challenge for the clinician, especially when they occur in young patients. PMID:29632566

Stereotypic circling behavior in mice with vestibular dysfunction: asymmetrical effects of intrastriatal microinjection of a dopamine agonist.

PubMed

Ishiguro, Akio; Inagaki, Masumi; Kaga, Makiko

2007-07-01

Bronx Waltzer (bv) mouse, which has been used as a model of hearing and vestibular dysfunction, shows remarkable repetitive circling behavior. This study investigated whether the behavior is caused by the asymmetry of striatal function by observing the behavior of the bv mice following microinjection of dopamine D1 agonist, A68930 into the striatum ipsilaterally and contralaterally to the preferred direction of rotation separately. High dose of the drug induced opposite effects on ipsilateral rotations by the side of injections with statistical significance (p = .0026). These results suggested that the stereotypic circling behavior involves striatum and is based on striatal asymmetry.

Tremorolytic effects of safinamide in animal models of drug-induced parkinsonian tremor.

PubMed

Podurgiel, Samantha; Collins-Praino, Lyndsey E; Yohn, Samantha; Randall, Patrick A; Roach, Arthur; Lobianco, Christophe; Salamone, John D

2013-04-01

Safinamide is an α-aminoamide derivative that is currently in Phase III clinical trial development as an add-on therapy to levodopa or dopamine agonists for patients with Parkinson's disease. Safinamide is a monoamine oxidase B inhibitor with additional non-dopaminergic actions. The present experiments were performed to evaluate the ability of safinamide to attenuate parkinsonian motor impairments using the tremulous jaw movement model, an animal model of parkinsonian tremor. In rats, tremulous jaw movements can be induced with dopamine (DA) antagonists, DA depletion, and cholinomimetics, and can be reversed by various antiparkinsonian drugs, including L-DOPA, DA agonists, anticholinergics and adenosine A2A antagonists. In these present experiments, tremulous jaw movements were induced with the anticholinesterase galantamine (3.0mg/kg IP), the muscarinic agonist pilocarpine (0.5mg/kg IP), and the dopamine D2 antagonist pimozide (1.0mg/kg IP). Safinamide significantly reduced the number of tremulous jaw movements induced by galantamine, pilocarpine, and pimozide, with consistent effects across all three drugs at a dose range of 5.0-10.0mg/kg. The results of this study support the use of safinamide as a treatment for parkinsonian tremor. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of serotonin 5-HT1A agonist in advanced Parkinson's disease.

PubMed

Bara-Jimenez, William; Bibbiani, Francesco; Morris, Michael J; Dimitrova, Tzvetelina; Sherzai, Abdullah; Mouradian, Maral M; Chase, Thomas N

2005-08-01

Intermittent stimulation of striatal dopaminergic receptors seems to contribute to motor dysfunction in advanced Parkinson's disease (PD). With severe dopaminergic denervation, exogenous levodopa is largely decarboxylated to dopamine in serotonergic terminals. If 5-HT1A autoreceptors regulate dopamine as well as serotonin release, in parkinsonian patients inhibition of striatal serotonergic neuron firing might help maintain more physiological intrasynaptic dopamine concentrations and thus ameliorate motor fluctuations and dyskinesias. To evaluate this hypothesis, effects of a selective 5-HT1A agonist, sarizotan, given orally at 2 and 5 mg twice daily to 18 relatively advanced parkinsonian patients, were compared with baseline placebo function during a 3-week, double-blind, placebo-controlled, proof-of-concept study. Sarizotan alone or with intravenous levodopa had no effect on parkinsonian severity. But at safe and tolerable doses, sarizotan coadministration reduced levodopa-induced dyskinesias and prolonged its antiparkinsonian response (P < or = 0.05). Under the conditions of this study, our findings suggest that 5-HT1A receptor stimulation in levodopa-treated parkinsonian patients can modulate striatal dopaminergic function and that 5-HT1A agonists may be useful as levodopa adjuvants in the treatment of PD. Copyright 2005 Movement Disorder Society

A Multicenter Comparative Study of Impulse Control Disorder in Latin American Patients With Parkinson Disease.

PubMed

Ramírez Gómez, Carolina Candelaria; Serrano Dueñas, Marcos; Bernal, Oscar; Araoz, Natalia; Sáenz Farret, Michel; Aldinio, Victoria; Montilla, Verónica; Micheli, Federico

Impulse control disorder (ICD) is a common adverse effect in patients with Parkinson disease who receive dopamine agonists; however, other factors are involved in its manifestations. To study the frequency and factors involved in the development of this adverse effect in a Latin American population, we conducted a cross-sectional multicenter study. Two hundred fifty-five patients in 3 Latin American centers were evaluated by examination and application of scales (Unified Parkinson's Disease Rating Scale, Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale, Hoehn and Yahr, Clinical Impression of Severity Index for Parkinson's Disease). Of the patients, 27.4% had ICD, most of whom were on dopamine agonists. Other associated risk factors included a younger age at onset of Parkinson disease, moderate symptoms, a shorter evolution of the clinical manifestations, rapid eye movement (REM) sleep disorder behavior, and the consumption of tea, mate, and alcohol. The frequency of ICD is higher in Latin America than in Anglo-Saxon populations. Consuming tea and mate, in addition to the use of dopamine agonists, is a factor that may demonstrate a genetic link that predisposes patients to the establishment of an ICD.

High fat diet and food restriction differentially modify the behavioral effects of quinpirole and raclopride in rats.

PubMed

Baladi, Michelle G; France, Charles P

2009-05-21

Nutritional status can impact dopamine systems in a manner that might be important to understanding possible common neurobiological mechanisms that mediate abnormal compulsive food (e.g., obesity) and drug taking. Limiting food intake, for example, can increase sensitivity to the behavioral effects of indirect-acting dopamine receptor agonists. Much less is known regarding possible diet-induced changes in sensitivity to direct-acting dopamine receptor drugs. The present study investigated the effects of a high fat diet and of food restriction on sensitivity of rats to the behavioral effects of a direct-acting dopamine receptor agonist and a dopamine receptor antagonist. Free access to high fat chow increased sensitivity to quinpirole-induced yawning without changing sensitivity to raclopride-induced catalepsy or quinpirole-induced hypothermia. Food restriction (10 g/day) decreased sensitivity to quinpirole-induced yawning and raclopride-induced catalepsy without affecting sensitivity to quinpirole-induced hypothermia. Free access to a standard chow restored sensitivity to the behavioral effects of both drugs in rats that were previously food-restricted but not in rats that previously ate a high fat diet. These data confirm that food restriction can decrease sensitivity to behavioral effects of direct-acting dopamine receptor drugs, they provide evidence (i.e., no change in hypothermic effects) indicating that these changes are not due to pharmacokinetic mechanisms, and they provide initial evidence showing enhanced sensitivity to behavioral effects of dopamine receptor drugs in rats eating a high fat diet. These changes in sensitivity of dopamine systems could be relevant to understanding the impact of nutrition on therapeutic and recreational drug use.

High fat diet and food restriction differentially modify the behavioral effects of quinpirole and raclopride in rats

PubMed Central

Baladi, Michelle G; France, Charles P

2009-01-01

Nutritional status can impact dopamine systems in a manner that might be important to understanding possible common neurobiological mechanisms that mediate abnormal compulsive food (e.g., obesity) and drug taking. Limiting food intake, for example, can increase sensitivity to the behavioral effects of indirect-acting dopamine receptor agonists. Much less is known regarding possible diet-induced changes in sensitivity to direct-acting dopamine receptor drugs. The present study investigated the effects of a high fat diet and of food restriction on sensitivity of rats to the behavioral effects of a direct-acting dopamine receptor agonist and a dopamine receptor antagonist. Free access to high fat chow increased sensitivity to quinpirole-induced yawning without changing sensitivity to raclopride-induced catalepsy or quinpirole-induced hypothermia. Food restriction (10 g/day) decreased sensitivity to quinpirole-induced yawning and raclopride-induced catalepsy without affecting sensitivity to quinpirole-induced hypothermia. Free access to a standard chow restored sensitivity to the behavioral effects of both drugs in rats that were previously food-restricted but not in rats that previously ate a high fat diet. These data confirm that food restriction can decrease sensitivity to behavioral effects of direct-acting dopamine receptor drugs, they provide evidence (i.e., no change in hypothermic effects) indicating that these changes are not due to pharmacokinetic mechanisms, and they provide initial evidence showing enhanced sensitivity to behavioral effects of dopamine receptor drugs in rats eating a high fat diet. These changes in sensitivity of dopamine systems could be relevant to understanding the impact of nutrition on therapeutic and recreational drug use. PMID:19327348

Characterization of [3H]LS-3-134, a Novel Arylamide Phenylpiperazine D3 Dopamine Receptor Selective Radioligand

PubMed Central

Rangel-Barajas, Claudia; Malik, Maninder; Taylor, Michelle; Neve, Kim A.; Mach, Robert H.; Luedtke, Robert R.

2014-01-01

LS-3-134 is a substituted N-phenylpiperazine derivative that has been reported to exhibit a) high-affinity binding (Ki value 0.2 nM) at human D3 dopamine receptors, b) >100-fold D3 vs. D2 dopamine receptor subtype binding selectivity and c) low-affinity binding (Ki values >5,000 nM) at sigma 1 and sigma 2 receptors. Based upon a forskolin-dependent activation of the adenylyl cyclase inhibition assay, LS-3-134 is a weak partial agonist at both D2 and D3 dopamine receptor subtypes (29% and 35% of full agonist activity, respectively). In this study, [3H]-labeled LS-3-134 was prepared and evaluated to further characterize its use as a D3 dopamine receptor selective radioligand. Kinetic and equilibrium radioligand binding studies were performed. This radioligand rapidly reaches equilibrium (10-15 min at 37°C) and binds with high affinity to both human (Kd = 0.06 ± 0.01 nM) and rat (Kd = 0.2 ± 0.02 nM) D3 receptors expressed in HEK-293 cells. Direct and competitive radioligand binding studies using rat caudate and nucleus accumbens tissue indicate that [3H]LS-3-134 selectively binds a homogeneous population of binding sites with a dopamine D3 receptor pharmacological profile. Based upon these studies we propose that [3H]LS-3-134 represents a novel D3 dopamine receptor selective radioligand that can be used for studying the expression and regulation of the D3 dopamine receptor subtype. PMID:25041389

Behavioural and biochemical responses following activation of midbrain dopamine pathways by receptor selective neurokinin agonists.

PubMed

Elliott, P J; Mason, G S; Stephens-Smith, M; Hagan, R M

1991-06-01

Preferential activation of mesolimbic and nigro-striatal dopamine (DA) pathways by receptor-selective and peptidase-resistant neurokinin (NK) agonists is reported. The DA cell body region of the mesolimbic pathway appears to be activated by NK agonists selective for NK-1 and NK-3 receptors whereas the DA cell bodies in the substantia nigra are under an excitatory NK-2 receptor-mediated influence. Stimulation of the mesolimbic DA pathway by NK-1 (Ava[L-Pro9,N-Me-Leu10]SP (7-11) [GR73632]) or NK-3 (Senktide) agonists increase locomotor activity. Additional studies showed that this elevated motor response observed after intra-VTA infusion of GR73632 was accompanied by a corresponding increase in DA turnover in the terminal fields of this pathway. Similarly, unilateral activation of the nigro-striatal DA pathway by NK-2 selective agonists (Ava (D-Pro9) SP (7-11) [GR51667] or [Lys3,Gly8,R-Lac-Leu9]NKA (3-10) [GR64349]) elicit contralateral rotational activity and an increase in DA turnover in the ipsilateral striatum. The rotational response was attenuated by prior administration of an NK-2 antagonist (cyclo (Gln, Trp, Phe, Gly, Leu, Met)] L-659877]) into the nigra. Peripheral injection of haloperidol, a DA antagonist, also blocked the NK-2 agonist induced rotations.

Dopaminergic Modulation of Sleep-Wake States.

PubMed

Herrera-Solis, Andrea; Herrera-Morales, Wendy; Nunez-Jaramillo, Luis; Arias-Carrion, Oscar

2017-01-01

The role of dopamine in sleep-wake regulation is considered as a wakefulness-promoting agent. For the clinical treatment of excessive daytime sleepiness, drugs have been commonly used to increase dopamine release. However, sleep disorders or lack of sleep are related to several dopaminerelated disorders. The effects of dopaminergic agents, nevertheless, are mediated by two families of dopamine receptors, D1 and D2-like receptors; the first family increases adenylyl cyclase activity and the second inhibits adenylyl cyclase. For this reason, the dopaminergic agonist effects on sleep-wake cycle are complex. Here, we review the state-of-the-art and discuss the different effects of dopaminergic agonists in sleep-wake states, and propose that these receptors account for the affinity, although not the specificity, of several effects on the sleep-wake cycle. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Antipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function.

PubMed

El Hage, Cynthia; Bédard, Anne-Marie; Samaha, Anne-Noël

2015-12-01

Chronic exposure to some antipsychotic medications can induce supersensitivity to dopamine receptor stimulation. This is linked to a worsening of clinical outcome and to antipsychotic treatment failure. Here we investigated the role of striatal subregions [nucleus accumbens (NAc) and caudate-putamen (CPu)] in the expression of antipsychotic-induced dopamine supersensitivity. We treated rats with haloperidol (HAL) or olanzapine (OLZ), using regimens that achieve clinically relevant kinetics of striatal D2 receptor occupancy. Under these conditions, HAL produces dopamine supersensitivity whereas OLZ does not. We then assessed behaviors evoked by the dopamine agonist amphetamine (AMPH). We either injected AMPH into the striatum or inhibited striatal function with microinjections of GABA receptor agonists prior to injecting AMPH systemically. HAL-treated rats were dopamine supersensitive, as indicated by sensitization to systemic AMPH-induced potentiation of both locomotor activity and operant responding for a conditioned reward (CR). Intra-CPu injections of AMPH had no effect on these behaviors, in any group. Intra-NAc injections of AMPH enhanced operant responding for CR in OLZ-treated and control rats, but not in HAL-treated rats. In HAL-treated rats, inhibition of the NAc also failed to disrupt systemic AMPH-induced potentiation of operant responding for CR. Furthermore, while intra-NAc AMPH enhanced locomotion in both HAL-treated and control animals, inhibition of the NAc disrupted systemic AMPH-induced locomotion only in control rats. Thus, antipsychotic-induced dopamine supersensitivity persistently disrupts NAc function, such that some behaviors that normally depend upon NAc dopamine no longer do so. This has implications for understanding dysfunctions in dopamine-mediated behaviors in patients undergoing chronic antipsychotic treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Lack of effect of dopaminergic denervation on caudate-putamen hyperthermia or hypothermia induced by drugs and mild stressors.

PubMed

Marcangione, Caterina; Constantin, Annie; Clarke, Paul B S

2010-07-01

A number of drugs and psychological stressors induce brain hyperthermia and increase extracellular dopamine in the caudate-putamen. The present study tested whether caudate-putamen hyperthermia produced by such stimuli is dependent on dopaminergic transmission. Rats were infused with 6-hydroxydopamine unilaterally into the medial forebrain bundle, and after a two-week recovery period, removable thermocouples were used to monitor temperature in the depleted and intact caudate-putamen in freely-moving animals. The indirect dopamine agonist d-amphetamine (1 and 2mg/kg s.c.) increased caudate-putamen temperature, whereas a low dose of the direct agonist apomorphine (0.1mg/kg s.c.) reduced it. Gamma-butyrolactone, which strongly inhibits dopamine release at the dose administered (700mg/kg i.p.), initially reduced and then increased caudate-putamen temperature. Brief (5-10min) presentation of mild stressors, including tail pinch, produced a rapid and transient caudate-putamen hyperthermia. Quantitative (125)I-RTI-55 autoradiography in post-mortem tissue revealed a 97-100% loss of binding to dopamine transporters in the lesioned caudate-putamen. Despite this near-total dopamine denervation, neither basal caudate-putamen temperature, nor any of the observed temperature responses to drugs or mild stressors, was altered. We conclude that in the caudate-putamen, endogenous dopamine is unlikely to modulate temperature significantly at a local level. Copyright 2010 Elsevier Inc. All rights reserved.

Differential effects of central injections of D1 and D2 receptor agonists and antagonists on male sexual behavior in Japanese quail.

PubMed

Kleitz-Nelson, H K; Cornil, C A; Balthazart, J; Ball, G F

2010-07-01

A key brain site in the control of male sexual behavior is the medial pre-optic area (mPOA) where dopamine stimulates both D1 and D2 receptor subtypes. Research completed to date in Japanese quail has only utilized systemic injections and therefore much is unknown about the specific role played by dopamine in the brain and mPOA in particular. The present study investigated the role of D1 and D2 receptors on male sexual behavior by examining how intracerebroventricular injections and microinjections into the mPOA of D1 and D2 agonists and antagonists influenced appetitive and consummatory aspects of sexual behavior in male quail. Experiments 1 and 2 investigated the effects of intracerebroventricular injections at three doses of D1 or D2 agonists and antagonists. The results indicated that D1 receptors facilitated consummatory male sexual behavior, whereas D2 receptors inhibited both appetitive and consummatory behaviors. Experiment 3 examined the effects of the same compounds specifically injected in the mPOA and showed that, in this region, both receptors stimulated male sexual behaviors. Together, these data indicated that the stimulatory action of dopamine in the mPOA may require a combined activation of D1 and D2 receptors. Finally, the regulation of male sexual behavior by centrally infused dopaminergic compounds in a species lacking an intromittent organ suggested that dopamine action on male sexual behavior does not simply reflect the modulation of genital reflexes due to general arousal, but relates to the central control of sexual motivation. Together, these data support the claim that dopamine specifically regulates male sexual behavior.

Differential effects of central injections of D1 and D2 receptor agonists and antagonists on male sexual behavior in Japanese quail

PubMed Central

Kleitz-Nelson, H.K.; Cornil, C.A.; Balthazart, J.; Ball, G.F.

2010-01-01

A key brain site in the control of male sexual behavior is the medial preoptic area (mPOA) where dopamine stimulates both D1 and D2 receptor subtypes. Research completed to date in Japanese quail has only utilized systemic injections, so much is unknown about the specific role played by dopamine in the brain and mPOA in particular. The present study investigates the role of D1 and D2 receptors on male sexual behavior by examining how intracerebroventricular (ICV) injections and microinjections into the mPOA of D1 and D2 agonists and antagonists influence appetitive and consummatory aspects of sexual behavior in male quail. Experiments 1 and 2 investigate the effects of ICV injections at three doses of D1 or D2 agonists and antagonists. Results indicate that D1 receptors facilitate consummatory male sexual behavior while D2 receptors inhibit both appetitive and consummatory behaviors. Experiment 3 examines the effects of the same compounds specifically injected in the mPOA and shows that in this region, both receptors stimulate male sexual behaviors. Together, these data indicate that the stimulatory action of dopamine in the mPOA may require a combined activation of D1 and D2 receptors. Finally, the regulation of male sexual behavior by centrally infused dopaminergic compounds in a species lacking an intromittent organ suggests that dopamine action on male sexual behavior does not simply reflect the modulation of genital reflexes due to general arousal, but relates to the central control of sexual motivation. Together, these data support the claim that dopamine specifically regulates male sexual behavior. PMID:20597974

Dopamine D1 and D3 Receptors Modulate Heroin-Induced Cognitive Impairment through Opponent Actions in Mice

PubMed Central

Zhu, Yongsheng; Wang, Yunpeng; Wei, Shuguang; Zhang, Hongbo; Yan, Peng; Li, Yunxiao; Qiao, Xiaomeng; Yin, Fangyuan

2017-01-01

Abstract Background: Chronic abuse of heroin leads to long-lasting and complicated cognitive impairment. Dopamine receptors are critically involved in the impulsive drug-driven behavior and the altered attention, processing speed, and mental flexibility that are associated with higher relapse rates. However, the effects of the different dopamine receptors and their possible involvement in heroin-induced cognitive impairment remain unclear. Methods: The 5-choice serial reaction time task was used to investigate the profiles of heroin-induced cognitive impairment in mice. The expression levels of dopamine D1- and D2-like receptors in the prefrontal cortex, nucleus accumbens, and caudate-putamen were determined. The effects of dopamine receptors on heroin-induced impulsivity in the 5-choice serial reaction time task were examined by agonist/antagonist treatment on D1 or D3 receptor mutant mice. Results: Systemic heroin administration influences several variables in the 5-choice serial reaction time task, most notably premature responses, a measure of motor impulsivity. These behavioral impairments are associated with increased D1 receptor and decreased D3 receptor mRNA and protein levels in 3 observed brain areas. The heroin-evoked increase in premature responses is mimicked by a D1 agonist and prevented by a D1 antagonist or genetic ablation of the D1 receptor gene. In contrast, a D3 agonist decreases both basal and heroin-evoked premature responses, while genetic ablation of the D3 receptor gene results in increased basal and heroin-evoked premature responses. Conclusions: Heroin-induced impulsive behavior in the 5-choice serial reaction time task is oppositely modulated by D1 and D3 receptor activation. The D1 receptors in the cortical-mesolimbic region play an indispensable role in modulating such behaviors. PMID:27815417

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds.

PubMed

Rangel-Barajas, Claudia; Malik, Maninder; Mach, Robert H; Luedtke, Robert R

2015-06-01

We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity. Copyright © 2015. Published by Elsevier Ltd.

Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile.

PubMed

Bartoszyk, G D; Van Amsterdam, C; Greiner, H E; Rautenberg, W; Russ, H; Seyfried, C A

2004-02-01

Sarizotan exhibited high affinities only to serotonin 5-HT1A receptors and dopamine DA D4>D3>D2 receptors with the profile of a 5-HT1A agonist and DA antagonist demonstrated by the inhibition of cAMP-stimulation and guinea pig ileum contraction, decreased accumulation of the 5-HT precursor 5-hydroxytryptophan and increased levels of 5-HT metabolites, increased accumulation of DA precursor dihydroxyphenylalanine (DOPA) and the reduced levels of DA metabolites in intact rats. However, sarizotan at higher doses decreased DA precursor accumulation in reserpinized rats and induced contralateral rotational behavior in unilaterally substantia nigra lesioned rats, indicating some intrinsic dopaminergic activity; at D2 receptors sarizotan may act as a partial agonist, depending on the dopaminergic impulse flow. Sarizotan represents a new approach for the treatment of extrapyramidal motor complications such as l-DOPA-induced dyskinesia in Parkinson's disease.

Pathological Gambling Associated With Aripiprazole or Dopamine Replacement Therapy

PubMed Central

Grall-Bronnec, Marie; Sauvaget, Anne; Perrouin, Fanny; Leboucher, Juliette; Etcheverrigaray, François; Challet-Bouju, Gaëlle; Gaboriau, Louise; Derkinderen, Pascal; Jolliet, Pascale; Victorri-Vigneau, Caroline

2016-01-01

Background In the last 10 years, dopamine replacement therapy (DRT) has become a well-known risk factor for developing an impulse control disorder, such as gambling disorder (GD). Another medication, aripiprazole (ARI), has been more recently identified as another risk factor. Dopamine replacement therapy and ARI share a dopamine agonist action. Our work aimed at comparing patients with PG according to their treatment with DRT or ARI. Methods Two methods were combined—a systematic review concentrated on case reports and the analysis of a French disordered gamblers cohort focused on patients using ARI or DRT at inclusion. Results We reported 48 cases of GD possibly due to DRT and 17 cases of GD possibly due to ARI. Because of their standardized assessment, only the EVALJEU patients could be compared. Two clinical patterns emerged. Patients in the ARI group were young, impulsive, and high novelty seekers and had a history of substance misuse. Their first gambling experience occurred during adolescence. Conversely, patients in the DRT group were old, and they began gambling late in life. They showed low levels of gambling-related cognition. Conclusions Patients in the ARI group seemed to be more severe pathological gamblers than patients in the DRT group. Aripiprazole is a partial D2 receptor agonist, whereas DRT includes full D2 receptor agonist. The trigger mechanism of PG development is complex and cannot only be attributed only to the pharmacodynamic effects of dopaminergic drugs. Indeed, individual vulnerability factors and environmental factors need to be considered. PMID:26658263

Dopamine-Induced Apoptosis of Lactotropes Is Mediated by the Short Isoform of D2 Receptor

PubMed Central

Radl, Daniela Betiana; Ferraris, Jimena; Boti, Valeria; Seilicovich, Adriana; Sarkar, Dipak Kumar; Pisera, Daniel

2011-01-01

Dopamine, through D2 receptor (D2R), is the major regulator of lactotrope function in the anterior pituitary gland. Both D2R isoforms, long (D2L) and short (D2S), are expressed in lactotropes. Although both isoforms can transduce dopamine signal, they differ in the mechanism that leads to cell response. The administration of D2R agonists, such as cabergoline, is the main pharmacological treatment for prolactinomas, but resistance to these drugs exists, which has been associated with alterations in D2R expression. We previously reported that dopamine and cabergoline induce apoptosis of lactotropes in primary culture in an estrogen-dependent manner. In this study we used an in vivo model to confirm the permissive action of estradiol in the apoptosis of anterior pituitary cells induced by D2R agonists. Administration of cabergoline to female rats induced apoptosis, measured by Annexin-V staining, in anterior pituitary gland from estradiol-treated rats but not from ovariectomized rats. To evaluate the participation of D2R isoforms in the apoptosis induced by dopamine we used lactotrope-derived PR1 cells stably transfected with expression vectors encoding D2L or D2S receptors. In the presence of estradiol, dopamine induced apoptosis, determined by ELISA and TUNEL assay, only in PR1-D2S cells. To study the role of p38 MAPK in apoptosis induced by D2R activation, anterior pituitary cells from primary culture or PR1-D2S were incubated with an inhibitor of the p38 MAPK pathway (SB203850). SB203580 blocked the apoptotic effect of D2R activation in lactotropes from primary cultures and PR1-D2S cells. Dopamine also induced p38 MAPK phosphorylation, determined by western blot, in PR1-D2S cells and estradiol enhanced this effect. These data suggest that, in the presence of estradiol, D2R agonists induce apoptosis of lactotropes by their interaction with D2S receptors and that p38 MAPK is involved in this process. PMID:21464994

Dopamine-induced apoptosis of lactotropes is mediated by the short isoform of D2 receptor.

PubMed

Radl, Daniela Betiana; Ferraris, Jimena; Boti, Valeria; Seilicovich, Adriana; Sarkar, Dipak Kumar; Pisera, Daniel

2011-03-25

Dopamine, through D2 receptor (D2R), is the major regulator of lactotrope function in the anterior pituitary gland. Both D2R isoforms, long (D2L) and short (D2S), are expressed in lactotropes. Although both isoforms can transduce dopamine signal, they differ in the mechanism that leads to cell response. The administration of D2R agonists, such as cabergoline, is the main pharmacological treatment for prolactinomas, but resistance to these drugs exists, which has been associated with alterations in D2R expression. We previously reported that dopamine and cabergoline induce apoptosis of lactotropes in primary culture in an estrogen-dependent manner. In this study we used an in vivo model to confirm the permissive action of estradiol in the apoptosis of anterior pituitary cells induced by D2R agonists. Administration of cabergoline to female rats induced apoptosis, measured by Annexin-V staining, in anterior pituitary gland from estradiol-treated rats but not from ovariectomized rats. To evaluate the participation of D2R isoforms in the apoptosis induced by dopamine we used lactotrope-derived PR1 cells stably transfected with expression vectors encoding D2L or D2S receptors. In the presence of estradiol, dopamine induced apoptosis, determined by ELISA and TUNEL assay, only in PR1-D2S cells. To study the role of p38 MAPK in apoptosis induced by D2R activation, anterior pituitary cells from primary culture or PR1-D2S were incubated with an inhibitor of the p38 MAPK pathway (SB203850). SB203580 blocked the apoptotic effect of D2R activation in lactotropes from primary cultures and PR1-D2S cells. Dopamine also induced p38 MAPK phosphorylation, determined by western blot, in PR1-D2S cells and estradiol enhanced this effect. These data suggest that, in the presence of estradiol, D2R agonists induce apoptosis of lactotropes by their interaction with D2S receptors and that p38 MAPK is involved in this process.

Effects of the single and combined treatment with dopamine agonist, somatostatin analog and mTOR inhibitors in a human lung carcinoid cell line: an in vitro study.

PubMed

Pivonello, Claudia; Rousaki, Panagoula; Negri, Mariarosaria; Sarnataro, Maddalena; Napolitano, Maria; Marino, Federica Zito; Patalano, Roberta; De Martino, Maria Cristina; Sciammarella, Concetta; Faggiano, Antongiulio; Rocco, Gaetano; Franco, Renato; Kaltsas, Gregory A; Colao, Annamaria; Pivonello, Rosario

2017-06-01

Somatostatin analogues and mTOR inhibitors have been used as medical therapy in lung carcinoids with variable results. No data are available on dopamine agonists as treatment for lung carcinoids. The main aim of the current study was to evaluate the effect of the combined treatment of somatostatin analogue octreotide and the dopamine agonist cabergoline with mTOR inhibitors in an in vitro model of typical lung carcinoids: the NCI-H727 cell line. In NCI-H727 cell line, reverse transcriptase-quantitative polymerase chain reaction and immunofluorescence were assessed to characterize the expression of the somatostatin receptor 2 and 5, dopamine receptor 2 and mTOR pathway components. Fifteen typical lung carcinoids tissue samples have been used for somatostatin receptor 2, dopamine receptor 2, and the main mTOR pathway component p70S6K expression and localization by immunohistochemistry. Cell viability, fluorescence-activated cell sorting analysis and western blot have been assessed to test the pharmacological effects of octreotide, cabergoline and mTOR inhibitors, and to evaluate the activation of specific cell signaling pathways in NCI-H727 cell line. NCI-H727 cell line expressed somatostatin receptor 2, somatostatin receptor 5 and dopamine receptor 2 and all mTOR pathway components at messenger and protein levels. Somatostatin receptor 2, dopamine receptor 2, and p70S6K (non phosphorylated and phosphorylated) proteins were expressed in most typical lung carcinoids tissue samples. Octreotide and cabergoline did not reduce cell viability as single agents but, when combined with mTOR inhibitors, they potentiate mTOR inhibitors effect after long-term exposure, reducing Akt and ERK phosphorylation, mTOR escape mechanisms, and increasing the expression DNA-damage-inducible transcript 4, an mTOR suppressor. In conclusion, the single use of octreotide and cabergoline is not sufficient to block cell viability but the combined approach of these agents with mTOR inhibitors might reduce the mTOR inhibitors-induced escape mechanisms and/or activate the endogenous mTOR suppressor, potentiating the effect of the mTOR inhibitors in an in vitro model of typical lung carcinoids.

The role of serotonin-2 (5-HT2) and dopamine receptors in the behavioral actions of the 5-HT2A/2C agonist, DOI, and putative 5-HT2C inverse agonist, SR46349B.

PubMed

Scarlota, Laura C; Harvey, John A; Aloyo, Vincent J

2011-02-01

Atypical antipsychotic efficacy is often attributed to actions at serotonin-2 (5-HT(2)) and dopamine receptors, indicating a potential benefit of understanding the interplay between these systems. Currently, it is known that 5-HT(2) receptors modulate dopamine release, although the role of specific dopamine receptors in 5-HT(2)-mediated behavior is not well understood. We examined the role of 5-HT(2A), 5-HT(2C), and dopamine (D1 and D2) receptors in the behavioral response to a 5-HT(2A/2C) agonist (DOI) and 5-HT(2A/2C) antagonist (SR46349B). Effects were assessed by measuring rabbit head bobs (previously characterized as 5-HT(2A) receptor-mediated) and body shakes (5-HT(2C)-mediated). As expected, DOI produced head bobs and body shakes, and these DOI-elicited behaviors were attenuated by the SR46349B pretreatment. Unexpectedly, SR46349B also induced head bobs when administered alone. However, SR46349B-elicited head bobs are distinguishable from those produced by DOI since the 5-HT(2A) antagonist, ketanserin, only attenuated DOI-elicited head bobs. Conversely, 5-HT(2C) ligands (SB242084 and SB206553) inhibited SR46349B but not DOI-induced head bobs. Furthermore, when administered alone, SB206553 (a 5-HT(2C) inverse agonist) produced head bobs, indicating the behavior can be either 5-HT(2A) or 5-HT(2C) mediated. Next, it was revealed that D1 and D2 receptors play a role in DOI-elicited head bobs, but only D1 receptors are required for SR46349B-elicited head bobs. 5-HT(2A) receptor agonism and 5-HT(2C) inverse agonism produce the same behavior, likely due to similar downstream actions at D1 receptors. Consequently, 5-HT(2C) agonism or D1 agonism may be effective therapies for disorders, such as schizophrenia, currently being treated with 5-HT(2A) antagonists.

Effects of Methylphenidate on Resting-State Functional Connectivity of the Mesocorticolimbic Dopamine Pathways in Cocaine Addiction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Konova, Anna B.; Moeller, Scott J.; Tomasi, Dardo

Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems–level effects of methylphenidate in this population have not yet been described. To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction.

Deficits in the Sensitivity of Striatal Muscarinic Receptors Induced by 56Fe Heavy-Particle Irradiation: Further ’Age-Radiation’ Parallels

DTIC Science & Technology

1993-01-01

behavioral func- agonists (as assessed by examining oxotremorine enhancement tions such as coordination and muscle strength [for reviews, of K4-evoked...interface and by comparing the response to oxotremorine -en- made by examining the oxotremorine (OXO)-enhanced hanced K4-evoked release of dopamine...Results showed that al- K+-evoked release of dopamine (DA) from perifused stria- though oxotremorine -enhanced K4-evoked release of dopamine tal slices

Systemic Blockade of D2-Like Dopamine Receptors Facilitates Extinction of Conditioned Fear in Mice

ERIC Educational Resources Information Center

Ponnusamy, Ravikumar; Nissim, Helen A.; Barad, Mark

2005-01-01

Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized…

Blonanserin ameliorates phencyclidine-induced visual-recognition memory deficits: the complex mechanism of blonanserin action involving D₃-5-HT₂A and D₁-NMDA receptors in the mPFC.

PubMed

Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2015-02-01

Blonanserin differs from currently used serotonin 5-HT₂A/dopamine-D₂ receptor antagonists in that it exhibits higher affinity for dopamine-D₂/₃ receptors than for serotonin 5-HT₂A receptors. We investigated the involvement of dopamine-D₃ receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT₂A receptor agonist) and 7-OH-DPAT (a dopamine-D₃ receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D₁ receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr(197) and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser(897) by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser(896) by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D₁-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D₃ and serotonin 5-HT₂A receptors in the mPFC.

Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques.

PubMed

Durdagi, Serdar; Salmas, Ramin Ekhteiari; Stein, Matthias; Yurtsever, Mine; Seeman, Philip

2016-02-17

We have recently reported G-protein coupled receptor (GPCR) model structures for the active and inactive states of the human dopamine D2 receptor (D2R) using adrenergic crystal structures as templates. Since the therapeutic concentrations of dopamine agonists that suppress the release of prolactin are the same as those that act at the high-affinity state of the D2 receptor (D2High), D2High in the anterior pituitary gland is considered to be the functional state of the receptor. In addition, the therapeutic concentrations of anti-Parkinson drugs are also related to the dissociation constants in the D2High form of the receptor. The discrimination between the high- and low-affinity (D2Low) components of the D2R is not obvious and requires advanced computer-assisted structural biology investigations. Therefore, in this work, the derived D2High and D2Low receptor models (GPCR monomer and dimer three-dimensional structures) are used as drug-binding targets to investigate binding interactions of dopamine and apomorphine. The study reveals a match between the experimental dissociation constants of dopamine and apomorphine at their high- and low-affinity sites of the D2 receptor in monomer and dimer and their calculated dissociation constants. The allosteric receptor-receptor interaction for dopamine D2R dimer is associated with the accessibility of adjacent residues of transmembrane region 4. The measured negative cooperativity between agonist ligand at dopamine D2 receptor is also correctly predicted using the D2R homodimerization model.

Dopamine and temporal attention: An attentional blink study in Parkinson's disease patients on and off medication.

PubMed

Slagter, H A; van Wouwe, N C; Kanoff, K; Grasman, R P P P; Claassen, D O; van den Wildenberg, W P M; Wylie, S A

2016-10-01

The current study aimed to shed more light on the role of dopamine in temporal attention. To this end, we pharmacologically manipulated dopamine levels in a large sample of Parkinson's disease patients (n=63) while they performed an attentional blink (AB) task in which they had to identify two targets (T1 and T2) presented in close temporal proximity among distractors. We specifically examined 1) differences in the magnitude of the AB between unmedicated Parkinson patients, who have depleted levels of striatal dopamine, and healthy controls, and 2) effects of two dopaminergic medications (l-DOPA and dopamine agonists) on the AB in the Parkinson patients at the group level and as a function of individual baseline performance. In line with the notion that relatively low levels of striatal dopamine may impair target detection in general, Parkinson patients OFF medications displayed overall poor target perception compared to healthy controls. Moreover, as predicted, effects of dopaminergic medication on AB performance critically depended on individual baseline AB size, although this effect was only observed for l-DOPA. l-DOPA generally decreased the size of the AB in patients with a large baseline AB (i.e., OFF medications), while l-DOPA generally increased the AB in patients with a small baseline AB. These findings may support a role for dopamine in the AB and temporal attention, more generally and corroborate the notion that there is an optimum dopamine level for cognitive function. They also emphasize the need for more studies that examine the separate effects of DA agonists and l-DOPA on cognitive functioning. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmacological stimuli decreasing nucleus accumbens dopamine can act as positive reinforcers but have a low addictive potential.

PubMed

Marinelli, M; Barrot, M; Simon, H; Oberlander, C; Dekeyne, A; Le Moal, M; Piazza, P V

1998-10-01

Opioid peptides, through mu and delta receptors, play an important part in reward. In contrast, the role of kappa receptors is more controversial. We examined the possible positive reinforcing effects of a selective kappa agonist, RU 51599, by studying intravenous self-administration in the rat. The effect of RU 51599 on dopamine release in the nucleus accumbens was also studied, as opioids and dopamine seem to interact in the mediation of reward. The behavioural and dopaminergic effects of RU 51599 were compared with those of the mu agonist heroin. Rats self-administered both RU 51599 (6.5, 20 and 60 microg/inj) and heroin (30 microg/inj) at low ratio requirement. When the ratio requirement, i.e. the number of responses necessary to receive one drug infusion, was increased, self-administration of RU 51599 rapidly extinguished, whereas self-administration of heroin was maintained. Intravenous infusion of RU 51599 (100, 200 and 400 microg) dose-dependently decreased (25, 30 and 40%, respectively) extracellular concentrations of dopamine, as measured by means of microdialysis in freely moving rats. In contrast, heroin increased accumbens dopamine (130% over baseline). These results indicate that kappa receptors, similarly to mu ones, can mediate positive reinforcing effects of opioid peptides. However, the strength of the reinforcement is very low for kappa receptors. This suggests that changes in accumbens dopamine do not correlate with the capacity of a stimulus to induce reward or aversion. In contrast, a parallel seems to exist between an increase in accumbens dopamine and the drive to reach or obtain a positive reinforcer.

Effect of dopamine agonist withdrawal after long-term therapy in prolactinomas. Studies with high-definition computerised tomography.

PubMed

Johnston, D G; Hall, K; Kendall-Taylor, P; Patrick, D; Watson, M; Cook, D B

1984-07-28

The clinical, radiological, and biochemical effects of dopamine agonist withdrawal after long-term treatment were investigated in seven women and eight men who had been treated for prolactinomas for 1.5 to 7 (mean 3.7) years. Before treatment, serum prolactin concentrations were 1473 to 115 000 mU/l, all patients had abnormal radiological findings, and six had suprasellar extensions of pituitary tumours. Treatment with either bromocriptine or pergolide relieved symptoms and suppressed prolactin secretion in most patients. The size of the residual tumour was defined by doing fourth generation computerised tomographic scans immediately before termination of therapy, and evidence of tumour re-expansion was sought on scans repeated 5-39 weeks later. After discontinuation of treatment, symptoms recurred in 13 of 15 patients and hyper-prolactinaemia redeveloped in 14. Other pituitary function tests remained unchanged or improved. In 13 of 15 patients tumour or gland size did not change after withdrawal of treatment. One man had a marginal increase in tumour size, while in another the pituitary tumour shrank. Thus, although cessation of long-term dopamine agonist therapy leads to recurrence of symptoms and hyperprolactinaemia, rapid tumour regrowth is uncommon and of small extent, and other pituitary function is not altered in the short term.

Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors.

PubMed

Prokop, Susanne; Perry, Nicole A; Vishnivetskiy, Sergey A; Toth, Andras D; Inoue, Asuka; Milligan, Graeme; Iverson, Tina M; Hunyady, Laszlo; Gurevich, Vsevolod V

2017-08-01

Non-visual arrestins interact with hundreds of different G protein-coupled receptors (GPCRs). Here we show that by introducing mutations into elements that directly bind receptors, the specificity of arrestin-3 can be altered. Several mutations in the two parts of the central "crest" of the arrestin molecule, middle-loop and C-loop, enhanced or reduced arrestin-3 interactions with several GPCRs in receptor subtype and functional state-specific manner. For example, the Lys139Ile substitution in the middle-loop dramatically enhanced the binding to inactive M 2 muscarinic receptor, so that agonist activation of the M 2 did not further increase arrestin-3 binding. Thus, the Lys139Ile mutation made arrestin-3 essentially an activation-independent binding partner of M 2 , whereas its interactions with other receptors, including the β 2 -adrenergic receptor and the D 1 and D 2 dopamine receptors, retained normal activation dependence. In contrast, the Ala248Val mutation enhanced agonist-induced arrestin-3 binding to the β 2 -adrenergic and D 2 dopamine receptors, while reducing its interaction with the D 1 dopamine receptor. These mutations represent the first example of altering arrestin specificity via enhancement of the arrestin-receptor interactions rather than selective reduction of the binding to certain subtypes. Copyright © 2017. Published by Elsevier Inc.

The Risky Business of Dopamine Agonists in Parkinson Disease and Impulse Control Disorders

PubMed Central

Claassen, Daniel O.; van den Wildenberg, Wery P.M.; Ridderinkhof, K. Richard; Jessup, Charles K.; Harrison, Madaline B.; Wooten, G. Frederick; Wylie, Scott A.

2011-01-01

Risk-taking behavior is characterized by pursuit of reward in spite of potential negative consequences. Dopamine neurotransmission along the mesocorticolimbic pathway is a potential modulator of risk behavior. In patients with Parkinson's Disease (PD), impulse control disorder (ICD) can result from dopaminergic medication use, particularly Dopamine Agonists (DAA). Behaviors associated with ICD include hypersexuality as well as compulsive gambling, shopping, and eating, and are potentially linked to alterations to risk processing. Using the Balloon Analogue Risk task, we assessed the role of agonist therapy on risk-taking behavior in PD patients with (n=22) and without (n=19) active ICD symptoms. Patients performed the task both ‘on’ and ‘off’ DAA. DAA increased risk-taking in PD patients with active ICD symptoms, but did not affect risk behavior of PD controls. DAA dose was also important in explaining risk behavior. Both groups similarly reduced their risk-taking in high compared to low risk conditions and following the occurrence of a negative consequence, suggesting that ICD patients do not necessarily differ in their ability to process and adjust to some aspects of negative consequences. Our findings suggest dopaminergic augmentation of risk-taking behavior as a potential contributing mechanism for the emergence of ICD in PD patients. PMID:21604834

Effect of dopamine-related drugs on duodenal ulcer induced by cysteamine or propionitrile: prevention and aggravation may not be mediated by gastrointestinal secretory changes in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gallagher, G.; Brown, A.; Szabo, S.

1987-03-01

Dose- and time-response studies have been performed with dopamine agonists and antagonists using the cysteamine and propionitrile duodenal ulcer models in the rat. The experiments demonstrate that the chemically induced duodenal ulcer is prevented by bromocriptine, lergotrile and reduced by apomorphine or L-dopa. Aggravation of cysteamine-induced duodenal ulcer was seen especially after (-)-butaclamol, (-)-sulpiride, haloperidol and, less effectively, after other dopaminergic antagonists. The duodenal antiulcerogenic action of dopamine agonists was more prominent after chronic administration than after a single dose, whereas the opposite was found concerning the proulcerogenic effect of dopamine antagonists. In the chronic gastric fistula rat, both themore » antiulcerogens bromocriptine or lergotrile and the proulcerogens haloperidol, pimozide or (-)-N-(2-chlorethyl)-norapomorphine decreased the cysteamine- or propionitrile-induced gastric secretion. No correlation was apparent between the influence of these drugs on duodenal ulcer development and gastric and duodenal (pancreatic/biliary) secretions. In the chronic duodenal fistula rat, decreased acid content was measured in the proximal duodenum after haloperidol, and diminished duodenal pepsin exposure was recorded after bromocriptine. Furthermore, the aggravation by dopamine antagonists of experimental duodenal ulcer probably involves a peripheral component. The site of dopamine receptors and physiologic effects which modulate experimental duodenal ulcer remain to be identified, but their elucidation may prove to be an important element in the pathogenesis and treatment of duodenal ulcer.« less

Dopamine and dopamine receptor D1 associated with decreased social interaction.

PubMed

Liu, Qiang; Shi, Jieyun; Lin, Rongfei; Wen, Tieqiao

2017-05-01

Deficits in social interaction are hallmarks of neurological and psychiatric disorders. However, its underlying mechanism is still unclear. Here, we show that the loss of dendritic cell factor 1 (Dcf1) in the nervous system of mice induces social interaction deficiency, autism-like behaviour, and influences social interaction via the dopamine system. Dopamine receptor D1 agonist rescues this social cognition phenotype, and improves short-term plasticity. Together, this study presents a new genetic mechanism that affects social interaction and may provide a new way to improve positive social interaction and treat autism spectrum disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

Hyperactivity induced by stimulation of separate dopamine D-1 and D-2 receptors in rats with bilateral 6-OHDA lesions.

PubMed

Arnt, J

1985-08-26

The effects of DA agonists and antagonists with different dopamine (DA) D-1 and D-2 receptor selectivity have been studied in rats with bilateral 6-OHDA lesions. The D-1 agonist SK & F 38393, the D-2 agonist pergolide and the mixed agonist apomorphine all induced marked hyperactivity in lesioned rats in doses which were without stimulant effect in sham-operated animals. The hyperactivity induced by SK & F 38393 was blocked by the DA D-1 antagonist SCH 23390, but unaffected by the D-2 antagonists spiroperidol or clebopride. Pergolide-induced hyperactivity showed the reverse selectivity. The mixed D-1/D-2 antagonists, cis(Z)-flupentixol and cis(Z)-clopenthixol, however blocked the effect of both agonists. Apomorphine-induced hyperactivity was neither blocked by selective D-1 nor D-2 antagonists, but was dose-dependently inhibited by cis(Z)-flupentixol and cis(Z)-clopenthixol. Potent blockade was also obtained by combined treatment with SCH 23390 and spiroperidol, indicating the need of blocking both D-1 and D-2 receptors simultaneously. The results indicate that D-1 and D-2 receptor function can be independently manipulated in denervated rats and they confirm similar results obtained in rats with unilateral 6-OHDA lesions using circling behaviour.

Synergy between growth factors and transmitters required for catecholamine differentiation in brain neurons.

PubMed

Du, X; Iacovitti, L

1995-07-01

The phenotypically plastic neurons of the embryonic mouse striatum were used to explore mechanisms of catecholamine differentiation in culture. De novo transcription and translation of the CA biosynthetic enzyme, tyrosine hydroxylase (TH), was induced in striatal neurons exposed, simultaneously or sequentially, to the growth factor, acidic fibroblast growth factor (aFGF) and a catecholamine. Although dopamine was the most potent aFGF partner (ED50 = 4 microM), a number of substances, including dopamine (D1) receptor agonists, beta-adrenoceptor agonists, and dopamine uptake inhibitors also trigger TH induction when accompanied by aFGF. However, since none of the receptor antagonists nor transport blockers tested could inhibit dopamine's action, the mechanism remains obscure. Structure-activity analysis suggests that effective aFGF partners all contain an amine group separated from a catechol nucleus by two carbons. Thus, TH expression can be novelly induced by the synergistic interaction of aFGF, and to a lesser extent basic FGF, and a variety of CA-containing partner molecules. We speculate that a similar association between growth factor and transmitter may be required in development for the differentiation of a CA phenotype in brain neurons.

Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia.

PubMed

Arnsten, Amy F T; Girgis, Ragy R; Gray, David L; Mailman, Richard B

2017-01-01

Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D 1 receptors (D 1 R). It has been appreciated for decades that optimal levels of dopamine are essential for dlPFC working memory function, with many beneficial actions arising from D 1 R stimulation. D 1 R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted-U dose response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D 1 agonists, e.g., the first full D 1 agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data, however, have spurred efforts toward the discovery and development of improved or novel new compounds, including D 1 agonists with better pharmacokinetics, functionally selective D 1 ligands, and D 1 R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D 1 R stimulation in the dlPFC that can be translated into clinical practice. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Mapping anhedonia onto reinforcement learning: a behavioural meta-analysis

PubMed Central

2013-01-01

Background Depression is characterised partly by blunted reactions to reward. However, tasks probing this deficiency have not distinguished insensitivity to reward from insensitivity to the prediction errors for reward that determine learning and are putatively reported by the phasic activity of dopamine neurons. We attempted to disentangle these factors with respect to anhedonia in the context of stress, Major Depressive Disorder (MDD), Bipolar Disorder (BPD) and a dopaminergic challenge. Methods Six behavioural datasets involving 392 experimental sessions were subjected to a model-based, Bayesian meta-analysis. Participants across all six studies performed a probabilistic reward task that used an asymmetric reinforcement schedule to assess reward learning. Healthy controls were tested under baseline conditions, stress or after receiving the dopamine D2 agonist pramipexole. In addition, participants with current or past MDD or BPD were evaluated. Reinforcement learning models isolated the contributions of variation in reward sensitivity and learning rate. Results MDD and anhedonia reduced reward sensitivity more than they affected the learning rate, while a low dose of the dopamine D2 agonist pramipexole showed the opposite pattern. Stress led to a pattern consistent with a mixed effect on reward sensitivity and learning rate. Conclusion Reward-related learning reflected at least two partially separable contributions. The first related to phasic prediction error signalling, and was preferentially modulated by a low dose of the dopamine agonist pramipexole. The second related directly to reward sensitivity, and was preferentially reduced in MDD and anhedonia. Stress altered both components. Collectively, these findings highlight the contribution of model-based reinforcement learning meta-analysis for dissecting anhedonic behavior. PMID:23782813

Aripiprazole, an Antipsychotic and Partial Dopamine Agonist, Inhibits Cancer Stem Cells and Reverses Chemoresistance.

PubMed

Suzuki, Shuhei; Okada, Masashi; Kuramoto, Kenta; Takeda, Hiroyuki; Sakaki, Hirotsugu; Watarai, Hikaru; Sanomachi, Tomomi; Seino, Shizuka; Yoshioka, Takashi; Kitanaka, Chifumi

2016-10-01

There is a growing interest in repurposing antipsychotic dopamine antagonists for cancer treatment; however, antipsychotics are often associated with an increased risk of fatal events. The anticancer activities of aripiprazole, an antipsychotic drug with partial dopamine agonist activity and an excellent safety profile, remain unknown. The effects of aripiprazole alone or in combination with chemotherapeutic agents on the growth, sphere-forming ability and stem cell/differentiation/chemoresistance marker expression of cancer stem cells, serum-cultured cancer cells from which they were derived, and normal cells were examined. At concentrations non-toxic to normal cells, aripiprazole inhibited the growth of serum-cultured cancer cells and cancer stem cells. Furthermore, aripiprazole induced differentiation and inhibited sphere formation, as well as stem cell marker expression of cancer stem cells while inhibiting their survivin expression and sensitizing them to chemotherapeutic agents. Repurposing aripiprazole as an anticancer stem cell drug may merit further consideration. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

The dopamine D1 receptor is expressed and facilitates relaxation in airway smooth muscle.

PubMed

Mizuta, Kentaro; Zhang, Yi; Xu, Dingbang; Mizuta, Fumiko; D'Ovidio, Frank; Masaki, Eiji; Emala, Charles W

2013-09-02

Dopamine signaling is mediated by Gs protein-coupled "D1-like" receptors (D1 and D5) and Gi-coupled "D2-like" receptors (D2-4). In asthmatic patients, inhaled dopamine induces bronchodilation. Although the Gi-coupled dopamine D2 receptor is expressed and sensitizes adenylyl cyclase activity in airway smooth muscle (ASM) cells, the Gs-coupled dopamine D1-like receptor subtypes have never been identified on these cells. Activation of Gs-coupled receptors stimulates cyclic AMP (cAMP) production through the stimulation of adenylyl cyclase, which promotes ASM relaxation. We questioned whether the dopamine D1-like receptor is expressed on ASM, and modulates its function through Gs-coupling. The mRNA and protein expression of dopamine D1-like receptor subtypes in both native human and guinea pig ASM tissue and cultured human ASM (HASM) cells was measured. To characterize the stimulation of cAMP through the dopamine D1 receptor, HASM cells were treated with dopamine or the dopamine D1-like receptor agonists (A68930 or SKF38393) before cAMP measurements. To evaluate whether the activation of dopamine D1 receptor induces ASM relaxation, guinea pig tracheal rings suspended under isometric tension in organ baths were treated with cumulatively increasing concentrations of dopamine or A68930, following an acetylcholine-induced contraction with or without the cAMP-dependent protein kinase (PKA) inhibitor Rp-cAMPS, the large-conductance calcium-activated potassium (BKCa) channel blocker iberiotoxin, or the exchange proteins directly activated by cAMP (Epac) antagonist NSC45576. Messenger RNA encoding the dopamine D1 and D5 receptors were detected in native human ASM tissue and cultured HASM cells. Immunoblots confirmed the protein expression of the dopamine D1 receptor in both native human and guinea pig ASM tissue and cultured HASM cells. The dopamine D1 receptor was also immunohistochemically localized to both human and guinea pig ASM. The dopamine D1-like receptor agonists stimulated cAMP production in HASM cells, which was reversed by the selective dopamine D1-like receptor antagonists SCH23390 or SCH39166. A68930 relaxed acetylcholine-contracted guinea pig tracheal rings, which was attenuated by Rp-cAMPS but not by iberiotoxin or NSC45576. These results demonstrate that the dopamine D1 receptors are expressed on ASM and regulate smooth muscle force via cAMP activation of PKA, and offer a novel target for therapeutic relaxation of ASM.

The dopamine D1 receptor is expressed and facilitates relaxation in airway smooth muscle

PubMed Central

2013-01-01

Background Dopamine signaling is mediated by Gs protein-coupled “D1-like” receptors (D1 and D5) and Gi-coupled “D2-like” receptors (D2-4). In asthmatic patients, inhaled dopamine induces bronchodilation. Although the Gi-coupled dopamine D2 receptor is expressed and sensitizes adenylyl cyclase activity in airway smooth muscle (ASM) cells, the Gs-coupled dopamine D1-like receptor subtypes have never been identified on these cells. Activation of Gs-coupled receptors stimulates cyclic AMP (cAMP) production through the stimulation of adenylyl cyclase, which promotes ASM relaxation. We questioned whether the dopamine D1-like receptor is expressed on ASM, and modulates its function through Gs-coupling. Methods The mRNA and protein expression of dopamine D1-like receptor subtypes in both native human and guinea pig ASM tissue and cultured human ASM (HASM) cells was measured. To characterize the stimulation of cAMP through the dopamine D1 receptor, HASM cells were treated with dopamine or the dopamine D1-like receptor agonists (A68930 or SKF38393) before cAMP measurements. To evaluate whether the activation of dopamine D1 receptor induces ASM relaxation, guinea pig tracheal rings suspended under isometric tension in organ baths were treated with cumulatively increasing concentrations of dopamine or A68930, following an acetylcholine-induced contraction with or without the cAMP-dependent protein kinase (PKA) inhibitor Rp-cAMPS, the large-conductance calcium-activated potassium (BKCa) channel blocker iberiotoxin, or the exchange proteins directly activated by cAMP (Epac) antagonist NSC45576. Results Messenger RNA encoding the dopamine D1 and D5 receptors were detected in native human ASM tissue and cultured HASM cells. Immunoblots confirmed the protein expression of the dopamine D1 receptor in both native human and guinea pig ASM tissue and cultured HASM cells. The dopamine D1 receptor was also immunohistochemically localized to both human and guinea pig ASM. The dopamine D1-like receptor agonists stimulated cAMP production in HASM cells, which was reversed by the selective dopamine D1-like receptor antagonists SCH23390 or SCH39166. A68930 relaxed acetylcholine-contracted guinea pig tracheal rings, which was attenuated by Rp-cAMPS but not by iberiotoxin or NSC45576. Conclusions These results demonstrate that the dopamine D1 receptors are expressed on ASM and regulate smooth muscle force via cAMP activation of PKA, and offer a novel target for therapeutic relaxation of ASM. PMID:24004608

Pharmacogenetics and Pharmacotherapy of Military Personnel Suffering from Post-traumatic Stress Disorder

PubMed Central

Naß, Janine; Efferth, Thomas

2017-01-01

Background: Posttraumatic stress disorder (PTSD) is a severe problem among soldiers with combating experience difficult to treat. The pathogenesis is still not fully understood at the psychological level. Therefore, genetic research became a focus of interest. The identification of single nucleotide polymorphisms (SNPs) may help to predict, which persons are at high risk to develop PTSD as a starting point to develop novel targeted drugs for treatment. Methods: We conducted a systematic review on SNPs in genes related to PTSD pathology and development of targeted pharmacological treatment options based on PubMed database searches. We focused on clinical trials with military personnel. Results: SNPs in 22 human genes have been linked to PTSD. These genes encode proteins acting as neurotransmitters and receptors, downstream signal transducers and metabolizing enzymes. Pharmacological inhibitors may serve as drug candidates for PTSD treatment, e.g. β2 adrenoreceptor antagonists, dopamine antagonists, partial dopamine D2 receptor agonists, dopamine β hydroxylase inhibitors, fatty acid amid hydrolase antagonists, glucocorticoid receptor agonists, tropomyosin receptor kinase B agonists, selective serotonin reuptake inhibitors, catechol-O-methyltransferase inhibitors, gamma-amino butyric acid receptor agonists, glutamate receptor inhibitors, monoaminoxidase B inhibitors, N-methyl-d-aspartate receptor antagonists. Conclusion: The combination of genetic and pharmacological research may lead to novel target-based drug developments with improved specificity and efficacy to treat PTSD. Specific SNPs may be identified as reliable biomarkers to assess individual disease risk. Focusing on soldiers suffering from PTSD will not only help to improve treatment options for this specific group, but for all PTSD patients and the general population. PMID:27834145

Rotigotine Transdermal Patch Improves Swallowing in Dysphagic Patients with Parkinson's Disease.

PubMed

Hirano, Makito; Isono, Chiharu; Sakamoto, Hikaru; Ueno, Shuichi; Kusunoki, Susumu; Nakamura, Yusaku

2015-08-01

Abnormal swallowing, dysphagia, is a potentially fatal symptom in Parkinson's disease (PD) and is characterized by frequent silent aspiration, an unrecognized risk of suffocation and aspiration pneumonia. Several studies have reported that the injection of apomorphine, a dopamine agonist, alleviated dysphagia in some patients with PD. The effects of other antiparkinson medications against dysphagia remain controversial. Rotigotine is another dopamine agonist with non-oral administration, i.e., a transdermal patch. Its noninvasiveness seems to render this medicine even more suitable than apomorphine for dysphasic patients. However, no direct evidence has been reported. In the present retrospective open-label study, we for the first time objectively showed that rotigotine improved swallowing on videofluoroscopic examination in dysphagic patients with PD.

Convergent Pathways for Steroid Hormone-and Neurotransmitter-Induced Rat Sexual Behavior

NASA Astrophysics Data System (ADS)

Mani, S. K.; Allen, J. M. C.; Clark, J. H.; Blaustein, J. D.; O'Malley, B. W.

1994-08-01

Estrogen and progesterone modulate gene expression in rodents by activation of intracellular receptors in the hypothalamus, which regulate neuronal networks that control female sexual behavior. However, the neurotransmitter dopamine has been shown to activate certain steroid receptors in a ligand-independent manner. A dopamine receptor stimulant and a D_1 receptor agonist, but not a D_2 receptor agonist, mimicked the effects of progesterone in facilitating sexual behavior in female rats. The facilitatory effect of the neurotransmitter was blocked by progesterone receptor antagonists, a D_1 receptor antagonist, or antisense oligonucleotides to the progesterone receptor. The results suggest that in rodents neurotransmitters may regulate in vivo gene expression and behavior by means of cross-talk with steroid receptors in the brain.

Mechanisms of Kappa Opioid Receptor Potentiation of Dopamine D2 Receptor Function in Quinpirole-Induced Locomotor Sensitization in Rats.

PubMed

Escobar, Angélica P; González, Marcela P; Meza, Rodrigo C; Noches, Verónica; Henny, Pablo; Gysling, Katia; España, Rodrigo A; Fuentealba, José A; Andrés, María E

2017-08-01

Increased locomotor activity in response to the same stimulus is an index of behavioral sensitization observed in preclinical models of drug addiction and compulsive behaviors. Repeated administration of quinpirole, a D2/D3 dopamine agonist, induces locomotor sensitization. This effect is potentiated and accelerated by co-administration of U69593, a kappa opioid receptor agonist. The mechanism underlying kappa opioid receptor potentiation of quinpirole-induced locomotor sensitization remains to be elucidated. Immunofluorescence anatomical studies were undertaken in mice brain slices and rat presynaptic synaptosomes to reveal kappa opioid receptor and D2R pre- and postsynaptic colocalization in the nucleus accumbens. Tonic and phasic dopamine release in the nucleus accumbens of rats repeatedly treated with U69593 and quinpirole was assessed by microdialysis and fast scan cyclic voltammetry. Anatomical data show that kappa opioid receptor and D2R colocalize postsynaptically in medium spiny neurons of the nucleus accumbens and the highest presynaptic colocalization occurs on the same dopamine terminals. Significantly reduced dopamine levels were observed in quinpirole, and U69593-quinpirole treated rats, explaining sensitization of D2R. Presynaptic inhibition induced by kappa opioid receptor and D2R of electrically evoked dopamine release was faster in U69593-quinpirole compared with quinpirole-repeatedly treated rats. Pre- and postsynaptic colocalization of kappa opioid receptor and D2R supports a role for kappa opioid receptor potentiating both the D2R inhibitory autoreceptor function and the inhibitory action of D2R on efferent medium spiny neurons. Kappa opioid receptor co-activation accelerates D2R sensitization by contributing to decrease dopamine release in the nucleus accumbens. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Identification of the dopamine autoreceptor in the guinea-pig retina as D2 receptor using novel subtype-selective antagonists

PubMed Central

Weber, Bernd; Schlicker, Eberhard; Sokoloff, Pierre; Stark, Holger

2001-01-01

Dopamine release in the retina is subject to modulation via autoreceptors, which belong to the D2 receptor family (encompassing the D2, D3 and D4 receptors). The aim of the present study was to determine the receptor subtype (D2 vs D3) involved in the inhibition of dopamine release in guinea-pig retinal discs, using established (haloperidol, (S)-nafadotride) and novel dopamine receptor antagonists (ST-148, ST-198). hD2L and hD3 receptors were expressed in CHO cells and the pKi values determined in binding studies with [125I]-iodosulpride were: haloperidol 9.22 vs 8.54; ST-148 7.85 vs 6.60; (S)-nafadotride 8.52 vs 9.51; ST-198 6.14 vs 7.92. The electrically evoked tritium overflow from retinal discs preincubated with [3H]-noradrenaline (which represents quasi-physiological dopamine release) was inhibited by the dopamine receptor agonists B-HT 920 (talipexole) and quinpirole (maximally by 82 and 71%; pEC50 5.80 and 5.83). The concentration-response curves of these agonists were shifted to the right by haloperidol (apparent pA2 8.69 and 8.23) and ST-148 (7.52 and 7.66). (S)-Nafadotride 0.01 μM and ST-198 0.32 μM did not affect the concentration-response curve of B-HT 920. The dopamine autoreceptor in the guinea-pig retina can be classified as a D2 receptor. ST-148 and ST-198 show an improved selectivity for D2 and D3 receptors when compared to haloperidol and (S)-nafadotride, respectively. PMID:11498509

Memory Enhancement Induced by Post-Training Intrabasolateral Amygdala Infusions of [beta]-Adrenergic or Muscarinic Agonists Requires Activation of Dopamine Receptors: Involvement of Right, but Not Left, Basolateral Amygdala

ERIC Educational Resources Information Center

LaLumiere, Ryan T.; McGaugh, James L.

2005-01-01

Previous findings indicate that the noradrenergic, dopaminergic, and cholinergic innervations of the basolateral amygdala (BLA) modulate memory consolidation. The current study investigated whether memory enhancement induced by post-training intra-BLA infusions of a [beta]-adrenergic or muscarinic cholinergic agonist requires concurrent activation…

The Metabotropic Glutamate 2/3 Receptor Agonist LY379268 Blocked Nicotine-Induced Increases in Nucleus Accumbens Shell Dopamine only in the Presence of a Nicotine-Associated Context in Rats

PubMed Central

D'Souza, Manoranjan S; Liechti, Matthias E; Ramirez-Niño, Ana M; Kuczenski, Ronald; Markou, Athina

2011-01-01

The metabotropic glutamate 2/3 (mGlu2/3) receptor agonist LY379268 ([−]-2-oxa-4-aminobicyclo [3.1.0] hexane-4,6-dicarboxylate) attenuates both nicotine self-administration and cue-induced nicotine seeking in rats. In this study, the effects of LY379268 (1 mg/kg) or saline pretreatment on nicotine-induced increases in nucleus accumbens (NAcc) shell dopamine were evaluated using in vivo microdialysis under different experimental conditions: (i) nicotine (0.4 mg/kg, base) was experimenter-administered subcutaneously to nicotine-naïve rats; (ii) nicotine was experimenter-administered either subcutaneously (0.4 mg/kg) or by a single experimenter-administered infusion (0.06 mg/kg, base) in rats with a history of nicotine self-administration (nicotine experienced) in the absence of a nicotine-associated context (ie, context and cues associated with nicotine self-administration); (iii) nicotine (0.06 mg/kg) was self-administered or experimenter-administered in nicotine-experienced rats in the presence of a nicotine-associated context. In saline-pretreated nicotine-naïve and nicotine-experienced rats, nicotine increased NAcc shell dopamine regardless of the context used for testing. Interestingly, LY379268 pretreatment blocked nicotine-induced increases in NAcc shell dopamine in nicotine-experienced rats only when tested in the presence of a nicotine-associated context. LY379268 did not block nicotine-induced increases in NAcc shell dopamine in nicotine-naïve or -experienced rats tested in the absence of a nicotine-associated context. These intriguing findings suggest that activation of mGlu2/3 receptors negatively modulates the combined effects of nicotine and nicotine-associated contexts/cues on NAcc dopamine. Thus, these data highlight a critical role for mGlu2/3 receptors in context/cue-induced drug-seeking behavior and suggest a neurochemical mechanism by which mGlu2/3 receptor agonists may promote smoking cessation by preventing relapse induced by the combination of nicotine and nicotine-associated contexts and cues. PMID:21654734

Human Laboratory Studies on Cannabinoids and Psychosis.

PubMed

Sherif, Mohamed; Radhakrishnan, Rajiv; D'Souza, Deepak Cyril; Ranganathan, Mohini

2016-04-01

Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any "beneficial" effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids. Copyright © 2016. Published by Elsevier Inc.

Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients.

PubMed

Weintraub, Daniel; Koester, Juergen; Potenza, Marc N; Siderowf, Andrew D; Stacy, Mark; Voon, Valerie; Whetteckey, Jacqueline; Wunderlich, Glen R; Lang, Anthony E

2010-05-01

An association between dopamine-replacement therapies and impulse control disorders (ICDs) in Parkinson disease (PD) has been suggested in preliminary studies. To ascertain point prevalence estimates of 4 ICDs in PD and examine their associations with dopamine-replacement therapies and other clinical characteristics. Cross-sectional study using an a priori established sampling procedure for subject recruitment and raters blinded to PD medication status. Three thousand ninety patients with treated idiopathic PD receiving routine clinical care at 46 movement disorder centers in the United States and Canada. The Massachusetts Gambling Screen score for current problem/pathological gambling, the Minnesota Impulsive Disorders Interview score for compulsive sexual behavior and buying, and Diagnostic and Statistical Manual of Mental Disorders research criteria for binge-eating disorder. An ICD was identified in 13.6% of patients (gambling in 5.0%, compulsive sexual behavior in 3.5%, compulsive buying in 5.7%, and binge-eating disorder in 4.3%), and 3.9% had 2 or more ICDs. Impulse control disorders were more common in patients treated with a dopamine agonist than in patients not taking a dopamine agonist (17.1% vs 6.9%; odds ratio [OR], 2.72; 95% confidence interval [CI], 2.08-3.54; P < .001). Impulse control disorder frequency was similar for pramipexole and ropinirole (17.7% vs 15.5%; OR, 1.22; 95% CI, 0.94-1.57; P = .14). Additional variables independently associated with ICDs were levodopa use, living in the United States, younger age, being unmarried, current cigarette smoking, and a family history of gambling problems. Dopamine agonist treatment in PD is associated with 2- to 3.5-fold increased odds of having an ICD. This association represents a drug class relationship across ICDs. The association of other demographic and clinical variables with ICDs suggests a complex relationship that requires additional investigation to optimize prevention and treatment strategies. clinicaltrials.gov Identifier: NCT00617019.

Dopamine D1 and D3 Receptors Modulate Heroin-Induced Cognitive Impairment through Opponent Actions in Mice.

PubMed

Zhu, Yongsheng; Wang, Yunpeng; Lai, Jianghua; Wei, Shuguang; Zhang, Hongbo; Yan, Peng; Li, Yunxiao; Qiao, Xiaomeng; Yin, Fangyuan

2017-03-01

Chronic abuse of heroin leads to long-lasting and complicated cognitive impairment. Dopamine receptors are critically involved in the impulsive drug-driven behavior and the altered attention, processing speed, and mental flexibility that are associated with higher relapse rates. However, the effects of the different dopamine receptors and their possible involvement in heroin-induced cognitive impairment remain unclear. The 5-choice serial reaction time task was used to investigate the profiles of heroin-induced cognitive impairment in mice. The expression levels of dopamine D1- and D2-like receptors in the prefrontal cortex, nucleus accumbens, and caudate-putamen were determined. The effects of dopamine receptors on heroin-induced impulsivity in the 5-choice serial reaction time task were examined by agonist/antagonist treatment on D1 or D3 receptor mutant mice. Systemic heroin administration influences several variables in the 5-choice serial reaction time task, most notably premature responses, a measure of motor impulsivity. These behavioral impairments are associated with increased D1 receptor and decreased D3 receptor mRNA and protein levels in 3 observed brain areas. The heroin-evoked increase in premature responses is mimicked by a D1 agonist and prevented by a D1 antagonist or genetic ablation of the D1 receptor gene. In contrast, a D3 agonist decreases both basal and heroin-evoked premature responses, while genetic ablation of the D3 receptor gene results in increased basal and heroin-evoked premature responses. Heroin-induced impulsive behavior in the 5-choice serial reaction time task is oppositely modulated by D1 and D3 receptor activation. The D1 receptors in the cortical-mesolimbic region play an indispensable role in modulating such behaviors. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Effect of "enriched environment" during development on adult rat behavior and response to the dopamine receptor agonist apomorphine.

PubMed

Hoffmann, L C; Schütte, S R M; Koch, M; Schwabe, K

2009-02-18

Enriched housing conditions (enriched environment, EE) during development has been shown to influence adult rat behavior and transmitter systems, especially dopamine function. We were interested in how different degrees of enrichment during development would affect adult rats' behavior and response to dopamine receptor challenge. Two groups of male Wistar rats (n=11-12) were raised under two different degrees of EE, i.e. "high enriched" and "low enriched" groups. A third group was kept under standard conditions and served as "non-enriched" control. As adults, rats were tested for anxiety (elevated plus-maze), for spatial learning (four-arm-baited eight-arm radial maze), and for motivation (breakpoint of the progressive ratio test). Finally, locomotor activity (activity box) and sensorimotor gating (prepulse inhibition (PPI) of the acoustic startle response (ASR)) were tested with and without challenge with the dopamine receptor agonist apomorphine. The time spent on the open or enclosed arms of the elevated plus-maze did not differ between groups, but the high enriched group showed higher rearing activity on the open arms. The breakpoint did not differ between groups. Learning and memory in the radial maze task only differed on the first few trials, but high enriched rats run faster compared with the other groups. In contrast, in the activity box enriched groups were less active, but apomorphine had the highest effect. Between groups, no difference in PPI and startle amplitude was found, but in the high and low EE group startle amplitude was enhanced after administration of apomorphine, while the PPI deficit induced by this drug was not different between groups. Altogether, we found no evidence that different amounts of environmental enrichment without differences in social EE affect rats' cognitive, emotional or motivational behavior. However, motor activity seems to be enhanced when rats are behaviorally or pharmacologically challenged by dopamine receptor agonists.

Development of uncoupling between D1- and D2-mediated motor behavior in rats depleted of dopamine as neonates.

PubMed

Byrnes, E M; Bruno, J P

1994-09-01

The D1- and D2-mediation of stimulated motor behavior was studied in pups (Days 10-11) and weanlings (Days 20-21) that had been depleted of dopamine (DA) on postnatal Day 3. Administration of the D1-like agonist SKF 38393 (30.0 mg/kg) or the D2-like agonist quinpirole (3.0 mg/kg) increased the incidence of sniffing and locomotion in intact and DA-depleted animals tested at either age. However, the ability of selective DA antagonists to reduce these stimulated responses interacted with both the depletion and the age at the time of testing. When tested as pups, both the D1 antagonist SCH 23390 (0.2 or 0.4 mg/kg) and the D2 antagonist clebopride (10.0 mg/kg) suppressed the behaviors induced by either class of DA agonist. When tested as weanlings, intact animals exhibited the profile of pups (i.e., either antagonist blocked each agonist). In DA-depleted weanlings, however, only the D1 antagonist blocked the D1 agonist-induced responses and only the D2 antagonist blocked the D2 agonist-induced responses. These data demonstrate that the interactions between D1 and D2 receptors in the expression of stimulated motor behaviors are altered following DA depletions in neonates. Moreover, this change in receptor function occurs sometime between 7 and 13 days after the DA depletion.

Dopaminergic control of food choice: contrasting effects of SKF 38393 and quinpirole on high-palatability food preference in the rat.

PubMed

Cooper, S J; Al-Naser, H A

2006-06-01

The aim of the present study was to determine the behavioural effects of the selective dopamine D1 receptor agonist, SKF 38393, and of the selective dopamine D2/D3 receptor agonist, quinpirole, on the feeding performance of food-deprived rats in a model of food-preference behaviour. The animals were familiarised with a choice between a high-palatability, high-fat, high-sugar food (chocolate biscuits/cookies) and their regular maintenance diet. Following administration of either SKF 38393 (1.0-10.0 mg/kg, s.c.) or quinpirole (0.03-0.3 mg/kg, s.c.), the animals were observed throughout a 15-min test period, and their feeding behaviour was carefully monitored. Other behavioural categories were also observed. The resulting data were subject to a microstructural analysis to determine the loci of the behavioural effects. The results indicated that SKF 38393 and quinpirole had contrasting effects on the preference for the high-palatability chocolate food. SKF 38393 enhanced the preference, whereas quinpirole eliminated it. These data reinforce the view that forebrain dopamine mechanisms are closely involved in responses to high-palatability energy-dense food constituents, including chocolate. The data also indicate that pharmacological characterization is important, such that dopamine receptor subtypes appear to mediate contrasting effects on food preference for a high-fat, high-sugar food. Hence, brain dopamine appears to be involved in potentially complex ways in determining food preferences, and this may carry implications in the growing evidence for a link between brain dopamine and human obesity.

[Drug treatment of early-stage (de novo and "honeymoon") Parkinson disease].

PubMed

Cesaro, P; Defebvre, L

2014-04-01

In this article, we discuss the management of motor symptoms during the early phases of Parkinson's disease, excluding that of any other clinical manifestation. We relied primarily upon recently published data and do not describe older publications relating to anticholinergic drugs or amantadine. The initial pharmacological treatment of idiopathic Parkinson's disease (IPD) is symptomatic and remains based upon dopaminergic drugs. However, the development of new drugs has broadened the range of strategic options and improved overall patient management. Announcing the diagnosis is a critical moment, as pointed out by patients' associations. Patients should be advised to maintain personal, professional, social and physical activities as long as possible. The potential benefit of early pharmacological treatment should be explained, focusing on the possible disease-modifying effect of drugs such as rasagiline. According to current guidelines, L-Dopa is preferred in patients above 65years of age, while those below 65 should be treated with dopamine agonists. Like monoamine oxidase inhibitors B (MAOI-B), synthetic dopamine agonists exhibit several advantages: easy-to-use treatment with a once-daily administration, delayed L-Dopa initiation, significant efficacy on motor symptoms (although lower than that of L-Dopa). MOAI can be prescribed in association with L-Dopa or dopamine agonists. Rasagiline also delays L-Dopa initiation, and consequently motor complications. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Dopamine agonist therapy in low-response children following traumatic brain injury.

PubMed

Patrick, Peter D; Blackman, James A; Mabry, Jennifer L; Buck, Marcia L; Gurka, Matthew J; Conaway, Mark R

2006-10-01

The objective of this study was to determine whether a dopamine agonist could improve mental status among children in a low-response state following traumatic brain injury. In an 8-week, prospective, double-blind, randomized trial, 10 children and adolescents ages 8 to 21 years (X = 16.7 years) with traumatic brain injury sustained at least 1 month previously and remaining in a low-response state (Rancho Los Amigos Scale level pound 3) received pramipexole or amantadine. Medication dosage was increased over 4 weeks, weaned over 2 weeks, and then discontinued. At baseline and weekly during the study, subjects were evaluated with the Coma Near Coma Scale, Western NeuroSensory Stimulation Profile, and Disability Rating Scale. Scores improved significantly from baseline to the medication phase on the Coma Near Coma Scale, Western NeuroSensory Stimulation Profile, and Disability Rating Scale (P < .005). The weekly rate of change was significantly better for all three measures on medication than off medication (P < .05). Rancho Los Amigos Scale levels improved significantly on medication as well (P < .05). There was no difference in efficacy between amantadine and pramipexole. No unexpected or significant side effects were observed with either drug. This clinical trial supports the benefit of two dopamine agonists in the restoration of functional arousal, awareness, and communication. These drugs can be helpful in accelerating eligibility for acute rehabilitation among children and adolescents who have sustained significant brain injuries.

Switching from an oral dopamine receptor agonist to rotigotine transdermal patch: a review of clinical data with a focus on patient perspective.

PubMed

Chung, Sun Ju; Asgharnejad, Mahnaz; Bauer, Lars; Benitez, Arturo; Boroojerdi, Babak; Heidbrede, Tanja; Little, Allison; Kim, Han Joon

2017-07-01

Dopamine receptor agonists (DAs) are commonly used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In certain situations, switching from oral DAs to rotigotine transdermal patch may be beneficial for the patient (e.g., optimal symptom control/side effects/perioperative management, preference for once-daily/non-oral administration, RLS augmentation treatment). Areas covered: This narrative review summarizes available data on DA dose equivalency, dose conversions, switching schedules, safety, tolerability, efficacy and patient treatment preferences of switching from oral DAs to rotigotine (and vice versa) in patients with PD/RLS. The studies were identified in a PubMed search (up to 8 November 2016) using terms ('dopamine receptor agonist' OR 'rotigotine') AND 'switch'. Expert commentary: Randomized controlled studies often do not address the challenges clinicians face in practice, e.g., switching medications within the same class when dosing is not a one-to-one ratio. The authors describe three open-label studies in PD where oral DAs were successfully switched to rotigotine, and review three studies in RLS where oral DAs/levodopa were switched to rotigotine. Finally, the authors provide a suggested tool for switching from oral DAs to rotigotine, which includes dose conversion factors and switching schedules. The authors' view is that low-dose oral DAs (equivalent to ≤8 mg/24 h rotigotine) may be switched overnight.

Novel Analogues of (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Sumanirole) Provide Clues to Dopamine D2/D3 Receptor Agonist Selectivity

PubMed Central

2016-01-01

Novel 1-, 5-, and 8-substituted analogues of sumanirole (1), a dopamine D2/D3 receptor (D2R/D3R) agonist, were synthesized. Binding affinities at both D2R and D3R were higher when determined in competition with the agonist radioligand [3H]7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [3H]N-methylspiperone. Although 1 was confirmed as a D2R-preferential agonist, its selectivity in binding and functional studies was lower than previously reported. All analogues were determined to be D2R/D3R agonists in both GoBRET and mitogenesis functional assays. Loss of efficacy was detected for the N-1-substituted analogues at D3R. In contrast, the N-5-alkyl-substituted analogues, and notably the n-butyl-arylamides (22b and 22c), all showed improved affinity at D2R over 1 with neither a loss of efficacy nor an increase in selectivity. Computational modeling provided a structural basis for the D2R selectivity of 1, illustrating how subtle differences in the highly homologous orthosteric binding site (OBS) differentially affect D2R/D3R affinity and functional efficacy. PMID:27035329

The role of dopamine in human addiction: from reward to motivated attention.

PubMed

Franken, Ingmar H A; Booij, Jan; van den Brink, Wim

2005-12-05

There is general consensus among preclinical researchers that dopamine plays an important role in the development and persistence of addiction. However, the precise role of dopamine in addictive behaviors is far from clear and only a few clinical studies on the role of dopamine in human addiction have been conducted so far. The present paper reviews studies addressing the role of dopamine in humans. There is substantial and consistent evidence that dopamine is involved in the experience of drug reward in humans. Dopamine may also be involved in motivational processes such as drug craving. However, given the inconsistent findings of studies using dopamine receptor (ant)agonists, the role of dopamine in the experience of craving is far from resolved. Recent theories claiming that dopamine signals salience and makes the brain paying attention to biological relevant stimuli may provide an interesting framework for explaining addictive behaviors. There is accumulating evidence that patients with drug and alcohol addiction have an aberrant focus on drug-related stimuli. Although there is some preliminary support for the role of dopamine in these attention processes, more studies have to be carried out in order to test the validity of these theories in human subjects.

The sigma-1 receptor modulates dopamine transporter conformation and cocaine binding and may thereby potentiate cocaine self-administration in rats.

PubMed

Hong, Weimin Conrad; Yano, Hideaki; Hiranita, Takato; Chin, Frederick T; McCurdy, Christopher R; Su, Tsung-Ping; Amara, Susan G; Katz, Jonathan L

2017-07-07

The dopamine transporter (DAT) regulates dopamine (DA) neurotransmission by recapturing DA into the presynaptic terminals and is a principal target of the psychostimulant cocaine. The sigma-1 receptor (σ 1 R) is a molecular chaperone, and its ligands have been shown to modulate DA neuronal signaling, although their effects on DAT activity are unclear. Here, we report that the prototypical σ 1 R agonist (+)-pentazocine potentiated the dose response of cocaine self-administration in rats, consistent with the effects of the σR agonists PRE-084 and DTG (1,3-di- o -tolylguanidine) reported previously. These behavioral effects appeared to be correlated with functional changes of DAT. Preincubation with (+)-pentazocine or PRE-084 increased the B max values of [ 3 H]WIN35428 binding to DAT in rat striatal synaptosomes and transfected cells. A specific interaction between σ 1 R and DAT was detected by co-immunoprecipitation and bioluminescence resonance energy transfer assays. Mutational analyses indicated that the transmembrane domain of σ 1 R likely mediated this interaction. Furthermore, cysteine accessibility assays showed that σ 1 R agonist preincubation potentiated cocaine-induced changes in DAT conformation, which were blocked by the specific σ 1 R antagonist CM304. Moreover, σ 1 R ligands had distinct effects on σ 1 R multimerization. CM304 increased the proportion of multimeric σ 1 Rs, whereas (+)-pentazocine increased monomeric σ 1 Rs. Together these results support the hypothesis that σ 1 R agonists promote dissociation of σ 1 R multimers into monomers, which then interact with DAT to stabilize an outward-facing DAT conformation and enhance cocaine binding. We propose that this novel molecular mechanism underlies the behavioral potentiation of cocaine self-administration by σ 1 R agonists in animal models. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation of /sup 3/H-dopamine release by presynaptic GABA and glutamate heteroreceptors in rat brain nucleus accumbens synaptosomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kovalev, G.I.; Hetey, L.

1987-06-01

The aim of this investigation was a neurochemical study of the effect of agonists of different types of GABA receptors - muscimol (type A receptor), baclofen (type B receptor), delta-aminolevulinic acid (DALA; GABA autoreceptor), and also of GABA itself - on tritium-labelled dopamine release, stimulated by potassium cations, from synaptosomes of the nuclei accumbenes of the rat brain.

Opiate-induced dopamine release is modulated by severity of alcohol dependence: an [(18)F]fallypride positron emission tomography study.

PubMed

Spreckelmeyer, Katja N; Paulzen, Michael; Raptis, Mardjan; Baltus, Thomas; Schaffrath, Sabrina; Van Waesberghe, Julia; Zalewski, Magdalena M; Rösch, Frank; Vernaleken, Ingo; Schäfer, Wolfgang M; Gründer, Gerhard

2011-10-15

Preclinical data implicate the reinforcing effects of alcohol to be mediated by interaction between the opioid and dopamine systems of the brain. Specifically, alcohol-induced release of β-endorphins stimulates μ-opioid receptors (MORs), which is believed to cause dopamine release in the brain reward system. Individual differences in opioid or dopamine neurotransmission have been suggested to be responsible for enhanced liability to abuse alcohol. In the present study, a single dose of the MOR agonist remifentanil was administered in detoxified alcohol-dependent patients and healthy control subjects to mimic the β-endorphin-releasing properties of ethanol and to assess the effects of direct MOR stimulation on dopamine release in the mesolimbic reward system. Availability of D(2/3) receptors was assessed before and after single-dose administration of the MOR agonist remifentanil in 11 detoxified alcohol-dependent patients and 11 healthy control subjects with positron emission tomography with the radiotracer [(18)F]fallypride. Severity of dependence as assessed with the Alcohol Use Disorders Identification Test was compared with remifentanil-induced percentage change in [(18)F]fallypride binding (Δ%BP(ND)). The [(18)F]fallypride binding potentials (BP(ND)s) were significantly reduced in the ventral striatum, dorsal putamen, and amygdala after remifentanil application in both patients and control subjects. In the patient group, ventral striatum Δ%BP(ND) was correlated with the Alcohol Use Disorders Identification Test score. The data provide evidence for a MOR-mediated interaction between the opioid and the dopamine system, supporting the assumption that one way by which alcohol unfolds its rewarding effects is via a MOR-(γ-aminobutyric acid)-dopamine pathway. No difference in dopamine release was found between patients and control subjects, but evidence for a patient-specific association between sensitivity to MOR stimulation and severity of alcohol dependence was found. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

In Vitro and In Vivo Identification of Novel Positive Allosteric Modulators of the Human Dopamine D2 and D3 Receptor.

PubMed

Wood, Martyn; Ates, Ali; Andre, Veronique Marie; Michel, Anne; Barnaby, Robert; Gillard, Michel

2016-02-01

Agonists at dopamine D2 and D3 receptors are important therapeutic agents in the treatment of Parkinson's disease. Compared with the use of agonists, allosteric potentiators offer potential advantages such as temporal, regional, and phasic potentiation of natural signaling, and that of receptor subtype selectivity. We report the identification of a stereoselective interaction of a benzothiazol racemic compound that acts as a positive allosteric modulator (PAM) of the rat and human dopamine D2 and D3 receptors. The R isomer did not directly stimulate the dopamine D2 receptor but potentiated the effects of dopamine. In contrast the S isomer attenuated the effects of the PAM and the effects of dopamine. In radioligand binding studies, these compounds do not compete for binding of orthosteric ligands, but indeed the R isomer increased the number of high-affinity sites for [(3)H]-dopamine without affecting K(d). We went on to identify a more potent PAM for use in native receptor systems. This compound potentiated the effects of D2/D3 signaling in vitro in electrophysiologic studies on dissociated striatal neurons and in vivo on the effects of L-dopa in the 6OHDA (6-hydroxydopamine) contralateral turning model. These PAMs lacked activity at a wide variety of receptors, lacked PAM activity at related Gi-coupled G protein-coupled receptors, and lacked activity at D1 receptors. However, the PAMs did potentiate [(3)H]-dopamine binding at both D2 and D3 receptors. Together, these studies show that we have identified PAMs of the D2 and D3 receptors both in vitro and in vivo. Such compounds may have utility in the treatment of hypodopaminergic function. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Psychotomimetic opiate receptors labeled and visualized with (+)-(/sup 3/H)3-(3-hydroxyphenyl)-N-(1-propyl)piperidine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Largent, B.L.; Gundlach, A.L.; Snyder, S.H.

1984-08-01

3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) has been proposed as a selective dopamine autoreceptor agonist in the central nervous system. This report describes the pharmacology and localization of specific high-affinity binding sites for (+)-(/sup 3/H)3-PPP in brain. The drug specificity of (+)-(/sup 3/H)3-PPP binding is identical to that of sigma receptors, which may mediate psychotomimetic effects of some opiates. Haloperidol and the opioid derivatives, pentazocine, cyclazocine, and SKF 10,047 are potent inhibitors of (+)-(/sup 3/H)3-PPP binding. Stereoselectivity is exhibited for the (+) isomers of cyclazocine and SKF 10.047 at the sigma site, opposite to the stereoselectivity seen at ..mu.., sigma, and k opiate receptors.more » (+)-(/sup 3/H)3-PPP does not label dopamine receptors, as potent dopamine agonists and antagonists are weak inhibitors of binding and the localization of specific (+)-(/sup 3/H)3-PPP binding sites does not parallel that of dopamine neurons. Discrete localizations of (+)-(/sup 3/H)3-PPP binding sites in many brain areas including limbic, midbrain, brainstem, and cerebellar regions may explain psychotomimetic actions of opiates and behavior effects of 3-PPP. 41 references, 2 figures, 1 table.« less

The γ-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens.

PubMed

Fu, Zhenyu; Yang, Hongfa; Xiao, Yuqiang; Zhao, Gang; Huang, Haiyan

2012-07-10

Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA) system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear. We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo. The present study demonstrated that morphine challenge (3 mg/kg, s.c.) obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5 mg/kg) significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3 days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge. Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse.

Optical Control of Dopamine Receptors Using a Photoswitchable Tethered Inverse Agonist.

PubMed

Donthamsetti, Prashant C; Winter, Nils; Schönberger, Matthias; Levitz, Joshua; Stanley, Cherise; Javitch, Jonathan A; Isacoff, Ehud Y; Trauner, Dirk

2017-12-27

Family A G protein-coupled receptors (GPCRs) control diverse biological processes and are of great clinical relevance. Their archetype rhodopsin becomes naturally light sensitive by binding covalently to the photoswitchable tethered ligand (PTL) retinal. Other GPCRs, however, neither bind covalently to ligands nor are light sensitive. We sought to impart the logic of rhodopsin to light-insensitive Family A GPCRs in order to enable their remote control in a receptor-specific, cell-type-specific, and spatiotemporally precise manner. Dopamine receptors (DARs) are of particular interest for their roles in motor coordination, appetitive, and aversive behavior, as well as neuropsychiatric disorders such as Parkinson's disease, schizophrenia, mood disorders, and addiction. Using an azobenzene derivative of the well-known DAR ligand 2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin (PPHT), we were able to rapidly, reversibly, and selectively block dopamine D1 and D2 receptors (D1R and D2R) when the PTL was conjugated to an engineered cysteine near the dopamine binding site. Depending on the site of tethering, the ligand behaved as either a photoswitchable tethered neutral antagonist or inverse agonist. Our results indicate that DARs can be chemically engineered for selective remote control by light and provide a template for precision control of Family A GPCRs.

Structure-5-HT/D2 Receptor Affinity Relationship in a New Group of 1-Arylpiperazynylalkyl Derivatives of 8-Dialkylamino-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione.

PubMed

Żmudzki, Paweł; Satała, Grzegorz; Chłoń-Rzepa, Grażyna; Bojarski, Andrzej J; Kazek, Grzegorz; Siwek, Agata; Gryboś, Anna; Głuch-Lutwin, Monika; Wesołowska, Anna; Pawłowski, Maciej

2016-10-01

In our previous papers, we have reported that some 8-amino-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives possessed high affinity and displayed agonistic, partial agonistic, or antagonistic activity for serotonin 5-HT 1A and dopamine D 2 receptors. In order to examine further the influence of the substituent in the position 8 of the purine moiety and the influence of the xanthine core on the affinity for serotonin 5-HT 1A , 5-HT 2A , 5-HT 6 , 5-HT 7 , and dopamine D 2 receptors, two series of 1-arylpiperazynylalkyl derivatives of 8-amino-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione were synthesized. All the final compounds were investigated in in vitro competition binding experiments for the serotonin 5-HT 1A , 5-HT 2A , 5-HT 6 , 5-HT 7 , and dopamine D 2 receptors. The structure-affinity relationships for this group of compounds were discussed. For selected compounds, the functional assays for the 5-HT 1A and D 2 receptors were carried out. The results of the assays indicated that these groups of derivatives possessed antagonistic activity for 5-HT 1A receptors and agonistic, partial agonistic, or antagonistic activity for D 2 receptors. In total, 26 new compounds were synthesized, 20 of which were tested in in vitro binding experiments and 5 were tested in in vitro functional assays. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pharmacogenetics and Pharmacotherapy of Military Personnel Suffering from Post-traumatic Stress Disorder.

PubMed

Naß, Janine; Efferth, Thomas

2017-01-01

Posttraumatic stress disorder (PTSD) is a severe problem among soldiers with combating experience difficult to treat. The pathogenesis is still not fully understood at the psychological level. Therefore, genetic research became a focus of interest. The identification of single nucleotide polymorphisms (SNPs) may help to predict, which persons are at high risk to develop PTSD as a starting point to develop novel targeted drugs for treatment. We conducted a systematic review on SNPs in genes related to PTSD pathology and development of targeted pharmacological treatment options based on PubMed database searches. We focused on clinical trials with military personnel. SNPs in 22 human genes have been linked to PTSD. These genes encode proteins acting as neurotransmitters and receptors, downstream signal transducers and metabolizing enzymes. Pharmacological inhibitors may serve as drug candidates for PTSD treatment, e.g. β2 adrenoreceptor antagonists, dopamine antagonists, partial dopamine D2 receptor agonists, dopamine β hydroxylase inhibitors, fatty acid amid hydrolase antagonists, glucocorticoid receptor agonists, tropomyosin receptor kinase B agonists, selective serotonin reuptake inhibitors, catechol-O-methyltransferase inhibitors, gamma-amino butyric acid receptor agonists, glutamate receptor inhibitors, monoaminoxidase B inhibitors, N-methyl-d-aspartate receptor antagonists. The combination of genetic and pharmacological research may lead to novel targetbased drug developments with improved specificity and efficacy to treat PTSD. Specific SNPs may be identified as reliable biomarkers to assess individual disease risk. Focusing on soldiers suffering from PTSD will not only help to improve treatment options for this specific group, but for all PTSD patients and the general population. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Blockade of Cocaine or σ Receptor Agonist Self Administration by Subtype-Selective σ Receptor Antagonists

PubMed Central

Hiranita, Takato; Kopajtic, Theresa A.; Rice, Kenner C.; Mesangeau, Christophe; Narayanan, Sanju; Abdelazeem, Ahmed H.; McCurdy, Christopher R.

2016-01-01

The identification of sigma receptor (σR) subtypes has been based on radioligand binding and, despite progress with σ1R cellular function, less is known about σR subtype functions in vivo. Recent findings that cocaine self administration experience will trigger σR agonist self administration was used in this study to assess the in vivo receptor subtype specificity of the agonists (+)-pentazocine, PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], and 1,3-di-o-tolylguanidine (DTG) and several novel putative σR antagonists. Radioligand binding studies determined in vitro σR selectivity of the novel compounds, which were subsequently studied for self administration and antagonism of cocaine, (+)-pentazocine, PRE-084, or DTG self administration. Across the dose ranges studied, none of the novel compounds were self administered, nor did they alter cocaine self administration. All compounds blocked DTG self administration, with a subset also blocking (+)-pentazocine and PRE-084 self administration. The most selective of the compounds in binding σ1Rs blocked cocaine self administration when combined with a dopamine transport inhibitor, either methylphenidate or nomifensine. These drug combinations did not decrease rates of responding maintained by food reinforcement. In contrast, the most selective of the compounds in binding σ2Rs had no effect on cocaine self administration in combination with either dopamine transport inhibitor. Thus, these results identify subtype-specific in vivo antagonists, and the utility of σR agonist substitution for cocaine self administration as an assay capable of distinguishing σR subtype selectivity in vivo. These results further suggest that effectiveness of dual σR antagonism and dopamine transport inhibition in blocking cocaine self administration is specific for σ1Rs and further support this dual targeting approach to development of cocaine antagonists. PMID:27189970

A role for sigma receptors in stimulant self-administration and addiction.

PubMed

Katz, Jonathan L; Hong, Weimin C; Hiranita, Takato; Su, Tsung-Ping

2016-04-01

Sigma-1 receptors (σ1Rs) are structurally unique intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to other subcellular compartments, and can influence a host of targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Drugs binding to σRs can induce or block the actions of σRs. Studies indicate that stimulant self-administration induces the reinforcing effects of σR agonists, because of dopamine transporter actions. Once established, the reinforcing effects of σR agonists are independent of dopaminergic mechanisms traditionally thought to be critical to the reinforcing effects of stimulants. Self-administered doses of σR agonists do not increase dopamine concentrations in the nucleus accumbens shell, a transmitter and brain region considered important for the reinforcing effects of abused drugs. However, self-administration of σR agonists is blocked by σR antagonists. Several effects of stimulants have been blocked by σR antagonists, including the reinforcing effects, assessed by a place-conditioning procedure. However, the self-administration of stimulants is largely unaffected by σR antagonists, indicating fundamental differences in the mechanisms underlying these two procedures used to assess the reinforcing effects. When σR antagonists are administered in combination with dopamine uptake inhibitors, an effective and specific blockade of stimulant self-administration is obtained. Actions of stimulant drugs related to their abuse induce unique changes in σR activity and the changes induced potentially create redundant and, once established, independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and σR proteins produces a selective antagonism of stimulant self-administration, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse.

A Role for σRs in Stimulant Self-administration and Addiction

PubMed Central

Katz, Jonathan L.; Hong, Weimin C.; Hiranita, Takato; Su, Tsung-Ping

2015-01-01

Sigma-1 receptors (σ1Rs) are structurally unique intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to other sub-cellular compartments, and can influence a host of targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Drugs binding to σRs can induce or block the actions of σRs. Studies indicate that stimulant self-administration induces reinforcing effects of σR agonists, due to dopamine transporter actions. Once established the reinforcing effects of σR agonists are independent of dopaminergic mechanisms traditionally thought to be critical in the reinforcing effects of stimulants. Self-administered doses of σR agonists do not increase dopamine concentrations in the nucleus accumbens shell, a transmitter and brain region considered important for reinforcing effects of abused drugs. However, the self-administration of σR agonists is blocked by σR antagonists. Several effects of stimulants have been blocked by σR antagonists, including reinforcing effects assessed by a place-conditioning procedure. However, the self-administration of stimulants is largely unaffected by σR antagonists, indicating fundamental differences in the mechanisms underlying these two procedures used to assess reinforcing effects. When σR antagonists are administered in combination with dopamine uptake inhibitors an effective and specific blockade of stimulant self-administration is obtained. Actions of stimulant drugs related to their abuse induce unique changes in σR activity and the changes induced potentially create redundant, and once established, independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and σR proteins produces a selective antagonism of stimulant self-administration, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse. PMID:26650253

The metabotropic glutamate receptor 8 agonist (S)-3,4-DCPG reverses motor deficits in prolonged but not acute models of Parkinson’s disease

PubMed Central

Johnson, Kari A.; Jones, Carrie K.; Tantawy, Mohammed N.; Bubser, Michael; Marvanova, Marketa; Ansari, M. Sib; Baldwin, Ronald M.; Conn, P. Jeffrey; Niswender, Colleen M.

2012-01-01

Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson’s disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu8-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (two hour) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18–20 hours) or reserpine (18–20 hours), DCPG robustly reverses haloperidol-induced catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting catalepsy induced by 20 hour pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu8 may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D2-like dopamine receptors is prolonged and indicate that selective activation of mGlu8 may represent a novel therapeutic strategy for alleviating the motor symptoms of PD. PMID:22546615

Dopaminergic modulation of the orbitofrontal cortex affects attention, motivation and impulsive responding in rats performing the five-choice serial reaction time task.

PubMed

Winstanley, Catharine A; Zeeb, Fiona D; Bedard, Amanda; Fu, Kent; Lai, Barbara; Steele, Christina; Wong, Adeline C

2010-07-11

Understanding the neurobiological factors underlying individual differences in impulsivity may provide valuable insight into vulnerability to impulse control disorders. Recent data implicate both the orbitofrontal cortex (OFC) and the dopaminergic system in psychiatric disorders associated with high levels of impulsivity, including substance abuse, mania and obsessive-compulsive disorder. However, the consequences of modulating dopaminergic activity within the OFC on impulsive behaviour are largely unknown. The effects of direct intra-OFC infusions of agonists and antagonists at the dopamine D(1) and D(2) receptors were therefore assessed in rats performing the five-choice serial reaction time test (5CSRT) of attention and motor impulsivity. Intra-OFC administration of SCH23390, a D(1) receptor antagonist, decreased impulsive responding in highly impulsive (HI) rats, but did not affect behaviour in less impulsive (LI) animals. Furthermore, the D(2) agonist quinpirole caused significant deficits in task performance, impairing accuracy, increasing omissions and decreasing the number of trials completed, which resembled the effects of systemic administration. In contrast, the D(1) agonist SKF 81297 had little effect on behaviour. Neither agonist increased impulsivity. These data provide partial support for the suggestion that high levels of impulsivity are associated with increased dopamine levels within the OFC, but further indicate that simulating dopamine's actions selectively at the D(1) or D(2) receptor cannot reproduce a highly impulsive phenotype. Dopaminergic activity within the OFC may therefore modulate impulsivity indirectly, perhaps in conjunction with other neurotransmitter systems. Furthermore, D(2)-mediated neurotransmission within the OFC could make a more fundamental contribution to cognitive behaviour. Copyright 2010 Elsevier B.V. All rights reserved.

Reversal of inhibition of putative dopaminergic neurons of the ventral tegmental area: Interaction of GABAB and D2 receptors

PubMed Central

Nimitvilai, Sudarat; Arora, Devinder S.; McElvain, Maureen A.; Brodie, Mark S.

2012-01-01

Neurons of the ventral tegmental area (VTA) are critical in the rewarding and reinforcing properties of drugs of abuse. Desensitization of VTA neurons to moderate extracellular concentrations of dopamine (DA) is dependent on protein kinase C (PKC) and intracellular calcium levels. This desensitization is called DA inhibition reversal (DIR), as it requires concurrent activation of D2 and D1-like receptors; activation of D2 receptors alone does not result in desensitization. Activation of other G-protein linked receptors can substitute for D1 activation. Like D2 receptors, GABAB receptors in the VTA are coupled to G-protein-linked potassium channels. In the present study, we examined interactions between a GABAB agonist, baclofen, and dopamine agonists, dopamine and quinpirole, to determine whether there was some interaction in the processes of desensitization of GABAB and D2 responses. Long-duration administration of baclofen alone produced reversal of the baclofen-induced inhibition indicative of desensitization, and this desensitization persisted for at least 60 min after baclofen washout. Desensitization to baclofen was dependent on protein kinase C. Dopamine inhibition was reduced for 30 min after baclofen-induced desensitization and conversely, the magnitude of baclofen inhibition was reduced for 30 min by long-duration application of dopamine, but not quinpirole. These results indicate that D2 and GABAB receptors share some protein kinase C-dependent mechanisms of receptor desensitization. PMID:22986166

Rotigotine transdermal system: developing continuous dopaminergic delivery to treat Parkinson's disease and restless legs syndrome.

PubMed

Benitez, Arturo; Edens, Heather; Fishman, Jesse; Moran, Kimberly; Asgharnejad, Mahnaz

2014-11-01

Rotigotine is a nonergoline dopamine receptor agonist with structural similarity to dopamine. Rotigotine binds to the D1 through D5 dopamine receptors, having several times more affinity than dopamine does to the D2 and D3 receptors. Although rotigotine was demonstrated to restore locomotor activity in animal models of Parkinson's disease (PD), the rapid metabolism of rotigotine limited the development of an orally administered formulation. Rotigotine's high lipid solubility and extended duration of action when applied to the skin in experimental models of PD suggested that rotigotine was a candidate for transdermal application. The constant transdermal delivery of rotigotine over 24 h is hypothesized to approximate continuous agonist-receptor stimulation, which conceptually more closely mimics physiologic striatal dopamine receptor function. Randomized clinical studies have demonstrated rotigotine's efficacy, safety, and tolerability in patients with early- and advanced-stage PD, including improvements in motor symptoms and off-time. Although the etiology is unknown, restless legs syndrome (RLS) is thought to involve dopaminergic dysregulation. Randomized clinical studies also have demonstrated the efficacy of rotigotine in improving the symptoms of moderate-to-severe primary RLS. This review examines rotigotine's developmental history for transdermal administration leading to its approval for the treatment of early- and advanced-stage PD and moderate-to-severe primary RLS. © 2014 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.

Psychomotor and cognitive effects of piribedil, a dopamine agonist, in young healthy volunteers.

PubMed

Schück, Stéphane; Bentué-Ferrer, Danièle; Kleinermans, Diane; Reymann, Jean-Michel; Polard, Elisabeth; Gandon, Jean-Marc; Allain, Hervé

2002-02-01

Piribedil is a dopamine agonist acting on D2 and D3 central nervous system dopamine receptors. This drug has been administered to 12 young healthy male volunteers (age 22 +/- 2 years) according to a single center randomized, double-blind, two ways cross-over, placebo controlled trial, including a washout period of one week. Placebo and piribedil were administered by a single intravenous infusion over 2 h (3 mg). Psychomotor performance and cognitive functions were assessed through a standardized and computerized psychometric tests battery and a continuous electroencephalogram (EEG) mapping. Piribedil improved simple reaction time (P=0.02), immediate (P=0.045 and 0.004), and delayed free recall (P=0.05), dual coding test (P=0.02) and increased theta and fast beta waves on the EEG (P < 0.05 and 0.001, respectively). No deleterious effect was observed on the tests exploring attention and concentration via the other procedures. It is concluded that a single intravenous perfusion of piribedil 3 mg improves alertness and the information processing speed within the central nervous system, in healthy volunteers.

Drug discrimination and neurochemical studies in alpha7 null mutant mice: tests for the role of nicotinic alpha7 receptors in dopamine release.

PubMed

Quarta, Davide; Naylor, Christopher G; Barik, Jacques; Fernandes, Cathy; Wonnacott, Susan; Stolerman, Ian P

2009-04-01

The nicotine discriminative stimulus has been linked to beta2-containing (beta2*) nicotinic receptors, with little evidence of a role for alpha7 nicotinic receptors, because nicotine discrimination was very weak in beta2 null mutant mice but normal in alpha7 mutants. As both alpha7 and beta2* nicotinic receptors have been implicated in nicotine-stimulated dopamine overflow, this study focused on the dopamine-mediated element in the nicotine stimulus by examining cross-generalisation between amphetamine and nicotine. Male alpha7 nicotinic receptor null mutant mice and wild-type controls were bred in-house and trained to discriminate nicotine (0.8 mg/kg) or (+)-amphetamine (0.6 mg/kg) from saline in a two-lever procedure with a tandem VI-30 FR-10 schedule of food reinforcement. Dopamine release from striatal slices was determined in parallel experiments. An alpha7 nicotinic receptor-mediated component of dopamine release was demonstrated in tissue from wild-type mice using choline as a selective agonist. This response was absent in tissue from null mutant animals. The mutation did not influence acquisition of drug discriminations but subtly affected the results of cross-generalisation tests. In mice trained to discriminate nicotine or amphetamine, there was partial cross-generalisation in wild-type mice and, at certain doses, these effects were attenuated in mutants. Further support for an alpha7 nicotinic receptor-mediated component was provided by the ability of the alpha7 nicotinic receptor antagonist methyllycaconitine to attenuate responses to nicotine and amphetamine in wild-type mice. These findings support the concept of an alpha7 nicotinic receptor-mediated dopaminergic element in nicotine discrimination, warranting further tests with selective dopamine agonists.

Effects of (-)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization.

PubMed

Rung, Johan P; Rung, Emilia; Helgeson, Lisa; Johansson, Anette M; Svensson, Kjell; Carlsson, Arvid; Carlsson, Maria L

2008-06-01

Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (-)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (-)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (-)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (-)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (-)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (-)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.

The dark side of dopaminergic therapies in Parkinson's disease: shedding light on aberrant salience.

PubMed

Poletti, Michele

2017-03-07

Psychotic subjects and patients with Parkinson's disease (PD) "on" dopaminergic drugs, especially on dopamine agonists, present a hyperdopaminergic state that interferes with learning processing. These clinical populations present with distinct alterations of learning that share an increased potential motivational significance of stimuli: psychotic subjects may attribute salience to neutral stimuli, while medicated PD patients may overvalue rewards. Herein is discussed the speculative hypothesis that the hyperdopaminergic state induced by dopaminergic treatments, especially with dopamine agonists, may also facilitate the attribution of salience to neutral stimuli in PD patients, altering the physiological attribution of salience. Preliminary empirical evidence is in agreement with this speculative hypothesis, which needs further empirical investigation. The clinical implications of this hypothesis are discussed in relation to behavioral addictions, psychosis proneness, and enhanced creativity in medicated PD patients.

Compulsive behaviors in patients with Parkinson's disease.

PubMed

Kenangil, Gülay; Ozekmekçi, Sibel; Sohtaoglu, Melis; Erginöz, Ethem

2010-05-01

Several impulse control disorders (ICDs) may develop in patients with Parkinson's disease (PD). We aimed to identify the frequency and phenomenology of ICDs in our PD population. Among 554 PD patients examined in a 3-year period, we identified 33 patients with ICDs. Disease duration, gender, and age-matched 65 PD patients without ICDs were selected as controls. We noted age-at-onset, duration, and severity of PD, dose and types of dopaminergic treatment, as well as presence of motor complications in both groups. Of 554 patients, 33 (5.9%) had ICDs, of whom, 27 were men (81%), mean age-at onset of PD was 48 and disease duration 8 years. While all patients with ICDs were on dopamine agonist drugs (+/- an adjuvant), all but 2 of controls were on dopamine agonists. Punding was the most frequent behavioral problem (57%), 42% exhibited aggressive hypersexuality, 27% compulsive eating, 24% pathologic shopping, and 21% compulsive medication. Severity of PD, presence of l-Dopa-induced motor complications, l-Dopa equivalent doses of dopamine agonists administered were not statistically different between 2 groups. In this study performed in a tertiary clinic for movement disorders in Turkey, several ICDs occurred in a small group of PD patients, mostly in men with young-onset disease, similar to the previous reported series. However, in contrast to the Western series, the number of gamblers was quite low because gambling is illegal in our country. We did not find any association between ICDs and severity of PD as well as doses of dopaminergic agents.

Dopamine D1 receptor activation maintains motor coordination and balance in rats.

PubMed

Avila-Luna, Alberto; Gálvez-Rosas, Arturo; Durand-Rivera, Alfredo; Ramos-Languren, Laura-Elisa; Ríos, Camilo; Arias-Montaño, José-Antonio; Bueno-Nava, Antonio

2018-02-01

Dopamine (DA) modulates motor coordination, and its depletion, as in Parkinson's disease, produces motor impairment. The basal ganglia, cerebellum and cerebral cortex are interconnected, have functional roles in motor coordination, and possess dopamine D 1 receptors (D 1 Rs), which are expressed at a particularly high density in the basal ganglia. In this study, we examined whether the activation of D 1 Rs modulates motor coordination and balance in the rat using a beam-walking test that has previously been used to detect motor coordination deficits. The systemic administration of the D 1 R agonist SKF-38393 at 2, 3, or 4 mg/kg did not alter the beam-walking scores, but the subsequent administration of the D 1 R antagonist SCH-23390 at 1 mg/kg did produce deficits in motor coordination, which were reversed by the full agonist SKF-82958. The co-administration of SKF-38393 and SCH-23390 did not alter the beam-walking scores compared with the control group, but significantly prevented the increase in beam-walking scores induced by SCH-23390. The effect of the D 1 R agonist to prevent and reverse the effect of the D 1 R antagonist in beam-walking scores is an indicator that the function of D 1 Rs is necessary to maintain motor coordination and balance in rats. Our results support that D 1 Rs mediate the SCH-23390-induced deficit in motor coordination.

Restless legs syndrome: differential diagnosis and management with rotigotine

PubMed Central

Merlino, Giovanni; Serafini, Anna; Robiony, Francesca; Valente, Mariarosaria; Gigli, Gian Luigi

2009-01-01

RLS is a common sleep disorder with distinctive clinical features. The prevalence of RLS in Caucasians and North Americans ranges from 5% to 10%. However, only some of these subjects (almost the 3% of the general population) report being affected by a frequent and severe form of the sleep disorder. RLS is diagnosed clinically by means of four internationally recognized criteria that summarize the main characteristics of the sleep disorder. Besides the essential criteria, supportive and associated features of RLS have been established by experts in order to help physicians treat patients with doubtful symptoms. Several clinical conditions may mimic this sleep disorder. In order to increase the sensibility and specificity of RLS diagnosis, doctors should perform a meticulous patient history and then an accurate physical and neurological examination. Dopamine agonists are recognized as the preferred first-line treatment for RLS. Rotigotine is a non-ergoline dopamine agonist with selectivity for D1, D2 and D3 receptors. The drug is administered via transdermal patches which release rotigotine for 24 hours. Four clinical trials demonstrated that this compound is able to improve RLS symptomatology with few and moderate adverse events. Head to head trials are required to compare the efficacy and tolerability of rotigotine with other dopamine agonists administered via oral intake. Rotigotine has been approved by the FDA and EMEA for Parkinson’s disease. For the treatment of moderate to severe idiopathic RLS, rotigotine has been recommended for approval by the EMEA and is under review by the FDA. PMID:19557102

Dopaminergic stimulation enhances confidence and accuracy in seeing rapidly presented words.

PubMed

Lou, Hans C; Skewes, Joshua C; Thomsen, Kristine Rømer; Overgaard, Morten; Lau, Hakwan C; Mouridsen, Kim; Roepstorff, Andreas

2011-02-23

Liberal acceptance, overconfidence, and increased activity of the neurotransmitter dopamine have been proposed to account for abnormal sensory experiences, for instance, hallucinations in schizophrenia. In normal subjects, increased sensory experience in Yoga Nidra meditation is linked to striatal dopamine release. We therefore hypothesize that the neurotransmitter dopamine may function as a regulator of subjective confidence of visual perception in the normal brain. Although much is known about the effect of stimulation by neurotransmitters on cognitive functions, their effect on subjective confidence of perception has never been recorded experimentally before. In a controlled study of 24 normal, healthy female university students with the dopamine agonist pergolide given orally, we show that dopaminergic activation increases confidence in seeing rapidly presented words. It also improves performance in a forced-choice word recognition task. These results demonstrate neurotransmitter regulation of subjective conscious experience of perception and provide evidence for a crucial role of dopamine.

Effects of molindone and fluphenazine on the brain concentration of some phenolic and catecholic amines in the mouse and the rat.

PubMed

Juorio, A V

1980-11-01

1 The concentrations of p- and m-tyramine, dopamine, 3,4-dihydroxyphenylacetic acid and homo-vanillic acid were measured in the mouse or rat striatum following the subcutaneous injection of molindone or fluphenazine. The mouse hypothalamic levels of the m- or p-isomers of octopamine were also analysed. 2 Endogenous concentrations of p- and m-tyramine in the mouse striatum and p- and m-octopamine in the mouse hypothalamus were 20.6, 5.7, 9.4 and 1.2 ng/g respectively. The rat striatum concentrations of p- and m-tyramine were 12.8 and 3.8 ng/g. 3 The administration of low doses of molindone (1 to 10 mg/kg) produced a reduction in striatal p-tyramine, an increase in m-tyramine and an increase in dopamine turnover. Similar effects were produced by all doses of fluphenazine (0.1 to 5 mg/kg) employed. These findings are consistent with those observed after blockade of dopamine postsynaptic receptors. 4 With high doses of molindone (100 mg/kg) the effects on both tyramines and on dopamine metabolism were reversed. These results can be interpreted as molindone acting as a partial agonist. 5 The concentrations of hypothalamic p- and m-octopamine were increased by the higher doses of molindone (20 to 100 mg/kg) employed while lower doses produced no significant effects. All doses of fluphenazine reduced hypothalamic p-octopamine. These changes seem to depend on differences in the availability of p-tyramine to be converted into p-octopamine. 6 These results suggest that molindone acts as a blocker or a partial agonist of dopamine receptor sites and fit well with the proposal of a reciprocal relation between dopamine and tyramine. It is not possible yet to ascertain whether tyramine controls dopamine or vice versa or if it is a direct or a more remote relation.

Effects of molindone and fluphenazine on the brain concentration of some phenolic and catecholic amines in the mouse and the rat.

PubMed Central

Juorio, A. V.

1980-01-01

1 The concentrations of p- and m-tyramine, dopamine, 3,4-dihydroxyphenylacetic acid and homo-vanillic acid were measured in the mouse or rat striatum following the subcutaneous injection of molindone or fluphenazine. The mouse hypothalamic levels of the m- or p-isomers of octopamine were also analysed. 2 Endogenous concentrations of p- and m-tyramine in the mouse striatum and p- and m-octopamine in the mouse hypothalamus were 20.6, 5.7, 9.4 and 1.2 ng/g respectively. The rat striatum concentrations of p- and m-tyramine were 12.8 and 3.8 ng/g. 3 The administration of low doses of molindone (1 to 10 mg/kg) produced a reduction in striatal p-tyramine, an increase in m-tyramine and an increase in dopamine turnover. Similar effects were produced by all doses of fluphenazine (0.1 to 5 mg/kg) employed. These findings are consistent with those observed after blockade of dopamine postsynaptic receptors. 4 With high doses of molindone (100 mg/kg) the effects on both tyramines and on dopamine metabolism were reversed. These results can be interpreted as molindone acting as a partial agonist. 5 The concentrations of hypothalamic p- and m-octopamine were increased by the higher doses of molindone (20 to 100 mg/kg) employed while lower doses produced no significant effects. All doses of fluphenazine reduced hypothalamic p-octopamine. These changes seem to depend on differences in the availability of p-tyramine to be converted into p-octopamine. 6 These results suggest that molindone acts as a blocker or a partial agonist of dopamine receptor sites and fit well with the proposal of a reciprocal relation between dopamine and tyramine. It is not possible yet to ascertain whether tyramine controls dopamine or vice versa or if it is a direct or a more remote relation. PMID:6777007

An updated view on the role of dopamine in myopia.

PubMed

Feldkaemper, Marita; Schaeffel, Frank

2013-09-01

A large body of data is available to support the hypothesis that dopamine (DA) is one of the retinal neurotransmitters involved in the signaling cascade that controls eye growth by vision. Initially, reduced retinal DA levels were observed in eyes deprived of sharp vision by either diffusers ("deprivation myopia", DM) or negative lenses ("lens induced myopia", LIM). Simulating high retinal DA levels by intravitreal application of a DA agonist can suppress the development of both DM and LIM. Also more recent studies using knock-out mouse models of DA receptors support the idea of an association between decreased DA levels and DM. There seem to be differences in the magnitude of the effects of DA on DM and LIM, with larger changes in DM but the degrees of image degradation by both treatments need to be matched to support this conclusion. Although a number of studies have shown that the inhibitory effects of dopamine agonists on DM and LIM are mediated through stimulation of the D2-receptor, there is also recent evidence that the balance of D2- and D1-receptor activation is important. Inhibition of D2-receptors can also slow the development of spontaneous myopia in albino guinea pigs. Retinal DA content displays a distinct endogenous diurnal, and partially circadian rhythm. In addition, retinal DA is regulated by a number of visual stimuli like retinal illuminance, spatial frequency content of the image, temporal contrast and, in chicks, by the light input from the pineal organ. A close interaction was found between muscarinergic and dopaminergic systems, and between nitric oxide and dopaminergic pathways, and there is evidence for crosstalk between the different pathways, perhaps multiple binding of the ligands to different receptors. It was shown that DA agonists interact with the immediate early signaling molecule ZENK which triggers the first steps in eye growth regulation. However, since long treatment periods were often needed to induce significant changes in retinal dopamine synthesis and release, the role of dopamine in the early steps is unclear. The wide spatial distribution of dopaminergic amacrine cells in the retina and the observation that changes in dopamine levels can be locally induced by local retinal deprivation is in line with the assumption that dopaminergic mechanisms control both central and peripheral eye growth. The protective effect of outdoor activity on myopia development in children seems to be partly mediated by the stimulatory effect of light on retinal dopamine production and release. However, the dose-response function linking light exposure to dopamine and to the suppression of myopia is not known and requires further studies. Copyright © 2013 Elsevier Ltd. All rights reserved.

Changes in artistic style and behaviour in Parkinson's disease: dopamine and creativity.

PubMed

Kulisevsky, Jaime; Pagonabarraga, Javier; Martinez-Corral, Mercè

2009-05-01

We present a PD patient in whom dopamine agonists awoke a hidden creativity that led to a gradual increase in painting productivity evolving to a disruptive impulsive behaviour that shared many features with punding. A dramatic change in painting style related to a more emotional experience during the process of creation developed after treatment onset. This case suggests that changes in creativity in PD seem to be related to dopaminergic imbalance in the limbic system.

The gamma-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens

PubMed Central

2012-01-01

Background Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA) system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear. Methods We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo. Results The present study demonstrated that morphine challenge (3 mg/kg, s.c.) obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5 mg/kg) significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3 days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge. Conclusions Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse. PMID:22559224

Antidepressant response to aripiprazole augmentation associated with enhanced FDOPA utilization in striatum: a preliminary PET study

PubMed Central

Conway, Charles R.; Chibnall, John T.; Cumming, Paul; Mintun, Mark A.; Gebara, Marie Anne I.; Perantie, Dana C.; Price, Joseph L.; Cornell, Martha E.; McConathy, Jonathan E.; Gangwani, Sunil; Sheline, Yvette I.

2014-01-01

Several double blind, prospective trials have demonstrated an antidepressant augmentation efficacy of aripiprazole in depressed patients unresponsive to standard antidepressant therapy. Although aripiprazole is now widely used for this indication, and much is known about its receptor-binding properties, the mechanism of its antidepressant augmentation remains ill-defined. In vivo animal studies and in vitro human studies using cloned dopamine dopamine D2 receptors suggest aripiprazole is a partial dopamine agonist; in this preliminary neuroimaging trial, we hypothesized that aripiprazole’s antidepressant augmentation efficacy arises from dopamine partial agonist activity. To test this, we assessed the effects of aripiprazole augmentation on the cerebral utilization of 6-[18F]-fluoro-3,4-dihydroxy-L-phenylalanine (FDOPA) using positron emission tomography (PET). Fourteen depressed patients, who had failed 8 weeks of antidepressant therapy with selective serotonin reuptake inhibitors, underwent FDOPA PET scans before and after aripiprazole augmentation; eleven responded to augmentation. Whole brain, voxel-wise comparisons of pre- and post-aripiprazole scans revealed increased FDOPA trapping in the right medial caudate of augmentation responders. An exploratory analysis of depressive symptoms revealed that responders experienced large improvements only in putatively dopaminergic symptoms of lassitude and inability to feel. These preliminary findings suggest that augmentation of antidepressant response by aripiprazole may be associated with potentiation of dopaminergic activity. PMID:24468015

Putative antipsychotics with pronounced agonism at serotonin 5-HT1A and partial agonist activity at dopamine D2 receptors disrupt basal PPI of the startle reflex in rats.

PubMed

Auclair, Agnès L; Galinier, Alexandra; Besnard, Joël; Newman-Tancredi, Adrian; Depoortère, Ronan

2007-07-01

Prepulse inhibition (PPI) of the startle reflex has been extensively studied because it is disrupted in several psychiatric diseases, most notably schizophrenia. In rats, and to a lesser extent, in humans, PPI can be diminished by dopamine (DA) D(2)/D(3) and serotonin 5-HT(1A) receptor agonists. A novel class of potential antipsychotics (SSR181507, bifeprunox, and SLV313) possess partial agonist/antagonist properties at D(2) receptors and various levels of 5-HT(1A) activation. It thus appeared warranted to assess, in Sprague-Dawley rats, the effects of these antipsychotics on basal PPI. SSR181507, sarizotan, and bifeprunox decreased PPI, with a near-complete abolition at 2.5-10 mg/kg; SLV313 had a significant effect at 0.16 mg/kg only. Co-treatment with the 5-HT(1A) receptor antagonist WAY100,635 (0.63 mg/kg) showed that the 5-HT(1A) agonist activity of SSR181507 was responsible for its effect. By contrast, antipsychotics with low affinity and/or efficacy at 5-HT(1A) receptors, such as aripiprazole (another DA D(2)/D(3) and 5-HT(1A) ligand), and established typical and atypical antipsychotics (haloperidol, clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) had no effect on basal PPI (0.01-2.5 to 2.5-40 mg/kg). The present data demonstrate that some putative antipsychotics with pronounced 5-HT(1A) agonist activity, coupled with partial agonist activity at DA D(2) receptors, markedly diminish PPI of the startle reflex in rats. These data raise the issue of the influence of such compounds on sensorimotor gating in humans.

Role of D2 dopamine receptors of the ventral pallidum in inhibitory avoidance learning.

PubMed

Lénárd, László; Ollmann, Tamás; László, Kristóf; Kovács, Anita; Gálosi, Rita; Kállai, Veronika; Attila, Tóth; Kertes, Erika; Zagoracz, Olga; Karádi, Zoltán; Péczely, László

2017-03-15

In our present experiments, the role of D2 dopamine (DA) receptors of the ventral pallidum (VP) was investigated in one trial step-through inhibitory avoidance paradigm. Animals were shocked 3 times in the conditioning trial, with 0.5mA current for 1s. Subsequently bilateral microinjection of the D2 DA receptor agonist quinpirole was administered into the VP in three doses (0.1μg, 1.0μg or 5.0μg in 0.4μl saline). We also applied the D2 DA receptor antagonist sulpiride (0.4μg in 0.4μl saline) alone or 15min prior to the agonist treatment to elucidate whether the agonist effect was specific for the D2 DA receptors. Control animals received saline. In a supplementary experiment, it was also investigated whether application of the same conditioning method leads to the formation of short-term memory in the experimental animals. In the experiment with the D2 DA receptor agonist, only the 0.1μg quinpirole increased significantly the step-through latency during the test trials: retention was significant compared to the controls even 2 weeks after conditioning. The D2 DA receptor antagonist sulpiride pretreatment proved that the effect was due to the agonist induced activation of the D2 DA receptors of the VP. The supplementary experiment demonstrated that short-term memory is formed after conditioning in the experimental animals, supporting that the agonist enhanced memory consolidation in the first two experiments. Our results show that the activation of the D2 DA receptors in the VP facilitates memory consolidation as well as memory-retention in inhibitory avoidance paradigm. Copyright © 2017 Elsevier B.V. All rights reserved.

Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation

PubMed Central

Lambe, Evelyn K.; Aghajanian, George K.

2007-01-01

The fine-tuning of network activity provides a modulating influence on how information is processed and interpreted in the brain. Here, we use brain slices of rat prefrontal cortex to study how recurrent network activity is affected by neuromodulators known to alter normal cortical function. We previously determined that glutamate spillover and stimulation of extrasynaptic NMDA receptors are required to support hallucinogen-induced cortical network activity. Since microdialysis studies suggest that psychedelic hallucinogens and dopamine D1/D5 receptor agonists have opposite effects on extracellular glutamate in prefrontal cortex, we hypothesized that these two families of psychoactive drugs would have opposite effects on cortical network activity. We found that network activity can be enhanced by DOI (a psychedelic hallucinogen that is a partial agonist of serotonin 5-HT2A/2C receptors) and suppressed by the selective D1/D5 agonist SKF 38393. This suppression could be mimicked by direct activation of adenylyl cyclase with forskolin or by addition of a cAMP analog. These findings are consistent with previous work showing that activation of adenylyl cyclase can upregulate neuronal glutamate transporters, thereby decreasing synaptic spillover of glutamate. Consistent with this hypothesis, a low concentration of the glutamate transporter inhibitor TBOA restored electrically-evoked recurrent activity in the presence of a selective D1/D5 agonist, whereas recurrent activity in the presence of a low level of the GABAA antagonist bicuculline was not resistant to suppression by the D1/D5 agonist. The tempering of network UP states by D1/D5 receptor activation may have implications for the proposed use of D1/D5 agonists in the treatment of schizophrenia. PMID:17293055

Hypothalamic neuropeptide Y (NPY) and the attenuation of hyperphagia in streptozotocin diabetic rats treated with dopamine D1/D2 agonists

PubMed Central

Kuo, Dong-Yih

2006-01-01

Dopamine is an appetite suppressant, while neuropeptide Y (NPY), an appetite stimulant in the brain, is reported to be involved in anorectic action induced by a combined administration of D1/D2 agonists in normal rats. In diabetic rats, however, these factors have not been studied. Rats (including normal, diabetic and insulin-treated diabetic rats) were given daily injections of saline or D1/D2 agonists for 6 days. Changes in food intake and hypothalamic NPY content of these rats were assessed and compared. The D1/D2 agonist-induced anorectic responses were altered in diabetic rats compared to normal rats treated similarly. Both the anorectic response on the first day of dosing and the tolerant response on the subsequent days were attenuated. This alteration was independent of the neuroendocrine disturbance on feeding behavior since the basic pattern of food intake during the time course of a 24-h day/night cycle was similar in normal and diabetic rats; the decrease of food intake following drug treatment was only shown at the initial interval of 0–6 h in both groups of rats. However, this alteration coincided with changes in NPY content following D1/D2 coadministration. The replacement of insulin in diabetic rats could normalize both NPY content and D1/D2 agonist-induced anorexia. It is demonstrated that the response of D1/D2 agonist-induced appetite suppression is attenuated in diabetic rats compared to normal rats and that elevated hypothalamic NPY content may contribute to this alteration. PMID:16702993

The delta-opioid receptor agonist SNC80 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] synergistically enhances the locomotor-activating effects of some psychomotor stimulants, but not direct dopamine agonists, in rats.

PubMed

Jutkiewicz, Emily M; Baladi, Michelle G; Folk, John E; Rice, Kenner C; Woods, James H

2008-02-01

The nonpeptidic delta-opioid agonist SNC80 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] produces many stimulant-like behavioral effects in rodents and monkeys, such as locomotor stimulation, generalization to cocaine in discrimination procedures, and antiparkinsonian effects. Tolerance to the locomotor-stimulating effects of SNC80 develops after a single administration of SNC80 in rats; it is not known whether cross-tolerance develops to the effects of other stimulant compounds. In the initial studies to determine whether SNC80 produced cross-tolerance to other stimulant compounds, it was discovered that amphetamine-stimulated locomotor activity was greatly enhanced in SNC80-pretreated rats. This study evaluated acute cross-tolerance between delta-opioid agonists and other locomotor-stimulating drugs. Locomotor activity was measured in male Sprague-Dawley rats implanted with radiotransmitters, and activity levels were recorded in the home cage environment. Three-hour SNC80 pretreatment produced tolerance to further delta-opioid receptor stimulation but also augmented greatly amphetamine-stimulated locomotor activity in a dose-dependent manner. Pretreatments with other delta-opioid agonists, (+)BW373U86 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,N-diethylbenzamide] and oxymorphindole (17-methyl-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7,2',3'-indolomorphinan), also modified amphetamine-induced activity levels. SNC80 pretreatment enhanced the stimulatory effects of the dopamine/norepinephrine transporter ligands cocaine and nomifensine (1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinanmine maleate salt), but not the direct dopamine receptor agonists SKF81297 [R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide] and quinpirole [trans-(-)-(4alphaR)-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g] quinoline monohydrochloride]. In conclusion, SNC80 enhanced the locomotor-stimulating effects of monoamine transporter ligands suggesting that delta-opioid receptor activation might alter the functional activity of monoamine transporters or presynaptic monoamine terminals.

Amineptine treatment of persistent catatonic symptoms in schizophrenia: a controlled study.

PubMed

Ungvari, Gabor S

2010-12-01

Data on the treatment response of enduring catatonic phenomena accompanying chronic schizophrenia are few and far between. The aim of this study was to explore the therapeutic effects of add-on amineptine, a dopamine agonist antidepressant in chronic catatonia occurring in schizophrenia. Fifteen subjects with DSM-IV schizophrenia presenting with persistent catatonic features underwent a 15-week, double-blind, placebo-controlled cross-over trial; they were treated for 6 weeks each with amineptine and a placebo, with a 3-week wash-out period in between. The primary outcome measures were the sum scores of the Bush-Francis Catatonia Rating Scale and the Modified Rogers Scale. Changes in other aspects of psychopathology and extrapyramidal side effects (EPS) constituted the secondary outcome measures. Amineptine augmentation of antipsychotic treatment had no appreciable effect on either of the catatonia ratings. Apart from a statistically significant but clinically negligible improvement in the negative symptom scores, there were no changes in the psychopathology and EPS ratings. The lack of a therapeutic effect of the dopamine agonist amineptine on persistent catatonic signs and symptoms suggests that the dopamine system may not have a decisive role in the pathophysiology of chronic catatonic syndrome arising in the context of schizophrenia.

Critical review of ropinirole and pramipexole - putative dopamine D(3)-receptor selective agonists - for the treatment of RLS.

PubMed

Varga, L I; Ako-Agugua, N; Colasante, J; Hertweck, L; Houser, T; Smith, J; Watty, A A; Nagar, S; Raffa, R B

2009-10-01

Ropinirole hydrochloride (REQUIP, ADARTREL) and pramipexole dihydrochloride (MIRAPEX, SIFROL) are two putative dopamine D(3) receptor subtype-selective agonists recently approved by the FDA for the treatment of 'restless legs syndrome' (RLS). RLS is a difficult to define condition that is possibly more prevalent than previously thought. Direct-to-consumer advertising has raised public and professional awareness of RLS, but questions, even skepticism about the very existence of the condition, persist. The drugs have adverse effects that can negatively impact on quality of life and thus, as true for all drugs, require consideration of the benefit : risk ratio. We review the definition, diagnostic criteria, pathophysiology, and treatment of RLS, and assess the clinical and preclinical evidence for a pharmacologic rationale for D(3) agonism in general and of the claimed D(3) selectivity of ropinirole and pramipexole in particular.

Ventral striatal network connectivity reflects reward learning and behavior in patients with Parkinson's disease.

PubMed

Petersen, Kalen; Van Wouwe, Nelleke; Stark, Adam; Lin, Ya-Chen; Kang, Hakmook; Trujillo-Diaz, Paula; Kessler, Robert; Zald, David; Donahue, Manus J; Claassen, Daniel O

2018-01-01

A subgroup of Parkinson's disease (PD) patients treated with dopaminergic therapy develop compulsive reward-driven behaviors, which can result in life-altering morbidity. The mesocorticolimbic dopamine network guides reward-motivated behavior; however, its role in this treatment-related behavioral phenotype is incompletely understood. Here, mesocorticolimbic network function in PD patients who develop impulsive and compulsive behaviors (ICB) in response to dopamine agonists was assessed using BOLD fMRI. The tested hypothesis was that network connectivity between the ventral striatum and the limbic cortex is elevated in patients with ICB and that reward-learning proficiency reflects the extent of mesocorticolimbic network connectivity. To evaluate this hypothesis, 3.0T BOLD-fMRI was applied to measure baseline functional connectivity on and off dopamine agonist therapy in age and sex-matched PD patients with (n = 19) or without (n = 18) ICB. An incentive-based task was administered to a subset of patients (n = 20) to quantify positively or negatively reinforced learning. Whole-brain voxelwise analyses and region-of-interest-based mixed linear effects modeling were performed. Elevated ventral striatal connectivity to the anterior cingulate gyrus (P = 0.013), orbitofrontal cortex (P = 0.034), insula (P = 0.044), putamen (P = 0.014), globus pallidus (P < 0.01), and thalamus (P < 0.01) was observed in patients with ICB. A strong trend for elevated amygdala-to-midbrain connectivity was found in ICB patients on dopamine agonist. Ventral striatum-to-subgenual cingulate connectivity correlated with reward learning (P < 0.01), but not with punishment-avoidance learning. These data indicate that PD-ICB patients have elevated network connectivity in the mesocorticolimbic network. Behaviorally, proficient reward-based learning is related to this enhanced limbic and ventral striatal connectivity. Hum Brain Mapp 39:509-521, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

The Aversive Agent Lithium Chloride Suppresses Phasic Dopamine Release Through Central GLP-1 Receptors.

PubMed

Fortin, Samantha M; Chartoff, Elena H; Roitman, Mitchell F

2016-02-01

Unconditioned rewarding stimuli evoke phasic increases in dopamine concentration in the nucleus accumbens (NAc) while discrete aversive stimuli elicit pauses in dopamine neuron firing and reductions in NAc dopamine concentration. The unconditioned effects of more prolonged aversive states on dopamine release dynamics are not well understood and are investigated here using the malaise-inducing agent lithium chloride (LiCl). We used fast-scan cyclic voltammetry to measure phasic increases in NAc dopamine resulting from electrical stimulation of dopamine cell bodies in the ventral tegmental area (VTA). Systemic LiCl injection reduced electrically evoked dopamine release in the NAc of both anesthetized and awake rats. As some behavioral effects of LiCl appear to be mediated through glucagon-like peptide-1 receptor (GLP-1R) activation, we hypothesized that the suppression of phasic dopamine by LiCl is GLP-1R dependent. Indeed, peripheral pretreatment with the GLP-1R antagonist exendin-9 (Ex-9) potently attenuated the LiCl-induced suppression of dopamine. Pretreatment with Ex-9 did not, however, affect the suppression of phasic dopamine release by the kappa-opioid receptor agonist, salvinorin A, supporting a selective effect of GLP-1R stimulation in LiCl-induced dopamine suppression. By delivering Ex-9 to either the lateral or fourth ventricle, we highlight a population of central GLP-1 receptors rostral to the hindbrain that are involved in the LiCl-mediated suppression of NAc dopamine release.

Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum.

PubMed

Goutier, W; Lowry, J P; McCreary, A C; O'Connor, J J

2016-05-01

Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D1 receptor (D1R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D1R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500 nM) induced a decrease in dopamine efflux at low frequency (single pulse or five pulses at 10 Hz) and an increase at high frequency (100 Hz) electrical field stimulation. The D1R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D1R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D1R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release.

Effect of inhibiting the lactogenic signal at calving on milk production and metabolic and immune perturbations in dairy cows.

PubMed

Vanacker, N; Ollier, S; Beaudoin, F; Blouin, R; Lacasse, P

2017-07-01

During the periparturient period, the abrupt increase in energy demand for milk production often induces metabolic and immunological disturbances in dairy cows. Our previous work has shown that reducing milk output by milking once a day or incompletely in the first few days of lactation reduces these disturbances. The aim of this study was to reduce metabolic and immunological disturbances by limiting milk production during the first week of lactation by inhibiting the lactogenic signal driven by prolactin. Twenty-two fresh cows received 8 i.m. injections of the prolactin-release inhibitor quinagolide (QUIN; 2 mg) or water as a control (CTL). The first injection was given just after calving, and the subsequent 7 injections were given every 12 h. Milk production was measured until d 28 after calving. Blood samples were taken from d 1 (calving) to d 5 and then on d 7, 10, 14, 21, and 28 to measure concentrations of urea, phosphorus, calcium, glucose, nonesterified fatty acids (NEFA), β-hydroxybutyrate, and prolactin. Other blood samples were taken on d 2, 5, 10, and 28 to analyze oxidative burst, phagocytosis, and the effect of the serum on the lymphoproliferation of peripheral blood mononuclear cells from donor cows. Blood prolactin concentration was lower from d 2 to 5 but higher from d 10 to 28 in the QUIN cows than in the CTL cows. Milk production was lower from d 2 to 6 in the QUIN cows than in the CTL cows (24.3 ± 6.4 and 34.8 ± 4.1 kg/d on average, respectively). We observed no residual effect of quinagolide on milk production after d 6. During the first week of lactation, blood glucose and calcium concentrations were higher and β-hydroxybutyrate concentration was lower in the QUIN cows than in the CTL cows. Blood NEFA, urea, and phosphorus concentrations were not affected by the treatment. At d 2 and 5, the phagocytosis ability of polymorphonuclear leukocytes was not affected by treatment; however, quinagolide injection enhanced the proportion of cells that entered oxidative burst, The mitogen-induced proliferation of peripheral blood mononuclear cells was greater when they were incubated with serum harvested from the CTL cows and was negatively correlated with the NEFA concentration in the serum. Reducing the prolactin peak at calving was effective in reducing milk production during the first week of lactation without compromising the dairy cow's overall productivity. Slowing the increase in milk production allowed a more gradual transition from pregnancy to lactation and led to a reduction in metabolic stress and an improvement in some immune system aspects during this period. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Primary structure and functional characterization of a Drosophila dopamine receptor with high homology to human D1/5 receptors.

PubMed

Gotzes, F; Balfanz, S; Baumann, A

1994-01-01

Members of the superfamily of G-protein coupled receptors share significant similarities in sequence and transmembrane architecture. We have isolated a Drosophila homologue of the mammalian dopamine receptor family using a low stringency hybridization approach. The deduced amino acid sequence is approximately 70% homologous to the human D1/D5 receptors. When expressed in HEK 293 cells, the Drosophila receptor stimulates cAMP production in response to dopamine application. This effect was mimicked by SKF 38393, a specific D1 receptor agonist, but inhibited by dopaminergic antagonists such as butaclamol and flupentixol. In situ hybridization revealed that the Drosophila dopamine receptor is highly expressed in the somata of the optic lobes. This suggests that the receptor might be involved in the processing of visual information and/or visual learning in invertebrates.

Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes.

PubMed

Borroto-Escuela, Dasiel O; Romero-Fernandez, Wilber; Narvaez, Manuel; Oflijan, Julia; Agnati, Luigi F; Fuxe, Kjell

2014-01-03

Dopamine D2LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor-receptor interactions. In the current study the existence of D2L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist (3)H-raclopride binding sites and significantly reduced the pKiH values of the high affinity D2R agonist binding sites in (3)H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists. Copyright © 2013 Elsevier Inc. All rights reserved.

N-octanoyl-dopamine is a potent inhibitor of platelet function.

PubMed

Ait-Hsiko, Lamia; Kraaij, Tineke; Wedel, Johannes; Theisinger, Bastian; Theisinger, Sonja; Yard, Benito; Bugert, Peter; Schedel, Angelika

2013-01-01

Dopamine (DA) is a co-agonist for platelet activation; yet, donor DA treatment is associated with improved transplantation outcome in renal and heart recipients. Recently, N-octanoyl-dopamine (NOD) was developed which displays superior effects compared to DA in terms of graft protecting properties. Whereas DA is a known platelet co-agonist, the effect of NOD on platelet function is unknown. This is a hypothesis generating study with the aim to assess the effects and molecular mechanisms of NOD and NOD-like compounds on platelet function. The influence of DA, NOD, and NOD-like compounds on platelet responses to classical agonists (adenosine 5'-diphosphate (ADP), U46619) was investigated in six healthy donors by applying whole blood aggregometry (Multiplate®) and flow cytometry for Pac-1, CD62P, and CD63 expression. Changes in platelet cAMP concentrations were assessed by ELISA. While DA showed synergy in platelet activation by ADP and U46619, NOD caused significant inhibition of platelet function both in whole blood aggregometry and flow cytometry. The inhibitory effect of NOD was not mediated via cAMP levels. The nonredox-active NOD-analog N-octanoyl-tyramine had no effects on platelet function. Acetylated NOD conferred to NOD by intracellular esterases showed similar inhibitory effects as NOD. In contrast to DA, NOD is a potent inhibitor of platelet function most likely through intracellular redox-active processes. This adds to the overall protective effect of NOD on pre-transplantation injury and makes NOD an attractive candidate compound for donor or organ conditioning prior to transplantation.

Hormonal induction of spawning in 4 species of frogs by coinjection with a gonadotropin-releasing hormone agonist and a dopamine antagonist

PubMed Central

2010-01-01

Background It is well known that many anurans do not reproduce easily in captivity. Some methods are based on administration of mammalian hormones such as human chorionic gonadotropin, which are not effective in many frogs. There is a need for simple, cost-effective alternative techniques to induce spawning. Methods Our new method is based on the injection of a combination of a gonadotropin-releasing hormone (GnRH) agonist and a dopamine antagonist. We have named this formulation AMPHIPLEX, which is derived from the combination of the words amphibian and amplexus. This name refers to the specific reproductive behavior of frogs when the male mounts and clasps the female to induce ovulation and to fertilize the eggs as they are laid. Results We describe the use of the method and demonstrate its applicability for captive breeding in 3 different anuran families. We tested several combinations of GnRH agonists with dopamine antagonists using Lithobates pipiens. The combination of des-Gly10, D-Ala6, Pro-LHRH (0.4 microrams/g body weight) and metoclopramide (10 micrograms/g BWt. MET) was most effective. It was used in-season, after short-term captivity and in frogs artificially hibernated under laboratory conditions. The AMPHIPLEX method was also effective in 3 Argentinian frogs, Ceratophrys ornata, Ceratophrys cranwelli and Odontophrynus americanus. Conclusion Our approach offers some advantages over other hormonally-based techniques. Both sexes are injected only once and at the same time, reducing handling stress. AMPHIPLEX is a new reproductive management tool for captive breeding in Anura. PMID:20398399

Link between D sub 1 and D sub 2 dopamine receptors is reduced in schizophrenia and Huntington diseased brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seeman, P.; Niznik, H.B.; Guan, H.C.

1989-12-01

Dopamine receptor types D{sub 1} and D{sub 2} can oppose enhance each other's actions for electrical, biochemical, and psychomotor effects. The authors report a D{sub 1}-D{sub 2} interaction in homogenized tissue as revealed by ligand binding. D{sub 2} agonists lowered the binding of ({sup 3}H)raclopride to D{sub 2} receptors in striatal and anterior pituitary tissues. Pretreating the tissue with the D{sub 1}-selective antagonist SCH 23390 prevented the agonist-induced decrease in ({sup 3}H)raclopride binding to D{sub 2} sites in the striatum but not in the anterior pituitary, which has no D{sub 1} receptors. Conversely, a dopamine-induced reduction in the binding ofmore » ({sup 3}H)SCH 23390 to D{sub 1} receptors could be prevented by the D{sub 2}-selective antagonist eticlopride. Receptor photolabeling experiments confirmed both these D{sub 1}-D{sub 2} interactions. The blocking effect by SCH 23390 was similar to that produced by a nonhydrolyzable guanine nucleotide analogue, and SCH 23390 reduced the number of agonist-labeled D{sub 2} receptors in the high-affinity state. Thus, the D{sub 1}-D{sub 2} link may be mediated by guanine nucleotide-binding protein components. The link may underlie D{sub 1}-D{sub 2} interactions influencing behavior, since the link was missing in over half the postmortem striata from patients with schizophrenia and Huntington disease (both diseases that show some hyperdopamine signs) but was present in human control, Alzheimer, and Parkinson striata.« less

Dopamine D1-like receptor in lateral habenula nucleus affects contextual fear memory and long-term potentiation in hippocampal CA1 in rats.

PubMed

Chan, Jiangping; Guan, Xin; Ni, Yiling; Luo, Lilu; Yang, Liqiang; Zhang, Pengyue; Zhang, Jichuan; Chen, Yanmei

2017-03-15

The Lateral Habenula (LHb) plays an important role in emotion and cognition. Recent experiments suggest that LHb has functional interaction with the hippocampus and plays an important role in spatial learning. LHb is reciprocally connected with midbrain monoaminergic brain areas such as the ventral tegmental area (VTA). However, the role of dopamine type 1 receptor (D1R) in LHb in learning and memory is not clear yet. In the present study, D1R agonist or antagonist were administered bilaterally into the LHb in rats. We found that both D1R agonist and antagonist impaired the acquisition of contextual fear memory in rats. D1R agonist or antagonist also impaired long term potentiation (LTP) in hippocampal CA3-CA1 synapses in freely moving rats and attenuated learning induced phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) at Ser831 and Ser845 in hippocampus. Taken together, our results suggested that dysfunction of D1R in LHb affected the function of hippocampus. Copyright © 2016 Elsevier B.V. All rights reserved.

Dopamine receptors play distinct roles in sexual behavior expression of rats with a different sexual motivational tone.

PubMed

Guadarrama-Bazante, Irma L; Canseco-Alba, Ana; Rodríguez-Manzo, Gabriela

2014-10-01

Dopamine (DA) plays a central role in the expression of male sexual behavior. The effects of DA-enhancing drugs on copulation seem to vary depending on the dose of the agonist used, the type of DA receptor activated, and the sexual condition of the animals. The aim of the present study was to carry out a systematic analysis of the effects of dopaminergic agonists on the expression of male sexual behavior by sexually competent rats in different sexual motivational states, that is when sexually active (sexually experienced) and when temporarily inhibited (sexually exhausted). To this end, the same doses of the nonselective DA receptor agonist apomorphine, the selective D2-like DA receptor agonist quinpirole, and the selective D1-like DA receptor agonist SKF38393 were injected intraperitoneally to sexually experienced or sexually exhausted male rats and their sexual behavior was recorded. Low apomorphine doses induced expression of sexual behavior in sexually satiated rats, but only reduced the intromission latency of sexually experienced rats. SKF38393 facilitated the expression of sexual behavior by sexually exhausted rats, but not that of sexually experienced males and quinpirole did not exert an effect in both types of animal. In line with these results, the apomorphine-induced reversal of sexual exhaustion was blocked by the D1-like receptor antagonist SCH23390. The data suggest that DA receptors play distinct roles in the expression of sexual behavior by male rats depending on their motivational state and that activation of D1-like receptors promotes the expression of sexual behavior in satiated rats.

5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice.

PubMed

Pogorelov, Vladimir M; Rodriguiz, Ramona M; Cheng, Jianjun; Huang, Mei; Schmerberg, Claire M; Meltzer, Herbert Y; Roth, Bryan L; Kozikowski, Alan P; Wetsel, William C

2017-10-01

All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D 2 or serotonin (5-HT 2A ) receptors, or both; however, these medications are not universally effective, they may produce undesirable side effects, and provide only partial amelioration of negative and cognitive symptoms. The heterogeneity of pharmacological responses in schizophrenic patients suggests that additional drug targets may be effective in improving aspects of this syndrome. Recent evidence suggests that 5-HT 2C receptors may be a promising target for schizophrenia since their activation reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action), they are expressed almost exclusively in CNS, and have weight-loss-promoting capabilities. A difficulty in developing 5-HT 2C agonists is that most ligands also possess 5-HT 2B and/or 5-HT 2A activities. We have developed selective 5-HT 2C ligands and herein describe their preclinical effectiveness for treating schizophrenia-like behaviors. JJ-3-45, JJ-3-42, and JJ-5-34 reduced amphetamine-stimulated hyperlocomotion, restored amphetamine-disrupted prepulse inhibition, improved social behavior, and novel object recognition memory in NMDA receptor hypofunctioning NR1-knockdown mice, and were essentially devoid of catalepsy. However, they decreased motivation in a breakpoint assay and did not promote reversal learning in MK-801-treated mice. Somewhat similar effects were observed with lorcaserin, a 5-HT 2C agonist with potent 5-HT 2B and 5-HT 2A agonist activities, which is approved for treating obesity. Microdialysis studies revealed that both JJ-3-42 and lorcaserin reduced dopamine efflux in the infralimbic cortex, while only JJ-3-42 decreased it in striatum. Collectively, these results provide additional evidence that 5-HT 2C receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.

Role of dopamine D4 receptors in copulatory behavior: Studies with selective D4 agonists and antagonists in male rats.

PubMed

Sanna, Fabrizio; Contini, Andrea; Melis, Maria Rosaria; Argiolas, Antonio

2015-10-01

Dopamine influences the anticipatory and consummatory phases of sexual behavior, by acting on receptors of the D2 family (D2, D3 and D4) and in particular of the D2 subtype, although evidence for a role of D4 receptors in erectile function and copulatory behavior is also available. In order to clarify such a role of D4 receptors, the effect of selective D4 receptor agonists and antagonists on copulatory behavior of sexually potent male rats in classic copulation tests with a receptive female, was compared with that of apomorphine and haloperidol, a classic dopamine receptor agonist and antagonist, respectively. PD-168,077 (0.05-0.2mg/kg) and ABT-724 (0.01-0.04mg/kg), two selective D4 receptor agonists, given subcutaneously, improved dose-dependently copulatory behavior as shown by the decrease of mount frequency and post ejaculatory interval induced by PD-168,077, and of mount frequency, ejaculation latency, post ejaculatory and inter intromission intervals induced by ABT-724, and by the increase of ejaculation frequency and copulatory efficacy induced by both drugs. Conversely, L-745,870 (1-5mg/kg), a selective D4 receptor antagonist, given intraperitoneally, impaired dose-dependently copulatory behavior, as shown by the increase in intromission and ejaculation latencies, mount frequency, post ejaculatory interval and the decrease in ejaculation frequency and copulatory efficacy induced by this drug. L-745,870 (5mg/kg) administered before PD-168,077 (0.2mg/kg) or ABT-724 (0.04mg/kg), also abolished completely the facilitatory effects of both PD-168,077 and ABT-724 on sexual behavior. These results confirm the involvement of D4 receptors in specific aspects of male rat copulatory behavior that overlap only partially with those influenced by apomorphine and haloperidol. Copyright © 2015 Elsevier Inc. All rights reserved.

Blockade of Cocaine or σ Receptor Agonist Self Administration by Subtype-Selective σ Receptor Antagonists.

PubMed

Katz, Jonathan L; Hiranita, Takato; Kopajtic, Theresa A; Rice, Kenner C; Mesangeau, Christophe; Narayanan, Sanju; Abdelazeem, Ahmed H; McCurdy, Christopher R

2016-07-01

The identification of sigma receptor (σR) subtypes has been based on radioligand binding and, despite progress with σ1R cellular function, less is known about σR subtype functions in vivo. Recent findings that cocaine self administration experience will trigger σR agonist self administration was used in this study to assess the in vivo receptor subtype specificity of the agonists (+)-pentazocine, PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], and 1,3-di-o-tolylguanidine (DTG) and several novel putative σR antagonists. Radioligand binding studies determined in vitro σR selectivity of the novel compounds, which were subsequently studied for self administration and antagonism of cocaine, (+)-pentazocine, PRE-084, or DTG self administration. Across the dose ranges studied, none of the novel compounds were self administered, nor did they alter cocaine self administration. All compounds blocked DTG self administration, with a subset also blocking (+)-pentazocine and PRE-084 self administration. The most selective of the compounds in binding σ1Rs blocked cocaine self administration when combined with a dopamine transport inhibitor, either methylphenidate or nomifensine. These drug combinations did not decrease rates of responding maintained by food reinforcement. In contrast, the most selective of the compounds in binding σ2Rs had no effect on cocaine self administration in combination with either dopamine transport inhibitor. Thus, these results identify subtype-specific in vivo antagonists, and the utility of σR agonist substitution for cocaine self administration as an assay capable of distinguishing σR subtype selectivity in vivo. These results further suggest that effectiveness of dual σR antagonism and dopamine transport inhibition in blocking cocaine self administration is specific for σ1Rs and further support this dual targeting approach to development of cocaine antagonists. U.S. Government work not protected by U.S. copyright.

Dopamine, T cells and multiple sclerosis (MS).

PubMed

Levite, Mia; Marino, Franca; Cosentino, Marco

2017-05-01

Dopamine is a key neurotransmitter that induces critical effects in the nervous system and in many peripheral organs, via 5 dopamine receptors (DRs): D1R-D5R. Dopamine also induces many direct and very potent effects on many DR-expressing immune cells, primarily T cells and dendritic cells. In this review, we focus only on dopamine receptors, effects and production in T cells. Dopamine by itself (at an optimal concentration of~0.1 nM) induces multiple function of resting normal human T cells, among them: T cell adhesion, chemotactic migration, homing, cytokine secretion and others. Interestingly, dopamine activates resting effector T cells (Teffs), but suppresses regulatory T cells (Tregs), and both effects lead eventually to Teff activation. Dopamine-induced effects on T cells are dynamic, context-sensitive and determined by the: T cell activation state, T cell type, DR type, and dopamine concentration. Dopamine itself, and also few dopaminergic molecules/ drugs that are in clinical use for cardiac, neurological and other non-immune indications, have direct effects on human T cells (summarized in this review). These dopaminergic drugs include: dopamine = intropin, L-DOPA, bromocriptine, pramipexole, pergolide, haloperidol, pimozide, and amantadine. Other dopaminergic drugs were not yet tested for their direct effects on T cells. Extensive evidence in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) show dopaminergic dysregulations in T cells in these diseases: D1-like DRs are decreased in Teffs of MS patients, and dopamine does not affect these cells. In contrast, D1-like DRs are increased in Tregs of MS patients, possibly causing functional Treg impairment in MS. Treatment of MS patients with interferon β (IFN-β) increases D1-like DRs and decreases D2-like DRs in Teffs, decreases D1-like DRs in Tregs, and most important: restores responsiveness of patient's Teffs to dopamine. DR agonists and antagonists confer some benefits in EAE-afflicted animals. In a single clinical trial, MS patients did not benefit from bromocriptine, which is a D2-like DR agonist. Nevertheless, multiple evidence showing dopaminergic abnormalities in T cells in MS encourages testing other DR analogues/drugs in MS, possibly as "add-on" to IFN-β or other MS-immunomodulating therapies. Together, abnormalities in DRs in T cells can contribute to MS, and DRs in T cells can be therapeutic targets in MS. Finally and in a more general scope: the direct effects of all dopaminergic drugs on human T cells should be studied in further depth, and also taken into consideration whenever treating patients with any disease, to avoid detrimental side effects on the immune system of the patients.

Adenosine A2A receptors modulate the dopamine D2 receptor-mediated inhibition of synaptic transmission in the mouse prefrontal cortex.

PubMed

Real, Joana I; Simões, Ana Patrícia; Cunha, Rodrigo A; Ferreira, Samira G; Rial, Daniel

2018-05-01

Prefrontal cortex (PFC) circuits are modulated by dopamine acting on D 1 - and D 2 -like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A 2A receptors (A 2 A R) also control PFC-related responses and A 2 A R antagonists are potential anti-psychotic drugs. As tight antagonistic A 2 A R-D 2 R and synergistic A 2 A R-D 1 R interactions occur in other brain regions, we now investigated the crosstalk between A 2 A R and D 1 /D 2 R controlling synaptic transmission between layers II/III and V in mouse PFC coronal slices. Dopamine decreased synaptic transmission, a presynaptic effect based on the parallel increase in paired-pulse responses. Dopamine inhibition was prevented by the D 2 R-like antagonist sulpiride but not by the D 1 R antagonist SCH23390 and was mimicked by the D 2 R agonist sumanirole, but not by the agonists of either D 4 R (A-412997) or D 3 R (PD128907). Dopamine inhibition was prevented by the A 2 A R antagonist, SCH58261, and attenuated in A 2 A R knockout mice. Accordingly, triple-labelling immunocytochemistry experiments revealed the co-localization of A 2 A R and D 2 R immunoreactivity in glutamatergic (vGluT1-positive) nerve terminals of the PFC. This reported positive A 2 A R-D 2 R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti-psychotic potential of A 2 A R antagonists. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

The dopamine beta-hydroxylase inhibitor nepicastat increases dopamine release and potentiates psychostimulant-induced dopamine release in the prefrontal cortex.

PubMed

Devoto, Paola; Flore, Giovanna; Saba, Pierluigi; Bini, Valentina; Gessa, Gian Luigi

2014-07-01

The dopamine-beta-hydroxylase inhibitor nepicastat has been shown to reproduce disulfiram ability to suppress the reinstatement of cocaine seeking after extinction in rats. To clarify its mechanism of action, we examined the effect of nepicastat, given alone or in association with cocaine or amphetamine, on catecholamine release in the medial prefrontal cortex and the nucleus accumbens, two key regions involved in the reinforcing and motivational effects of cocaine and in the reinstatement of cocaine seeking. Nepicastat effect on catecholamines was evaluated by microdialysis in freely moving rats. Nepicastat reduced noradrenaline release both in the medial prefrontal cortex and in the nucleus accumbens, and increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. Moreover, nepicastat markedly potentiated cocaine- and amphetamine-induced extracellular dopamine accumulation in the medial prefrontal cortex but not in the nucleus accumbens. Extracellular dopamine accumulation produced by nepicastat alone or by its combination with cocaine or amphetamine was suppressed by the α2 -adrenoceptor agonist clonidine. It is suggested that nepicastat, by suppressing noradrenaline synthesis and release, eliminated the α2 -adrenoceptor mediated inhibitory mechanism that constrains dopamine release and cocaine- and amphetamine-induced dopamine release from noradrenaline or dopamine terminals in the medial prefrontal cortex. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

Where attention falls: Increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function.

PubMed

Sarter, Martin; Albin, Roger L; Kucinski, Aaron; Lustig, Cindy

2014-07-01

Falls are a major source of hospitalization, long-term institutionalization, and death in older adults and patients with Parkinson's disease (PD). Limited attentional resources are a major risk factor for falls. In this review, we specify cognitive-behavioral mechanisms that produce falls and map these mechanisms onto a model of multi-system degeneration. Results from PET studies in PD fallers and findings from a recently developed animal model support the hypothesis that falls result from interactions between loss of basal forebrain cholinergic projections to the cortex and striatal dopamine loss. Striatal dopamine loss produces inefficient, low-vigor gait, posture control, and movement. Cortical cholinergic deafferentation impairs a wide range of attentional processes, including monitoring of gait, posture and complex movements. Cholinergic cell loss reveals the full impact of striatal dopamine loss on motor performance, reflecting loss of compensatory attentional supervision of movement. Dysregulation of dorsomedial striatal circuitry is an essential, albeit not exclusive, mediator of falls in this dual-system model. Because cholinergic neuromodulatory activity influences cortical circuitry primarily via stimulation of α4β2* nicotinic acetylcholine receptors, and because agonists at these receptors are known to benefit attentional processes in animals and humans, treating PD fallers with such agonists, as an adjunct to dopaminergic treatment, is predicted to reduce falls. Falls are an informative behavioral endpoint to study attentional-motor integration by striatal circuitry. Copyright © 2014 Elsevier Inc. All rights reserved.

Where attention falls: Increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function

PubMed Central

Sarter, Martin; Albin, Roger L.; Kucinski, Aaron; Lustig, Cindy

2015-01-01

Falls are a major source of hospitalization, long-term institutionalization, and death in older adults and patients with Parkinson’s disease (PD). Limited attentional resources are a major risk factor for falls. In this review, we specify cognitive–behavioral mechanisms that produce falls and map these mechanisms onto a model of multi-system degeneration. Results from PET studies in PD fallers and findings from a recently developed animal model support the hypothesis that falls result from interactions between loss of basal forebrain cholinergic projections to the cortex and striatal dopamine loss. Striatal dopamine loss produces inefficient, low-vigor gait, posture control, and movement. Cortical cholinergic deafferentation impairs a wide range of attentional processes, including monitoring of gait, posture and complex movements. Cholinergic cell loss reveals the full impact of striatal dopamine loss on motor performance, reflecting loss of compensatory attentional supervision of movement. Dysregulation of dorsomedial striatal circuitry is an essential, albeit not exclusive, mediator of falls in this dual-system model. Because cholinergic neuromodulatory activity influences cortical circuitry primarily via stimulation of α4β2* nicotinic acetylcholine receptors, and because agonists at these receptors are known to benefit attentional processes in animals and humans, treating PD fallers with such agonists, as an adjunct to dopaminergic treatment, is predicted to reduce falls. Falls are an informative behavioral endpoint to study attentional–motor integration by striatal circuitry. PMID:24805070

Effect of dopaminergic drugs on the reserpine-induced lowering of hippocampal theta wave frequency in rats.

PubMed

Nakagawa, T; Ukai, K; Ohyama, T; Gomita, Y; Okamura, H

2000-05-01

The effects of dopaminergic drugs on the lowering of hippocampal theta wave frequency induced by reserpine 1 mg/kg s.c. were examined. Sibutramine (monoamine reuptake inhibitor) 10 mg/kg p.o., methamphetamine (monoamine releaser) 1 mg/kg, quinpirole (dopamine D2 receptor agonist) 10 mg/kg i.p., and SKF 38393 (dopamine D1 receptor agonist) 10 mg/kg i.p. each antagonized the reserpine-induced lowering of hippocampal theta wave frequency in rats. Moreover, the combined administration of SKF 38393 1 mg/kg i.p. and quinpirole 1 mg/kg i.p. synergistically antagonized a reserpine-induced lowering of this frequency. Dosulepin, amitriptyline, and desipramine, which are weak inhibitors of dopamine reuptake, each had little effect on the reserpine-induced lowering of theta wave frequency at a dose of 40 mg/kg p.o. Furthermore, atropine (muscarinic anticholinergic drug) 20 mg/kg p.o. decreased theta wave power in the low-frequency range following a shift to the lower range by reserpine. A positive correlation was observed for each of the above drugs between a reversal of reserpine-induced lowering of theta wave frequency and a reversal of impairment of reserpine-induced conditioned avoidance responses (ACAR) in rats. These results suggest that the reserpine-induced lowering of hippocampal theta wave frequency plays a role in the impairment of reserpine-induced ACAR, and that dopamine D1 and D2 receptors play important roles in antagonizing this lowering of frequency.

Memantine block depends on agonist presentation at the NMDA receptor in substantia nigra pars compacta dopamine neurones

PubMed Central

Wild, A.R.; Akyol, E.; Brothwell, S.L.C.; Kimkool, P.; Skepper, J.N.; Gibb, A.J.; Jones, S.

2015-01-01

NMDA glutamate receptors (NMDARs) have critical functional roles in the nervous system but NMDAR over-activity can contribute to neuronal damage. The open channel NMDAR blocker, memantine is used to treat certain neurodegenerative diseases, including Parkinson’s disease (PD) and is well tolerated clinically. We have investigated memantine block of NMDARs in substantia nigra pars compacta (SNc) dopamine neurones, which show severe pathology in PD. Memantine (10 μM) caused robust inhibition of whole-cell (synaptic and extrasynaptic) NMDARs activated by NMDA at a high concentration or a long duration, low concentration. Less memantine block of NMDAR-EPSCs was seen in response to low frequency synaptic stimulation, while responses to high frequency synaptic stimulation were robustly inhibited by memantine; thus memantine inhibition of NMDAR-EPSCs showed frequency-dependence. By contrast, MK-801 (10 μM) inhibition of NMDAR-EPSCs was not significantly different at low versus high frequencies of synaptic stimulation. Using immunohistochemistry, confocal imaging and stereological analysis, NMDA was found to reduce the density of cells expressing tyrosine hydroxylase, a marker of viable dopamine neurones; memantine prevented the NMDA-evoked decrease. In conclusion, memantine blocked NMDAR populations in different subcellular locations in SNc dopamine neurones but the degree of block depended on the intensity of agonist presentation at the NMDAR. This profile may contribute to the beneficial effects of memantine in PD, as glutamatergic activity is reported to increase, and memantine could preferentially reduce over-activity while leaving some physiological signalling intact. PMID:23727219

Venom of a parasitoid wasp induces prolonged grooming in the cockroach

PubMed

Weisel-Eichler; Haspel; Libersat

1999-04-01

The parasitoid wasp Ampulex compressa hunts cockroaches Periplaneta americana, stinging them first in the thorax and then in the head, the sting penetrating towards the subesophageal ganglion. After being stung the cockroach grooms almost continuously for approximately 30 min, performing all the normal components of grooming behavior. This excessive grooming is only seen after the head sting and cannot be attributed to stress, to contamination of the body surface or to systemic or peripheral effects. This suggests that the venom is activating a neural network for grooming. We suggest that the venom induces prolonged grooming by stimulating dopamine receptors in the cockroach, for the following reasons. (1) Reserpine, which causes massive release of monoamines, induces excessive grooming. (2) Dopamine injected into the hemocoel also induces excessive grooming and is significantly more effective than octopamine or serotonin. In addition, the dopamine agonist SKF 82958 induces excessive grooming when injected directly into the subesophageal ganglion. (3) Injection of the dopamine antagonist flupenthixol greatly reduces venom-induced grooming. (4) Dopamine, or a dopamine-like substance, is present in the venom.

Dopamine modulates the neural representation of subjective value of food in hungry subjects.

PubMed

Medic, Nenad; Ziauddeen, Hisham; Vestergaard, Martin D; Henning, Elana; Schultz, Wolfram; Farooqi, I Sadaf; Fletcher, Paul C

2014-12-10

Although there is a rich literature on the role of dopamine in value learning, much less is known about its role in using established value estimations to shape decision-making. Here we investigated the effect of dopaminergic modulation on value-based decision-making for food items in fasted healthy human participants. The Becker-deGroot-Marschak auction, which assesses subjective value, was examined in conjunction with pharmacological fMRI using a dopaminergic agonist and an antagonist. We found that dopamine enhanced the neural response to value in the inferior parietal gyrus/intraparietal sulcus, and that this effect predominated toward the end of the valuation process when an action was needed to record the value. Our results suggest that dopamine is involved in acting upon the decision, providing additional insight to the mechanisms underlying impaired decision-making in healthy individuals and clinical populations with reduced dopamine levels. Copyright © 2014 the authors 0270-6474/14/3416856-09$15.00/0.

Effects of local infusions of apomorphine on the extracellular citrulline level in the striatum: Involvement of D1 and D2 dopamine receptors.

PubMed

Savel'ev, S A

2006-11-01

Studies using vital microdialysis and high-performance liquid chromatography showed that local infusion of the NO synthase inhibitor N-nitro-L-arginine (1 mM) into the striatum decreased, while infusion of the dopamine receptor agonist apomorphine (100 microM) increased the level of citrulline (a side product of nitric oxide synthesis) in the intercellular space of this structure in Sprague-Dawley rats. The increase in the citrulline level induced by infusions of apomorphine was completely prevented by local infusions of N-nitro-L-arginine (1 mM) and raclopride (10 microm), a dopamine D2 receptor blocker, but not by infusion of SCH-23390 (50 microm), a dopamine D1 receptor blocker. These data suggest that the increase in extracellular citrulline in the striatum induced by dopaminergic stimulation results from local increases in NO synthase activity and that this effect involves D2, but not D1 dopamine receptors.

Evidence for Noncanonical Neurotransmitter Activation: Norepinephrine as a Dopamine D2-Like Receptor Agonist

PubMed Central

Sánchez-Soto, Marta; Bonifazi, Alessandro; Cai, Ning Sheng; Ellenberger, Michael P.; Newman, Amy Hauck

2016-01-01

The Gαi/o-coupled dopamine D2-like receptor family comprises three subtypes: the D2 receptor (D2R), with short and long isoform variants (D2SR and D2LR), D3 receptor (D3R), and D4 receptor (D4R), with several polymorphic variants. The common overlap of norepinephrine innervation and D2-like receptor expression patterns prompts the question of a possible noncanonical action by norepinephrine. In fact, previous studies have suggested that norepinephrine can functionally interact with D4R. To our knowledge, significant interactions between norepinephrine and D2R or D3R receptors have not been demonstrated. By using radioligand binding and bioluminescent resonance energy transfer (BRET) assays in transfected cells, the present study attempted a careful comparison between dopamine and norepinephrine in their possible activation of all D2-like receptors, including the two D2R isoforms and the most common D4R polymorphic variants. Functional BRET assays included activation of G proteins with all Gαi/o subunits, adenylyl cyclase inhibition, and β arrestin recruitment. Norepinephrine acted as a potent agonist for all D2-like receptor subtypes, with the general rank order of potency of D3R > D4R ≥ D2SR ≥ D2L. However, for both dopamine and norepinephrine, differences depended on the Gαi/o protein subunit involved. The most striking differences were observed with Gαi2, where the rank order of potencies for both dopamine and norepinephrine were D4R > D2SR = D2LR >> D3R. Furthermore the results do not support the existence of differences in the ability of dopamine and norepinephrine to activate different human D4R variants. The potency of norepinephrine for adrenergic α2A receptor was only about 20-fold higher compared with D3R and D4R across the three functional assays. PMID:26843180

Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G protein coupled receptor.

PubMed

Weiss, Dahlia R; Ahn, SeungKirl; Sassano, Maria F; Kleist, Andrew; Zhu, Xiao; Strachan, Ryan; Roth, Bryan L; Lefkowitz, Robert J; Shoichet, Brian K

2013-05-17

A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency.

Interactions between aromatase (estrogen synthase) and dopamine in the control of male sexual behavior in quail.

PubMed

Balthazart, Jacques; Baillien, Michelle; Ball, Gregory F

2002-05-01

In male quail, like in other vertebrates including rodents, testosterone acting especially through its estrogenic metabolites is necessary for the activation of male sexual behavior. Also, the administration of dopamine agonists and antagonists profoundly influences male sexual behavior. How the steroid-sensitive neural network and dopamine interact physiologically, remains largely unknown. It is often implicitly assumed that testosterone or its metabolite estradiol, stimulates male sexual behavior via the modification of dopaminergic transmission. We have now identified in quail two possible ways in which dopamine could potentially affect sexual behavior by modulating the aromatization of testosterone into an estrogen. One is a long-acting mechanism that presumably involves the modification of dopaminergic transmission followed by the alteration of the genomic expression of aromatase. The other is a more rapid mechanism that does not appear to be dopamine receptor-mediated and may involve a direct interaction of dopamine with aromatase (possibly via substrate competition). We review here the experimental data supporting the existence of these controls of aromatase activity by dopamine and discuss the possible contribution of these controls to the activation of male sexual behavior.

Lack of dopamine supersensitivity in rats after chronic administration of blonanserin: Comparison with haloperidol.

PubMed

Hashimoto, Takashi; Baba, Satoko; Ikeda, Hiroko; Oda, Yasunori; Hashimoto, Kenji; Shimizu, Isao

2018-07-05

Long-term treatment with antipsychotic drugs in patients with schizophrenia can lead to dopamine supersensitivity psychosis. It is reported that repeated administration of haloperidol caused dopamine supersensitivity in rats. Blonanserin is an atypical antipsychotic drug with high affinity for dopamine D 2 , D 3 and serotonin 2A receptors. In this study, we investigated whether chronic administration of blonanserin leads to dopamine supersensitivity. Following oral treatment with blonanserin (0.78 mg/kg) or haloperidol (1.1 mg/kg) twice daily for 28 days, the dopamine D 2 agonist quinpirole-induced hyperlocomotion test and a dopamine D 2 receptor binding assay were conducted. We found that haloperidol significantly enhanced both quinpirole-induced hyperlocomotion and striatal dopamine D 2 receptor density in rats. On the other hand, repeated administration of blonanserin had no effect on either locomotor activity or striatal dopamine D 2 receptor density. Further, our results show that mRNA levels of dopamine D 2 and D 3 receptors in several brain regions were unaffected by repeated administration of both agents. In addition, we examined the effect of the dopamine D 3 receptor antagonist PG-01037 on development of dopamine supersensitivity induced by chronic haloperidol treatment and showed that PG-01037 prevents the development of supersensitivity to quinpirole in chronic haloperidol-treated rats. Given the higher affinity of blonanserin at dopamine D 3 receptors than haloperidol, antagonism of blonanserin at dopamine D 3 receptors may play a role in lack of dopamine supersensitivity after chronic administration. The present findings suggest long-term treatment with antipsychotic dose of blonanserin may be unlikely to lead to dopamine supersensitivity. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Treatment of Parkinson’s disease: nanostructured sol–gel silica–dopamine reservoirs for controlled drug release in the central nervous system

PubMed Central

López, Tessy; Bata-García, José L; Esquivel, Dulce; Ortiz-Islas, Emma; Gonzalez, Richard; Ascencio, Jorge; Quintana, Patricia; Oskam, Gerko; Álvarez-Cervera, Fernando J; Heredia-López, Francisco J; Góngora-Alfaro, José L

2011-01-01

Introduction We have evaluated the use of silica–dopamine reservoirs synthesized by the sol–gel approach with the aim of using them in the treatment of Parkinson’s disease, specifically as a device for the controlled release of dopamine in the striatum. Theoretical calculations illustrate that dopamine is expected to assume a planar structure and exhibit weak interactions with the silica surface. Methods Several samples were prepared by varying the wt% of dopamine added during the hydrolysis of tetraethyl orthosilicate. The silica–dopamine reservoirs were characterized by N2 adsorption, scanning and transmission electron microscopy, and Fourier transform infrared spectroscopy. The in vitro release profiles were determined using ultraviolet visible absorbance spectroscopy. The textural analyses showed a maximum value for the surface area of 620 m2/g nanostructured silica materials. The stability of dopamine in the silica network was confirmed by infrared and 13C-nuclear magnetic resonance spectroscopy. The reservoirs were evaluated by means of apomorphine-induced rotation behavior in hemiparkisonian rats. Results The in vitro dopamine delivery profiles indicate two regimes of release, a fast and sustained dopamine delivery was observed up to 24 hours, and after this time the rate of delivery became constant. Histologic analysis of formalin-fixed brains performed 24–32 weeks after reservoir implantation revealed that silica–dopamine implants had a reddish-brown color, suggesting the presence of oxidized dopamine, likely caused by the fixation procedure, while implants without dopamine were always translucent. Conclusion The major finding of the study was that intrastriatal silica–dopamine implants reversed the rotational asymmetry induced by apomorphine, a dopamine agonist, in hemiparkinsonian rats. No dyskinesias or other motor abnormalities were observed in animals implanted with silica or silica–dopamine. PMID:21289978

Development of a Rapid Insulin Assay by Homogenous Time-Resolved Fluorescence

PubMed Central

Vallaghe, Julie; Gregor, Nathalie; Donthamsetti, Prashant; Harris, Paul E.; Pierre, Nicolas; Freyberg, Robin; Charrier-Savournin, Fabienne; Javitch, Jonathan A.; Freyberg, Zachary

2016-01-01

Direct measurement of insulin is critical for basic and clinical studies of insulin secretion. However, current methods are expensive and time-consuming. We developed an insulin assay based on homogenous time-resolved fluorescence that is significantly more rapid and cost-effective than current commonly used approaches. This assay was applied effectively to an insulin secreting cell line, INS-1E cells, as well as pancreatic islets, allowing us to validate the assay by elucidating mechanisms by which dopamine regulates insulin release. We found that dopamine functioned as a significant negative modulator of glucose-stimulated insulin secretion. Further, we showed that bromocriptine, a known dopamine D2/D3 receptor agonist and newly approved drug used for treatment of type II diabetes mellitus, also decreased glucose-stimulated insulin secretion in islets to levels comparable to those caused by dopamine treatment. PMID:26849707

Aripiprazole.

PubMed

Prommer, Eric

2017-03-01

Delirium is a palliative care emergency where patients experience changes in perception, awareness, and behavior. Common features include changes in the sleep-wake cycle, emotional lability, delusional thinking, and language and thought disorders. Delirium results from neurotransmitter imbalances involving several neurotransmitters such as dopamine, glutamate, norepinephrine, acetylcholine, gamma-aminobutyric acid, and serotonin. Untreated delirium causes significant morbidity and mortality. Nonpharmacologic and pharmacologic approaches treat delirium. Current pharmacologic management of delirium involves using agents such as haloperidol or second-generation antipsychotics. Third-generation atypical antipsychotic drugs have emerged as a potential choice for delirium management. Aripiprazole is a third-generation antipsychotic with a dopamine receptor-binding profile distinct from other second-generation antipsychotics. Aripiprazole acts as partial agonist at dopamine D 2 and 5-hydroxytryptamine (5-HT) 1A receptors, stabilizing the dopamine receptor leading to improvement in symptoms. The article reviews the pharmacology, pharmacodynamics, metabolism, and evidence of clinical efficacy for this new antipsychotic agent. This article explores possible roles in palliative care.

A Shared Molecular and Genetic Basis for Food and Drug Addiction: Overcoming Hypodopaminergic Trait/State by Incorporating Dopamine Agonistic Therapy in Psychiatry.

PubMed

Gold, Mark S; Badgaiyan, Rajendra D; Blum, Kenneth

2015-09-01

This article focuses on the shared molecular and neurogenetics of food and drug addiction tied to the understanding of reward deficiency syndrome. Reward deficiency syndrome describes a hypodopaminergic trait/state that provides a rationale for commonality in approaches for treating long-term reduced dopamine function across the reward brain regions. The identification of the role of DNA polymorphic associations with reward circuitry has resulted in new understanding of all addictive behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

Methamphetamine-like discriminative stimulus effects of bupropion and its two hydroxy metabolites in male rhesus monkeys.

PubMed

Banks, Matthew L; Smith, Douglas A; Blough, Bruce E

2016-04-01

The dopamine transporter (DAT) inhibitor and nicotinic acetylcholine (nACh) receptor antagonist bupropion is being investigated as a candidate 'agonist' medication for methamphetamine addiction. In addition to its complex pharmacology, bupropion also has two distinct pharmacologically active metabolites. However, the mechanism by which bupropion produces methamphetamine-like 'agonist' effects remains unknown. The aim of the present study was to determine the role of DAT inhibition, nACh receptor antagonism, and the hydroxybupropion metabolites in the methamphetamine-like discriminative stimulus effects of bupropion in rhesus monkeys. In addition, varenicline, a partial agonist at the nACh receptor, and risperidone, a dopamine antagonist, were tested as controls. Monkeys (n=4) were trained to discriminate 0.18 mg/kg intramuscular methamphetamine from saline in a two-key food-reinforced discrimination procedure. The potency and time course of methamphetamine-like discriminative stimulus effects were determined for all compounds. Bupropion, methylphenidate, and 2S,3S-hydroxybupropion produced full, at least 90%, methamphetamine-like effects. 2R,3R-Hydroxybupropion, mecamylamine, and nicotine also produced full methamphetamine-like effects, but drug potency was more variable between monkeys. Varenicline produced partial methamphetamine-like effects, whereas risperidone did not. Overall, these results suggest DAT inhibition as the major mechanism of the methamphetamine-like 'agonist' effects of bupropion, although nACh receptor antagonism appeared, at least partially, to contribute. Furthermore, the contribution of the 2S,3S-hydroxybupropion metabolite could not be completely ruled out.

Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole.

PubMed

Modi, Meera E; Inoue, Kiyoshi; Barrett, Catherine E; Kittelberger, Kara A; Smith, Daniel G; Landgraf, Rainer; Young, Larry J

2015-07-01

The central melanocortin (MC) system has been widely studied for its effects on food intake and sexual behavior. However, the MC system, and more specifically the MC4 receptor (MC4R), also interacts with neurochemical systems that regulate socioemotional behaviors, including oxytocin (OT) and dopamine. In monogamous prairie voles, OT and dopamine interact to promote partner preference formation, a laboratory measure of an enduring social bond between mates. Here we investigated the effects of MC receptor activation on partner preference formation in prairie voles, as well as the interaction between the MC and OT systems during this process. Peripheral administration of the brain penetrant MC3/4R receptor peptide agonist, Melanotan II (MTII), and the highly selective, small-molecule MC4R agonist, Pf-446687, enhanced partner preference formation in the prairie vole, but not in the non-monogamous meadow vole. MTII-induced partner preferences were enduring, as they were present 1 week after drug manipulation. The prosocial effects of MCR agonists may be mediated, in part, through modulation of OT, as coadministration of an OT receptor antagonist prevented MTII-induced partner preferences. MTII also selectively activated hypothalamic OT neurons and potentiated central OT release. As OT has been shown to enhance some aspects of social cognition in humans, our data suggest that the MC4R may be a viable therapeutic target for enhancing social function in psychiatric disorders, including autism spectrum disorders and schizophrenia, potentially through activation of the OT system.

Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole

PubMed Central

Modi, Meera E; Inoue, Kiyoshi; Barrett, Catherine E; Kittelberger, Kara A; Smith, Daniel G; Landgraf, Rainer; Young, Larry J

2015-01-01

The central melanocortin (MC) system has been widely studied for its effects on food intake and sexual behavior. However, the MC system, and more specifically the MC4 receptor (MC4R), also interacts with neurochemical systems that regulate socioemotional behaviors, including oxytocin (OT) and dopamine. In monogamous prairie voles, OT and dopamine interact to promote partner preference formation, a laboratory measure of an enduring social bond between mates. Here we investigated the effects of MC receptor activation on partner preference formation in prairie voles, as well as the interaction between the MC and OT systems during this process. Peripheral administration of the brain penetrant MC3/4R receptor peptide agonist, Melanotan II (MTII), and the highly selective, small-molecule MC4R agonist, Pf-446687, enhanced partner preference formation in the prairie vole, but not in the non-monogamous meadow vole. MTII-induced partner preferences were enduring, as they were present 1 week after drug manipulation. The prosocial effects of MCR agonists may be mediated, in part, through modulation of OT, as coadministration of an OT receptor antagonist prevented MTII-induced partner preferences. MTII also selectively activated hypothalamic OT neurons and potentiated central OT release. As OT has been shown to enhance some aspects of social cognition in humans, our data suggest that the MC4R may be a viable therapeutic target for enhancing social function in psychiatric disorders, including autism spectrum disorders and schizophrenia, potentially through activation of the OT system. PMID:25652247

Development of dopamine receptor radiopharmaceuticals for the study of neurological and psychiatric disorders

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dr. Jogeshwar Mukherjee

Our goals in this grant application are directed towards the development of radiotracers that may allow the study of the high-affinity state (functional state) of the dopamine receptors. There have been numerous reports on the presence of two inter-convertible states of these (G-protein coupled) receptors in vitro. However, there is no report that establishes the presence of these separate affinity states in vivo. We have made efforts in this direction in order to provide such direct in vivo evidence about the presence of the high affinity state. This understanding of the functional state of the receptors is of critical significancemore » in our overall diagnosis and treatment of diseases that implicate the G-protein coupled receptors. Four specific aims have been listed in the grant application: (1). Design and syntheses of agonists (2). Radiosyntheses of agonists (3). In vitro pharmacology of agonists (4). In vivo distribution and pharmacology of labeled derivatives. We have accomplished the syntheses and radiosyntheses of three agonist radiotracers labeled with carbon-11. In vitro and in vivo pharmacological experiments have been accomplished in rats and preliminary PET studies in non-human primates have been carried out. Various accomplishments during the funded years, briefly outlined in this document, have been disseminated by several publications in various journals and presentations in national and international meetings (Society of Nuclear Medicine, Society for Neuroscience and International Symposium on Radiopharmaceutical Chemistry).« less

Characterization of the effects of serotonin on the release of (/sup 3/H)dopamine from rat nucleus accumbens and striatal slices

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nurse, B.; Russell, V.A.; Taljaard, J.J.

1988-05-01

The effect of serotonin agonists on the depolarization (K+)-induced, calcium-dependent, release of (/sup 3/H)dopamine (DA) from rat nucleus accumbens and striatal slices was investigated. Serotonin enhanced basal /sup 3/H overflow and reduced K+-induced release of (/sup 3/H)DA from nucleus accumbens slices. The effect of serotonin on basal /sup 3/H overflow was not altered by the serotonin antagonist, methysergide, or the serotonin re-uptake blocker, chlorimipramine, but was reversed by the DA re-uptake carrier inhibitors nomifensine and benztropine. With the effect on basal overflow blocked, serotonin did not modulate K+-induced release of (/sup 3/H)DA in the nucleus accumbens or striatum. The serotoninmore » agonists, quipazine (in the presence of nomifensine) and 5-methoxytryptamine, did not significantly affect K+-induced release of (/sup 3/H)DA in the nucleus accumbens. This study does not support suggestions that serotonin receptors inhibit the depolarization-induced release of dopamine in the nucleus accumbens or striatum of the rat brain. The present results do not preclude the possibility that serotonin may affect the mesolimbic reward system at a site which is post-synaptic to dopaminergic terminals in the nucleus accumbens.« less

Clinical Pharmacokinetics and Pharmacodynamics of Safinamide.

PubMed

Müller, Thomas; Foley, Paul

2017-03-01

The symptoms of Parkinson's disease (PD) reflect disruptions of a number of brain neurotransmitter systems of varying type and degree. Pharmacological agents with multiple neurochemical mechanisms of action are therefore promising candidates for countering these problems and providing comprehensive symptomatic relief for patients. The pharmacological profile of safinamide includes reversible monoamine oxidase B inhibition, blockage of voltage-dependent Na + channels, modulation of Ca 2+ channels, and inhibition of glutamate release. Safinamide is administered once daily at oral doses of 50-100 mg; it is well-tolerated and safe. Clinical trials have found that it ameliorates motor symptoms when added to established levodopa or single dopamine receptor agonist therapy. The future role of safinamide in PD may be that it enables a reduction in the dosage of dopamine replacement therapies, thereby reducing the adverse effects associated with these treatments. The clinical convenience (once-daily administration), safety, and tolerability of safinamide are better than those of dopamine receptor agonists. The introduction of safinamide reflects a change of approach to drug development for anti-parkinsonian agents in that its broad spectrum of action corresponds to the multiple heterogeneous alterations of brain neurochemistry in PD, rather than being targeted at a single receptor type or neurochemical process. Safinamide is a promising new instrument for the effective symptomatic therapy of PD.

An expert opinion on safinamide in Parkinson's disease.

PubMed

Onofrj, Marco; Bonanni, Laura; Thomas, Astrid

2008-07-01

Dopamine replacement therapies (levodopa, dopamine receptor agonists, anticholinergics, monoamine oxidase B inhibitors, and catechol-O-methyltransferase inhibitors) remain the cornerstones of therapeutic interventions for Parkinson's disease (PD). Despite the treatment options for PD symptoms, a cure remains elusive. An optimal treatment would be one that combined relief in both motor and nonmotor symptoms with neuroprotective properties. Safinamide is an investigational drug for PD currently in development as add-on therapy to both dopamine agonists and levodopa. Safinamide is a unique molecule with a novel mode of action, targeting both dopaminergic and glutaminergic systems, and potentially provides motor symptom control. Preliminary results from experimental models suggest potential neuroprotective effects. Studies on the potential effects on nonmotor symptoms are ongoing. To review the mechanism of action and pharmacokinetics, and to evaluate the available clinical safety and efficacy results of safinamide. A search of the electronic database MEDLINE (PubMed, no time limits) was performed on 14 December 2007. The full text of all citations was obtained for review. Furthermore, two abstracts on safinamide published as proceedings of a European conference were reviewed. Safinamide is a promising investigational drug for PD with a novel mode of action. Early reports confirm the potential efficacy of safinamide in PD. Further studies on potential effects on cognition and neuroprotection are needed.

Dopamine Mediates the Vagal Modulation of the Immune System by Electroacupuncture

PubMed Central

Torres-Rosas, Rafael; Yehia, Ghassan; Peña, Geber; Mishra, Priya; del Rocio Thompson-Bonilla, Maria; Moreno-Eutimio, Mario Adán; Arriaga-Pizano, Lourdes Andrea; Isibasi, Armando; Ulloa, Luis

2014-01-01

Previous anti-inflammatory strategies against sepsis, a leading cause of death in hospitals, had limited efficacy in clinical trials, in part because they targeted single cytokines and the experimental models failed to mimic clinical settings1-3. Neuronal networks represent physiological mechanisms selected by evolution to control inflammation that can be exploited for the treatment of inflammatory and infectious disorders3. Here, we report that sciatic nerve activation with electroacupuncture controls systemic inflammation and rescues mice from polymicrobial peritonitis. Electroacupuncture at the sciatic nerve controls systemic inflammation by inducing a vagal activation of DOPA decarboxylase leading to the production of dopamine in the adrenal medulla. Experimental models with adrenolectomized animals mimic clinical adrenal insufficiency4, increase the susceptibility to sepsis, and prevent the anti-inflammatory potential of electroacupuncture. Dopamine inhibits cytokine production via dopaminergic type-1 receptors. Dopaminergic D1-agonists suppress systemic inflammation and rescue mice from polymicrobial peritonitis in animals with adrenal insufficiency. Our results suggest a novel anti-inflammatory mechanism mediated by the sciatic and the vagus nerves modulating the production of catecholamines in the adrenal glands. From a pharmacological perspective, selective dopaminergic agonists mimic the anti-inflammatory potential of electroacupuncture and can provide therapeutic advantages to control inflammation in infectious and inflammatory disorders. PMID:24562381

Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats.

PubMed

Zbukvic, Isabel C; Ganella, Despina E; Perry, Christina J; Madsen, Heather B; Bye, Christopher R; Lawrence, Andrew J; Kim, Jee Hyun

2016-06-01

Adolescent drug users display resistance to treatment such as cue exposure therapy (CET), as well as increased liability to relapse. The basis of CET is extinction learning, which involves dopamine signaling in the medial prefrontal cortex (mPFC). This system undergoes dramatic alterations during adolescence. Therefore, we investigated extinction of a cocaine-associated cue in adolescent and adult rats. While cocaine self-administration and lever-alone extinction were not different between the two ages, we observed that cue extinction reduced cue-induced reinstatement in adult but not adolescent rats. Infusion of the selective dopamine 2 receptor (D2R)-like agonist quinpirole into the infralimbic cortex (IL) of the mPFC prior to cue extinction significantly reduced cue-induced reinstatement in adolescents. This effect was replicated by acute systemic treatment with the atypical antipsychotic aripiprazole (Abilify), a partial D2R-like agonist. These data suggest that adolescents may be more susceptible to relapse due to a deficit in cue extinction learning, and highlight the significance of D2R signaling in the IL for cue extinction during adolescence. These findings inspire new tactics for improving adolescent CET, with aripiprazole representing an exciting potential pharmacological adjunct for behavioral therapy. © The Author 2016. Published by Oxford University Press.

Specific effect of a dopamine partial agonist on counterfactual learning: evidence from Gilles de la Tourette syndrome.

PubMed

Salvador, Alexandre; Worbe, Yulia; Delorme, Cécile; Coricelli, Giorgio; Gaillard, Raphaël; Robbins, Trevor W; Hartmann, Andreas; Palminteri, Stefano

2017-07-24

The dopamine partial agonist aripiprazole is increasingly used to treat pathologies for which other antipsychotics are indicated because it displays fewer side effects, such as sedation and depression-like symptoms, than other dopamine receptor antagonists. Previously, we showed that aripiprazole may protect motivational function by preserving reinforcement-related signals used to sustain reward-maximization. However, the effect of aripiprazole on more cognitive facets of human reinforcement learning, such as learning from the forgone outcomes of alternative courses of action (i.e., counterfactual learning), is unknown. To test the influence of aripiprazole on counterfactual learning, we administered a reinforcement learning task that involves both direct learning from obtained outcomes and indirect learning from forgone outcomes to two groups of Gilles de la Tourette (GTS) patients, one consisting of patients who were completely unmedicated and the other consisting of patients who were receiving aripiprazole monotherapy, and to healthy subjects. We found that whereas learning performance improved in the presence of counterfactual feedback in both healthy controls and unmedicated GTS patients, this was not the case in aripiprazole-medicated GTS patients. Our results suggest that whereas aripiprazole preserves direct learning of action-outcome associations, it may impair more complex inferential processes, such as counterfactual learning from forgone outcomes, in GTS patients treated with this medication.

Classics in Chemical Neuroscience: Aripiprazole.

PubMed

Casey, Austen B; Canal, Clinton E

2017-06-21

Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D 2 autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D 2 receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D 2 receptor antagonists. Extensive blockade of these receptors, however, typically produces extrapyramidal (movement) side effects, which plagued first-generation antipsychotics, such as haloperidol. Second-generation antipsychotics, such as clozapine, with unique polypharmacology and D 2 receptor binding kinetics, have significantly lower risk of movement side effects but can cause myriad additional ones, such as severe weight gain and metabolic dysfunction. Aripiprazole's polypharmacology, characterized by its unique agonist activity at dopamine D 2 and D 3 and serotonin 5-HT 1A receptors, as well as antagonist activity at serotonin 5-HT 2A receptors, translates to successful reduction of positive, negative, and cognitive symptoms of schizophrenia, while also mitigating risk of weight gain and movement side effects. New observations, however, link aripiprazole to compulsive behaviors in a small group of patients, an unusual side effect for antipsychotics. In this review, we discuss the chemical synthesis, pharmacology, pharmacogenomics, drug metabolism, and adverse events of aripiprazole, and we present a current understanding of aripiprazole's neurotherapeutic mechanisms, as well as the history and importance of aripiprazole to neuroscience.

Pharmacological analysis of zebrafish lphn3.1 morphant larvae suggests that saturated dopaminergic signaling could underlie the ADHD-like locomotor hyperactivity.

PubMed

Lange, Merlin; Froc, Cynthia; Grunwald, Hannah; Norton, William H J; Bally-Cuif, Laure

2018-06-08

Polymorphisms in the gene coding for the adhesion G-protein coupled receptor LPHN3 are a risk factor for attention-deficit/hyperactivity disorder (ADHD). Transient down-regulation of latrophilin3.1 (lphn3.1), the zebrafish LPHN3 homologue, causes hyperactivity. Zebrafish injected with a lphn3.1-specific morpholino are hyperactive and display an impairment in dopaminergic neuron development. In the present study we used lphn3.1 morphants to further characterize the changes to dopaminergic signaling that trigger hyperactivity. We applied dopamine agonists (Apomorphine, Quinpirole, SKF-38393) and antagonists (Haloperidol, Eticlopride, SCH-23390) to Lphn3.1 morpholino-injected or control-injected animals. The percentage of change in locomotor activity was then determined at three different time periods (10-20 min, 30-40 min and 60-70 min). Our results show that drugs targeting dopamine receptors appear to elicit similar effects on locomotion in zebrafish larvae and mammals. In addition, we observed that lphn3.1 morphants have an overall hyposensitivity to dopamine agonists and antagonists compared to control fish. These results are compatible with a model whereby dopaminergic neurotransmission is saturated in lphn3.1 morphants. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical neuromodulation of frontal-executive functions in humans and other animals.

PubMed

Robbins, T W

2000-07-01

Neuromodulation of frontal-executive function is reviewed in the context of experiments on rats, monkeys and human subjects. The different functions of the chemically identified systems of the reticular core are analysed from the perspective of their possible different interactions with the prefrontal cortex. The role of dopamine in spatial working memory is reviewed, taking account of its deleterious as well as facilitatory effects. Baseline-dependent effects of dopaminergic manipulation are described in rats on an attentional task, including evidence of enhanced function following infusions of D1 receptor agonists into the prefrontal cortex. The precise nature of the cognitive task under study is shown to be a powerful determinant of the effects of mesofrontal dopamine depletion in monkeys. Parallels are identified in human subjects receiving drugs such as the indirect catecholamine agonists L-dopa, methylphenidate and the dopamine D2 receptor blocker sulpiride. The effects of these drugs on different types of cognitive function sensitive to frontal lobe dysfunction are contrasted with those of a manipulation of 5-HT function, dietary tryptophan depletion. Hypotheses are advanced that accord the ascending systems a greater deal of specificity in modulating prefrontal cortical function than has hitherto been entertained, and clinical and theoretical implications of this hypothesis are discussed.

Differential involvement of dopamine D-1 and D-2 receptors in the circling behaviour induced by apomorphine, SK & F 38393, pergolide and LY 171555 in 6-hydroxydopamine-lesioned rats.

PubMed

Arnt, J; Hyttel, J

1985-01-01

The antagonistic effect of dopamine (DA) D-1 and D-2 antagonists against circling behaviour induced by various DA agonists in 6-OHDA-lesioned rats has been investigated. DA D-1/D-2 selectivity of agonists in vitro was measured by the stimulatory effect on DA-sensitive adenylate cyclase in rat striatal homogenates (D-1), the inhibitory effect on electrically-induced release of 3H-DA in rabbit striatal slices (D-2) and the affinity to 3H-piflutixol (D-1) and 3H-spiroperidol (D-2) binding sites in rat striatal membranes. The contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 was blocked by the DA D-1 antagonist, SCH 23390, and by the mixed DA D-1/D-2 antagonist cis(Z)-flupentixol, but was not influenced by the DA D-2 antagonists spiroperidol and clebopride. In contrast, circling behaviour induced by the preferential DA D-2 agonists pergolide and LY 171555 was blocked by clebopride, spiroperidol, and cis(Z)-flupentixol, but weakly or not influenced by SCH 23390. Apomorphine-induced circling behaviour was blocked by cis(Z)-flupentixol, partially antagonized by SCH 23390 and clebopride but not inhibited by spiroperidol, although the time-course of circling was changed. Combinations of SCH 23390 with spiroperidol or clebopride in low doses completely blocked the effect of apomorphine. These results indicate that DA D-1 and D-2 receptors mediate circling behaviour through separate mechanisms which can be independently manipulated with respective agonists and antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced dopamine D2 autoreceptor function in the adult prefrontal cortex contributes to dopamine hypoactivity following adolescent social stress.

PubMed

Weber, Matthew A; Graack, Eric T; Scholl, Jamie L; Renner, Kenneth J; Forster, Gina L; Watt, Michael J

2018-06-14

Adult psychiatric disorders characterized by cognitive deficits reliant on prefrontal cortex (PFC) dopamine are promoted by teenage bullying. Similarly, male Sprague-Dawley rats exposed to social defeat in mid-adolescence (P35-39) show impaired working memory in adulthood (P56-70), along with decreased medial PFC (mPFC) dopamine activity that results in part from increased dopamine transporter-mediated clearance. Here, we determined if dopamine synthesis and D2 autoreceptor-mediated inhibition of dopamine release in the adult mPFC are also enhanced by adolescent defeat to contribute to later dopamine hypofunction. Control and previously defeated rats did not differ in either DOPA accumulation following amino acid decarboxylase inhibition (NSD-1015 100 mg/kg ip.) or total/phosphorylated tyrosine hydroxylase protein expression, suggesting dopamine synthesis in the adult mPFC is not altered by adolescent defeat. However, exposure to adolescent defeat caused greater decreases in extracellular dopamine release (measured using in vivo chronoamperometry) in the adult mPFC upon local infusion of the D2 receptor agonist quinpirole (3 nM), implying greater D2 autoreceptor function. Equally enhanced D2 autoreceptor-mediated inhibition of dopamine release is seen in the adolescent (P40 or P49) mPFC, which declines in control rats by adulthood. However, this developmental decrease in autoreceptor function is absent following adolescent defeat, suggesting retention of an adolescent-like phenotype into adulthood. Current and previous findings indicate adolescent defeat decreases extracellular dopamine availability in the adult mPFC via both enhanced inhibition of dopamine release and increased dopamine clearance, which may be viable targets for improving treatment of cognitive deficits seen in neuropsychiatric disorders promoted by adolescent stress. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson's disease.

PubMed

Fox, Susan H; Katzenschlager, Regina; Lim, Shen-Yang; Barton, Brandon; de Bie, Rob M A; Seppi, Klaus; Coelho, Miguel; Sampaio, Cristina

2018-03-23

The objective of this review was to update evidence-based medicine recommendations for treating motor symptoms of Parkinson's disease (PD). The Movement Disorder Society Evidence-Based Medicine Committee recommendations for treatments of PD were first published in 2002 and updated in 2011, and we continued the review to December 31, 2016. Level I studies of interventions for motor symptoms were reviewed. Criteria for inclusion and quality scoring were as previously reported. Five clinical indications were considered, and conclusions regarding the implications for clinical practice are reported. A total of 143 new studies qualified. There are no clinically useful interventions to prevent/delay disease progression. For monotherapy of early PD, nonergot dopamine agonists, oral levodopa preparations, selegiline, and rasagiline are clinically useful. For adjunct therapy in early/stable PD, nonergot dopamine agonists, rasagiline, and zonisamide are clinically useful. For adjunct therapy in optimized PD for general or specific motor symptoms including gait, rivastigmine is possibly useful and physiotherapy is clinically useful; exercise-based movement strategy training and formalized patterned exercises are possibly useful. There are no new studies and no changes in the conclusions for the prevention/delay of motor complications. For treating motor fluctuations, most nonergot dopamine agonists, pergolide, levodopa ER, levodopa intestinal infusion, entacapone, opicapone, rasagiline, zonisamide, safinamide, and bilateral STN and GPi DBS are clinically useful. For dyskinesia, amantadine, clozapine, and bilateral STN DBS and GPi DBS are clinically useful. The options for treating PD symptoms continues to expand. These recommendations allow the treating physician to determine which intervention to recommend to an individual patient. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society.

You are what you eat: influence of type and amount of food consumed on central dopamine systems and the behavioral effects of direct- and indirect-acting dopamine receptor agonists

PubMed Central

Baladi, Michelle G; Daws, Lynette C; France, Charles P

2012-01-01

The important role of dopamine (DA) in mediating feeding behavior and the positive reinforcing effects of some drugs is well recognized. Less widely studied is how feeding conditions might impact the sensitivity of drugs acting on DA systems. Food restriction, for example, has often been the focus of aging and longevity studies; however, other studies have demonstrated that mild food restriction markedly increases sensitivity to direct- and indirect-acting DA receptor agonists. Moreover, it is becoming clear that not only the amount of food, but the type of food, is an important factor in modifying the effects of drugs. Given the increased consumption of high fat and sugary foods, studies are exploring how consumption of highly palatable food impacts DA neurochemistry and the effects of drugs acting on these systems. For example, eating high fat chow increases sensitivity to some behavioral effects of direct- as well as indirect-acting DA receptor agonists. A compelling mechanistic possibility is that the central DA pathways that mediate the effects of some drugs are regulated by one or more of the endocrine hormones (e.g. insulin) that undergo marked changes during food restriction or after consuming high fat or sugary foods. Although traditionally recognized as an important signaling molecule in regulating energy homeostasis, insulin can also regulate DA neurochemistry. Because direct- and indirect-acting DA receptor drugs are used therapeutically and some are abused, a better understanding of how food intake impacts response to these drugs would likely facilitate improved treatment of clinical disorders and provide information that would be relevant to the causes of vulnerability to abuse drugs. PMID:22710441

Amantadine and the Risk of Dyskinesia in Patients with Early Parkinson’s Disease: An Open-Label, Pragmatic Trial

PubMed Central

Kim, Aryun; Kim, Young Eun; Yun, Ji Young; Kim, Han-Joon; Yang, Hui-Jun; Lee, Woong-Woo; Shin, Chae Won; Park, Hyeyoung; Jung, Yu Jin; Kim, Ahro; Kim, Yoon; Jang, Mihee

2018-01-01

Objective We examined whether amantadine can prevent the development of dyskinesia. Methods Patients with drug-naïve Parkinson’s disease (PD), younger than 70 years of age and in the early stage of PD (Hoehn and Yahr scale < 3), were recruited from April 2011 to December 2014. The exclusion criteria included the previous use of antiparkinsonian medication, the presence of dyskinesia, significant psychological disorders, and previous history of a hypersensitivity reaction. Patients were consecutively assigned to one of 3 treatment groups in an open label fashion: Group A-1, amantadine first and then levodopa when needed; Group A-2, amantadine first, dopamine agonist when needed, and then levodopa; and Group B, dopamine agonist first and then levodopa when needed. The primary endpoint was the development of dyskinesia, which was analyzed by the Kaplan-Meier survival rate. Results A total of 80 patients were enrolled: Group A-1 (n = 27), Group A-2 (n = 27), and Group B (n = 26). Twenty-four patients were excluded from the analysis due to the following: withdrawal of amantadine or dopamine agonist (n = 9), alternative diagnosis (n = 2), withdrawal of consent (n = 1), and breach in the protocol (n = 12). After exclusion, 5 of the 56 (8.93%) patients developed dyskinesia. Patients in Group A-1 and A-2 tended to develop dyskinesia less often than those in Group B (cumulative survival rates of 0.933, 0.929, and 0.700 for A-1, A-2, and B, respectively; p = 0.453). Conclusion Amantadine as an initial treatment may decrease the incidence of dyskinesia in patients with drug-naïve PD. PMID:29860788

IGF-1 levels may increase paradoxically with dopamine agonist treatment for prolactinomas.

PubMed

Akirov, Amit; Greenman, Yona; Glaser, Benjamin; S'chigol, Irena; Mansiterski, Yossi; Eizenberg, Yoav; Shraga-Slutzky, Ilana; Shimon, Ilan

2018-05-04

Hyperprolactinemia is common in acromegaly and in these patients, insulin-like growth factor (IGF)-1 level may decrease with dopamine agonist. We report a series of patients with prolactinoma and a paradoxical increase of IGF-1 levels during cabergoline treatment. Clinical characteristics and response to treatment of patients with prolactinomas, in whom normal or slightly elevated baseline IGF-1 levels increased with cabergoline. The cohort consisted of ten prolactinoma patients (nine males, mean age 48 ± 14 years). Mean adenoma size was 23.8 ± 16.2 mm, with cavernous sinus invasion in eight. In five patients baseline IGF-1 levels were normal and in four levels were 1.2-1.5-fold the upper limit of the normal (ULN). One patient had IGF-1 measured shortly after initiating cabergoline and it was 1.4 × ULN. During cabergoline treatment (dose range 0.5-2 mg/week) PRL normalization was achieved in all and tumor shrinkage occurred in seven patients. The mean IGF-1 increase on cabergoline was 1.7 ± 0.4 × ULN. Cabergoline dose reduction or interruption was attempted in five patients and resulted in decreased IGF-1 levels in all, including normalization in two patients. Three patients were eventually diagnosed with acromegaly, one was referred for pituitary surgery followed by complete remission, another patient was switched to somatostatin analogue, and the third was treated by combination of somatostatin analogues with pegvisomant, with reduction of IGF-1 in all these patients. IGF-1 levels may increase to clinically significant levels during cabergoline treatment for PRL-adenoma. We suggest IGF-1 monitoring in all patients treated with dopamine agonists and not only in those presenting symptoms of acromegaly.

The effects of the dopamine agonist rotigotine on hemispatial neglect following stroke.

PubMed

Gorgoraptis, Nikos; Mah, Yee-Haur; Machner, Bjoern; Singh-Curry, Victoria; Malhotra, Paresh; Hadji-Michael, Maria; Cohen, David; Simister, Robert; Nair, Ajoy; Kulinskaya, Elena; Ward, Nick; Greenwood, Richard; Husain, Masud

2012-08-01

Hemispatial neglect following right-hemisphere stroke is a common and disabling disorder, for which there is currently no effective pharmacological treatment. Dopamine agonists have been shown to play a role in selective attention and working memory, two core cognitive components of neglect. Here, we investigated whether the dopamine agonist rotigotine would have a beneficial effect on hemispatial neglect in stroke patients. A double-blind, randomized, placebo-controlled ABA design was used, in which each patient was assessed for 20 testing sessions, in three phases: pretreatment (Phase A1), on transdermal rotigotine for 7-11 days (Phase B) and post-treatment (Phase A2), with the exact duration of each phase randomized within limits. Outcome measures included performance on cancellation (visual search), line bisection, visual working memory, selective attention and sustained attention tasks, as well as measures of motor control. Sixteen right-hemisphere stroke patients were recruited, all of whom completed the trial. Performance on the Mesulam shape cancellation task improved significantly while on rotigotine, with the number of targets found on the left side increasing by 12.8% (P = 0.012) on treatment and spatial bias reducing by 8.1% (P = 0.016). This improvement in visual search was associated with an enhancement in selective attention but not on our measures of working memory or sustained attention. The positive effect of rotigotine on visual search was not associated with the degree of preservation of prefrontal cortex and occurred even in patients with significant prefrontal involvement. Rotigotine was not associated with any significant improvement in motor performance. This proof-of-concept study suggests a beneficial role of dopaminergic modulation on visual search and selective attention in patients with hemispatial neglect following stroke.

Controversies in neurology: why monoamine oxidase B inhibitors could be a good choice for the initial treatment of Parkinson's disease.

PubMed

Löhle, Matthias; Reichmann, Heinz

2011-09-22

Early initiation of pharmacotherapy in Parkinson's disease (PD) is nowadays widely advocated by experts since the delay of treatment has shown to be associated with a significant deterioration of health related quality of life in affected patients. Due to marked advances in PD treatment during the last decades, physicians are nowadays fortunately equipped with a variety of substances that can effectively ameliorate emerging motor symptoms of the disease, among them levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors. Despite numerous drug intervention trials in early PD, there is however still ongoing controversy among neurologists which substance to use for the initial treatment of the disease. In multiple studies, MAO-B inhibitors, such as selegiline and rasagiline, have shown to provide mild symptomatic effects, delay the need for levodopa, and to reduce the incidence of motor fluctuations. Although their symptomatic efficacy is inferior compared to dopamine agonists and levodopa, MAO-B inhibitors undoubtedly have fewer side effects and are easy to administer. In contrary to their competitors, MAO-B inhibitors may furthermore offer a chance for disease modification, which so far remains a major unmet need in the management of PD and eventually makes them ideal candidates for the early treatment of the disease. MAO-B inhibitors may constitute a preferable therapeutic option for early PD, mainly due to their favourable safety profile and their putative neuroprotective capabilities. Since the symptomatic effects of MAO-B inhibitors are comparatively mild, dopamine agonists and levodopa should however be considered for initial treatment in those PD patients, in whom robust and immediate symptomatic relief needs to be prioritized.

Dopamine inhibits somatolactin gene expression in tilapia pituitary cells through the dopamine D2 receptors.

PubMed

Jiang, Quan; Lian, Anji; He, Qi

2016-07-01

Dopamine (DA) is an important neurotransmitter in the central nervous system of vertebrates and possesses key hypophysiotropic functions. Early studies have shown that DA has a potent inhibitory effect on somatolactin (SL) release in fish. However, the mechanisms responsible for DA inhibition of SL gene expression are largely unknown. To this end, tilapia DA type-1 (D1) and type-2 (D2) receptor transcripts were examined in the neurointermediate lobe (NIL) of the tilapia pituitary by real-time PCR. In tilapia, DA not only was effective in inhibiting SL mRNA levels in vivo and in vitro, but also could abolish pituitary adenylate cyclase-activating polypeptide (PACAP)- and salmon gonadotropin-releasing hormone (sGnRH)-stimulated SL gene expression at the pituitary level. In parallel studies, the specific D2 receptor agonists quinpirole and bromocriptine could mimic the DA-inhibited SL gene expression. Furthermore, the D2 receptor antagonists domperidone and (-)-sulpiride could abolish the SL response to DA or the D2 agonist quinpirole, whereas D1 receptor antagonists SCH23390 and SKF83566 were not effective in this respect. In primary cultures of tilapia NIL cells, D2 agonist quinpirole-inhibited cAMP production could be blocked by co-treatment with the D2 antagonist domperidone and the ability of forskolin to increase cAMP production was also inhibited by quinpirole. Using a pharmacological approach, the AC/cAMP pathway was shown to be involved in quinpirole-inhibited SL mRNA expression. These results provide evidence that DA can directly inhibit SL gene expression at the tilapia pituitary level via D2 receptor through the AC/cAMP-dependent mechanism. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of dopamine D1 and D2 receptor agonists on environmental enrichment attenuated sucrose cue reactivity in rats.

PubMed

Glueck, Edwin; Ginder, Darren; Hyde, Jeff; North, Katherine; Grimm, Jeffrey W

2017-03-01

Acute or chronic environmental enrichment (EE) reduces sucrose cue reactivity in rats. This effect may be mediated by dopamine receptors. We examined whether dopamine D1 or D2 receptor agonism could reverse the EE effect. We also examined whether any reversal effects would vary with the incubation of sucrose craving. Following 10 days (2 h/day) of sucrose self-administration, rats experienced either 1 or 30 days of forced abstinence and either overnight (acute) or 29 day (chronic) EE. D1 (SKF 81297; 0, 0.3, or 1 mg/kg) or D2 (quinpirole; 0, 0.1, or 0.3 mg/kg) agonist was administered systemically immediately prior to a subsequent 2-h cue reactivity test the next day (n = 9-12 per group). Dose-dependent effects were limited to the day 1 test. High doses of the agonists increased day 1 acute EE cue reactivity to levels comparable to control animals. On the day 30 test, SKF 81297 increased cue reactivity in acute EE, chronic EE, and control rats. In contrast, quinpirole resulted in similar cue reactivity for control and enriched rats, more from a reduction in responding by controls vs. a recovery of responding by EE-experienced rats. Both D1 and D2 receptors may be involved in the acute EE-mediated decrease in cue reactivity observed following 1 day of forced abstinence. In contrast, at 30 days of forced abstinence, D1 receptors may be critical in cue reactivity as SKF 81297 was effective at both restoring responding of enriched animals and potentiating responding of controls.

Development of 7TM receptor-ligand complex models using ligand-biased, semi-empirical helix-bundle repacking in torsion space: application to the agonist interaction of the human dopamine D2 receptor.

PubMed

Malo, Marcus; Persson, Ronnie; Svensson, Peder; Luthman, Kristina; Brive, Lars

2013-03-01

Prediction of 3D structures of membrane proteins, and of G-protein coupled receptors (GPCRs) in particular, is motivated by their importance in biological systems and the difficulties associated with experimental structure determination. In the present study, a novel method for the prediction of 3D structures of the membrane-embedded region of helical membrane proteins is presented. A large pool of candidate models are produced by repacking of the helices of a homology model using Monte Carlo sampling in torsion space, followed by ranking based on their geometric and ligand-binding properties. The trajectory is directed by weak initial restraints to orient helices towards the original model to improve computation efficiency, and by a ligand to guide the receptor towards a chosen conformational state. The method was validated by construction of the β1 adrenergic receptor model in complex with (S)-cyanopindolol using bovine rhodopsin as template. In addition, models of the dopamine D2 receptor were produced with the selective and rigid agonist (R)-N-propylapomorphine ((R)-NPA) present. A second quality assessment was implemented by evaluating the results from docking of a library of 29 ligands with known activity, which further discriminated between receptor models. Agonist binding and recognition by the dopamine D2 receptor is interpreted using the 3D structure model resulting from the approach. This method has a potential for modeling of all types of helical transmembrane proteins for which a structural template with sequence homology sufficient for homology modeling is not available or is in an incorrect conformational state, but for which sufficient empirical information is accessible.

The effects of the dopamine agonist rotigotine on hemispatial neglect following stroke

PubMed Central

Gorgoraptis, Nikos; Mah, Yee-Haur; Machner, Bjoern; Singh-Curry, Victoria; Malhotra, Paresh; Hadji-Michael, Maria; Cohen, David; Simister, Robert; Nair, Ajoy; Kulinskaya, Elena; Ward, Nick; Greenwood, Richard

2012-01-01

Hemispatial neglect following right-hemisphere stroke is a common and disabling disorder, for which there is currently no effective pharmacological treatment. Dopamine agonists have been shown to play a role in selective attention and working memory, two core cognitive components of neglect. Here, we investigated whether the dopamine agonist rotigotine would have a beneficial effect on hemispatial neglect in stroke patients. A double-blind, randomized, placebo-controlled ABA design was used, in which each patient was assessed for 20 testing sessions, in three phases: pretreatment (Phase A1), on transdermal rotigotine for 7–11 days (Phase B) and post-treatment (Phase A2), with the exact duration of each phase randomized within limits. Outcome measures included performance on cancellation (visual search), line bisection, visual working memory, selective attention and sustained attention tasks, as well as measures of motor control. Sixteen right-hemisphere stroke patients were recruited, all of whom completed the trial. Performance on the Mesulam shape cancellation task improved significantly while on rotigotine, with the number of targets found on the left side increasing by 12.8% (P = 0.012) on treatment and spatial bias reducing by 8.1% (P = 0.016). This improvement in visual search was associated with an enhancement in selective attention but not on our measures of working memory or sustained attention. The positive effect of rotigotine on visual search was not associated with the degree of preservation of prefrontal cortex and occurred even in patients with significant prefrontal involvement. Rotigotine was not associated with any significant improvement in motor performance. This proof-of-concept study suggests a beneficial role of dopaminergic modulation on visual search and selective attention in patients with hemispatial neglect following stroke. PMID:22761293

CHANGES IN APICAL DENDRITIC STRUCTURE CORRELATE WITH SUSTAINED ERK1/2 PHOSPHORYLATION IN MEDIAL PREFRONTAL CORTEX OF A RAT MODEL OF DOPAMINE D1 RECEPTOR AGONIST SENSITIZATION

PubMed Central

Papadeas, Sophia T.; Halloran, Christopher; McCown, Thomas J.; Breese, George R.; Blake, Bonita L.

2008-01-01

Rats lesioned with 6-hydroxydopamine (6-OHDA) as neonates exhibit behavioral and neurochemical abnormalities in adulthood that mimic Lesch-Nyhan disease, schizophrenia and other developmental disorders of frontostriatal circuit dysfunction. In these animals, a latent sensitivity to D1 agonists is maximally exposed by repeated administration of dopamine agonists in the post-pubertal period (D1 priming). In neonate-lesioned, adult rats primed with SKF-38393, we found selective, persistent alterations in the morphology of pyramidal neuron apical dendrites in the prelimbic area of the medial prefrontal cortex (mPFC). In these animals, dendrite bundling patterns and the typically straight trajectories of primary dendritic shafts were disrupted, whereas the diameter of higher-order oblique branches was increased. Although not present in neonate-lesioned rats treated with saline, these morphological changes persisted at least 21 days after repeated dosing with SKF-38393, and were not accompanied by markers of neurodegenerative change. A sustained increase in phospho-ERK immunoreactivity in wavy dendritic shafts over the same period suggested a relationship between prolonged ERK phosphorylation and dendritic remodeling in D1-primed rats. In support of this hypothesis, pretreatment with the MEK1/2-ERK1/2 pathway inhibitors PD98059 or SL327, prior to each priming dose of SKF-38393, prevented the morphological changes associated with D1 priming. Together, these findings demonstrate that repeated stimulation of D1 receptors in adulthood interacts with the developmental loss of dopamine to profoundly and persistently modify neuronal signaling and dendrite morphology in the mature prefrontal cortex. Furthermore, sustained elevation of ERK activity in mPFC pyramidal neurons may play a role in guiding these morphological changes in vivo. PMID:18785628

Effects of dopaminergic agents on progression of naturally occurring myopia in albino guinea pigs (Cavia porcellus).

PubMed

Jiang, Liqin; Long, Keli; Schaeffel, Frank; Zhou, Xiangtian; Zheng, Yibo; Ying, Huangfang; Lu, Fan; Stell, William K; Qu, Jia

2014-09-30

Disruption of dopaminergic signaling has been implicated in the abnormalities of ocular development in albinism, and many experiments have shown that retinal dopamine is a major regulator of postnatal eye growth and myopia in animal models. Therefore, in the present study we investigated whether progressive myopia, which can occur in albino guinea pigs without experimental manipulation of visual conditions, is affected by dopaminergic agents. Two-week-old albino guinea pigs, selected for being myopic (range refractive error [RE], -2 to -10 diopters [D]), received unilateral peribulbar injections of apomorphine (nonselective dopamine receptor agonist; 0, 7.5, 25, 75, 250, 750, and 2500 ng; n = 112), SKF38393 (D1-like agonist; 0, 10, 100, 1000 ng; n = 63), SCH23390 (D1-like antagonist; 0, 2500 ng; n = 27), quinpirole (D2-like agonist; 0, 10, 100, 1000 ng; n = 58), or sulpiride (D2-like antagonist; 0, 2500 ng; n = 24) once a day for four weeks. One noninjected group (n = 19) served as untreated control. Refractive states and axial dimensions of the eyes were measured without cycloplegia or general anesthetic, using eccentric infrared photoretinoscopy and A-scan ultrasonography, respectively, before treatment, and after 2 and 4 weeks of treatment. The main drug effects were analyzed by paired t-test or 2-way repeated measures ANOVA, as required. The naturally occurring progression of myopic RE was inhibited by apomorphine at relatively high doses (250 and 750 ng), SKF38393 at 100 ng (D1-like agonist), and sulpiride at 2500 ng (D2-like antagonist), but promoted by apomorphine at a lower dose (25 ng), quinpirole at 100 ng (D2-like agonist), and SCH23390 at 2500 ng (D1-like antagonist). All drugs affected primarily vitreous chamber depth, rather than anterior segment dimensions. Our data suggest that the activation of D1-like receptors inhibits, whereas activation of D2-like receptors promotes, progressive myopia in this animal model. The robust effects of antagonists suggest that ocular dopamine receptors in these albinos may be in a chronic state of partial excitation. The precise location and identity of the receptors responsible for these effects remain to be determined. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Analogues of doxanthrine reveal differences between the dopamine D 1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines

USGS Publications Warehouse

Cueva, J.P.; Chemel, B.R.; Juncosa, J.I.; Lill, M.A.; Watts, V.J.; Nichols, D.E.

2012-01-01

Efforts to develop selective agonists for dopamine D 1-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric ??-phenyldopamine-type full agonist ligands that display selectivity and potency at D 1-like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D 1- and D 2-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D 1-like receptor binding, suggesting important differences between the interactions of these ligands with the D 1 receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor. ?? 2011 Elsevier Ltd. All rights reserved.

Impulse Control Disorders and Related Complications of Parkinson’s Disease Therapy

PubMed Central

Lopez, Alexander M.; Weintraub, Daniel; Claassen, Daniel O.

2017-01-01

Impulsive and compulsive behaviors in Parkinson’s disease (PD) patients are most often attributed to dopamine agonist therapy; dysregulation of the mesocorticolimbic system accounts for this behavioral phenotype. The clinical presentation is commonly termed impulse control disorder (ICD): Behaviors include hypersexuality, compulsive eating, shopping, pathological gambling, and compulsive hobby participation. However, not all PD individuals taking dopamine agonists develop these behavioral changes. In this review, the authors focus on the similarities between the phenotypic presentation of ICDs with that of other reward-based behavioral disorders, including binge eating disorder, pathological gambling, and substance use disorders. With this comparison, we emphasize that the transition from an impulsive to compulsive behavior likely follows a ventral to dorsal striatal pattern, where an altered dopaminergic reward system underlies the emergence of these problematic behaviors. The authors discuss the neurobiological similarities between these latter disorders and ICDs, emphasizing similar pathophysiological processes and discussing treatment options that have potential for translation to PD patients. PMID:28511259

Contribution of the serotonin 5-HT1A receptor agonism of 8-OH-DPAT and EMD 128130 to the regulation of haloperidol-induced muscle rigidity in rats.

PubMed

Lorenc-Koci, E; Wardas, J; Bartoszyk, G D; Wolfarth, S

2003-12-01

The aim of the present study was to find out whether (+/-)-8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a prototypical 5-HT1A agonist, and (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane HCl (EMD 128130), a compound with serotonin 5-HT1A-agonist and dopamine D2-like antagonist properties, are able to attenuate the haloperidol-induced (1 mg/kg) muscle rigidity in rats. Muscle tone was examined using a combined mechano- and electromyographic (EMG) method that simultaneously measured the mechanical muscle resistance (MMG) of the rat's hind foot to passive movements in the ankle joint, and the EMG activity of two antagonist muscles. Both 8-OH-DPAT (0.125-0.5 mg/kg i.p.) and EMD 128130 (1-10 mg/kg i.p.) dose-dependently decreased the haloperidol-enhanced MMG to passive movements, as well as the tonic and the long-latency reflex EMG activities. Provided these results can be extrapolated to humans, the efficacy of EMD 128130 in relieving the haloperidol-induced muscle rigidity supports the concept that novel antipsychotics with 5-HT1A agonist and dopamine D2 antagonist activities should have a favourable extrapyramidal side-effect profile.

Arrestin–dependent but G–protein coupled receptor kinase–independent uncoupling of D2–dopamine receptors

PubMed Central

Celver, Jeremy; Sharma, Meenakshi; Thanawala, Vaidehi; Octeau, J. Christopher; Kovoor, Abraham

2016-01-01

We reconstituted D2 like dopamine receptor (D2R) and the delta opioid receptor (DOR) coupling to G-protein gated inwardly rectifying potassium channels (Kir3) and directly compared the effects of co-expression of G-protein coupled receptor kinase (GRK) and arrestin on agonist-dependent desensitization of the receptor response. We found, as described previously, that co-expression of a GRK and an arrestin synergistically increased the rate of agonist-dependent desensitization of DOR. In contrast, only arrestin expression was required to produce desensitization of D2R responses. Furthermore, arrestin-dependent GRK-independent desensitization of D2R-Kir3 coupling could be transferred to DOR by substituting the third cytoplasmic loop of DOR with that of D2R. The arrestin-dependent GRK-independent desensitization of D2R desensitization was inhibited by staurosporine treatment, and blocked by alanine substitution of putative protein kinase C phosphorylation sites in the third cytoplasmic loop of D2R. Finally, the D2R construct in which putative protein kinase C phosphorylation sites were mutated did not undergo significant agonist-dependent desensitization even after GRK co-expression, suggesting that GRK phosphorylation of D2R does not play an important role in uncoupling of the receptor. PMID:23815307

Arrestin-dependent but G-protein coupled receptor kinase-independent uncoupling of D2-dopamine receptors.

PubMed

Celver, Jeremy; Sharma, Meenakshi; Thanawala, Vaidehi; Christopher Octeau, J; Kovoor, Abraham

2013-10-01

We reconstituted D2 like dopamine receptor (D2R) and the delta opioid receptor (DOR) coupling to G-protein gated inwardly rectifying potassium channels (K(ir)3) and directly compared the effects of co-expression of G-protein coupled receptor kinase (GRK) and arrestin on agonist-dependent desensitization of the receptor response. We found, as described previously, that co-expression of a GRK and an arrestin synergistically increased the rate of agonist-dependent desensitization of DOR. In contrast, only arrestin expression was required to produce desensitization of D2R responses. Furthermore, arrestin-dependent GRK-independent desensitization of D2R-K(ir)3 coupling could be transferred to DOR by substituting the third cytoplasmic loop of DOR with that of D2R. The arrestin-dependent GRK-independent desensitization of D2R desensitization was inhibited by staurosporine treatment, and blocked by alanine substitution of putative protein kinase C phosphorylation sites in the third cytoplasmic loop of D2R. Finally, the D2R construct in which putative protein kinase C phosphorylation sites were mutated did not undergo significant agonist-dependent desensitization even after GRK co-expression, suggesting that GRK phosphorylation of D2R does not play an important role in uncoupling of the receptor. © 2013 International Society for Neurochemistry.

Dopamine D3 Receptors Mediate the Discriminative Stimulus Effects of Quinpirole in Free-Feeding Rats

PubMed Central

Baladi, Michelle G.; Newman, Amy H.

2010-01-01

The discriminative stimulus effects of dopamine (DA) D3/D2 receptor agonists are thought to be mediated by D2 receptors. To maintain responding, access to food is often restricted, which can alter neurochemical and behavioral effects of drugs acting on DA systems. This study established stimulus control with quinpirole in free-feeding rats and tested the ability of agonists to mimic and antagonists to attenuate the effects of quinpirole. The same antagonists were studied for their ability to attenuate quinpirole-induced yawning and hypothermia. DA receptor agonists apomorphine and lisuride, but not amphetamine and morphine, occasioned responding on the quinpirole lever. The discriminative stimulus effects of quinpirole were attenuated by the D3 receptor-selective antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl (PG01037) and the nonselective D3/D2 receptor antagonist raclopride, but not by the D2 receptor-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl-1H-indole (L-741,626); the potencies of PG01037 and raclopride to antagonize this effect of quinpirole paralleled their potencies to antagonize the ascending limb of the quinpirole yawning dose-response curve (thought to be mediated by D3 receptors). L-741,626 selectively antagonized the descending limb of the quinpirole yawning dose-response curve, and both L-741,626 and raclopride, but not PG01037, antagonized the hypothermic effects of quinpirole (thought to be mediated by D2 receptors). Food restriction (10 g/day/7 days) significantly decreased quinpirole-induced yawning without affecting the quinpirole discrimination. Many discrimination studies on DA receptor agonists use food-restricted rats; together with those studies, the current experiment using free-feeding rats suggests that feeding conditions affecting the behavioral effects of direct-acting DA receptor agonists might also have an impact on the effects of indirect-acting agonists such as cocaine and amphetamine. PMID:19797621

Dopamine D3 receptors mediate the discriminative stimulus effects of quinpirole in free-feeding rats.

PubMed

Baladi, Michelle G; Newman, Amy H; France, Charles P

2010-01-01

The discriminative stimulus effects of dopamine (DA) D3/D2 receptor agonists are thought to be mediated by D2 receptors. To maintain responding, access to food is often restricted, which can alter neurochemical and behavioral effects of drugs acting on DA systems. This study established stimulus control with quinpirole in free-feeding rats and tested the ability of agonists to mimic and antagonists to attenuate the effects of quinpirole. The same antagonists were studied for their ability to attenuate quinpirole-induced yawning and hypothermia. DA receptor agonists apomorphine and lisuride, but not amphetamine and morphine, occasioned responding on the quinpirole lever. The discriminative stimulus effects of quinpirole were attenuated by the D3 receptor-selective antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl (PG01037) and the nonselective D3/D2 receptor antagonist raclopride, but not by the D2 receptor-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl-1H-indole (L-741,626); the potencies of PG01037 and raclopride to antagonize this effect of quinpirole paralleled their potencies to antagonize the ascending limb of the quinpirole yawning dose-response curve (thought to be mediated by D3 receptors). L-741,626 selectively antagonized the descending limb of the quinpirole yawning dose-response curve, and both L-741,626 and raclopride, but not PG01037, antagonized the hypothermic effects of quinpirole (thought to be mediated by D2 receptors). Food restriction (10 g/day/7 days) significantly decreased quinpirole-induced yawning without affecting the quinpirole discrimination. Many discrimination studies on DA receptor agonists use food-restricted rats; together with those studies, the current experiment using free-feeding rats suggests that feeding conditions affecting the behavioral effects of direct-acting DA receptor agonists might also have an impact on the effects of indirect-acting agonists such as cocaine and amphetamine.

The ventral tegmental area as a putative target for tachykinins in cardiovascular regulation

PubMed Central

Deschamps, Kathleen; Couture, Réjean

2005-01-01

Tachykinin receptor agonists and antagonists were microinjected into the ventral tegmental area (VTA) to study the relative participation of the three tachykinin receptors in cardiovascular regulation in freely behaving rat. Selective agonists (1–100 pmol) for NK1 ([Sar9, Met (O2)11]SP), NK2 ([β-Ala8]NKA (4–10)) and NK3 (senktide) receptors evoked increases in blood pressure, heart rate (HR) along with behavioural manifestations (face washing, sniffing, head scratching, rearing, wet dog shake). At 1 pmol, NK1 and NK3 agonists did not affect behaviour and blood pressure but only HR. Tachykinin agonists-induced cardiovascular responses were selectively and reversibly blocked by the prior injection of antagonists for NK1 receptors (LY 303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane), 5 nmol), NK2 receptors (SR 48968 ([(S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl)butyl]benzamide]), 250 pmol) and NK3 receptors (SB 235375 ((−)-(S)-N-(α-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide), 25 nmol). With the exception of the NK2 agonist, most behavioural effects were also blocked by antagonists. Tachykinin agonists-induced cardiovascular responses were inhibited by intravenous (i.v.) treatments with antagonists for D1 dopamine receptor (SCH23390, 0.2 mg kg−1) and β1-adrenoceptor (atenolol, 5 mg kg−1) but not for D2 dopamine receptor (raclopride, 0.16 mg kg−1). Behavioural responses were blocked by SCH23390 only. The present study provides the first pharmacological evidence that the three tachykinin receptors in the rat VTA can affect the autonomic control of blood pressure and HR by increasing midbrain dopaminergic transmission. This mechanism may be involved in the coordination of behavioural and cardiovascular responses to stress and noxious stimulation. PMID:15895109

Investigational agents in the treatment of Parkinson's disease: focus on safinamide.

PubMed

Malek, Naveed M; Grosset, Donald G

2012-01-01

The authors review management issues in Parkinson's disease (PD) and provide an overview of the current pharmacological management strategies, with a specific focus on safinamide. Current therapeutic management of PD largely involves strategies to optimize the replacement of deficient dopamine, using levodopa, dopamine agonists, and inhibitors of dopamine-metabolizing enzymes. Currently under investigation for use in the treatment of PD, safinamide has multiple modes of action including monoamine oxidase B inhibition. It is well absorbed orally, has a long plasma half-life, and does not have liver enzyme-inducing or liver enzyme-inhibiting activity. Peak plasma concentration occurs 2-4 hours after single oral doses. Safinamide as monotherapy and as an adjunct to dopamine agonists improves Unified Parkinson's Disease Rating Scale motor scores. One randomized, placebo-controlled trial involving 168 patients given a median safinamide dose of 70 mg/day (range 40-90 mg/day) significantly increased the proportion of responders - defined as patients improving their Unified Parkinson's Disease Rating Scale motor scores by 30% or more from baseline - after 3 months (37.5% for safinamide versus 21.4% for placebo; P < 0.05). Safinamide increased "on" time with no or minor dyskinesia compared with the placebo in another trial, but dyskinesia severity was not reduced. Safinamide was well tolerated, with an adverse effect profile similar to that of the placebo. Further Phase III trial data for safinamide efficacy is awaited, and will be of interest in a comparison with other developments in PD therapeutics: modified formulations of available compounds, new drug classes such as adenosine receptor antagonists, and gene-based therapies.

Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice.

PubMed

Higashino, Kosuke; Ago, Yukio; Umeki, Takahiro; Hasebe, Shigeru; Onaka, Yusuke; Hashimoto, Hitoshi; Takuma, Kazuhiro; Matsuda, Toshio

2016-02-01

The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine are used for the treatment of Alzheimer's disease. We previously demonstrated that donepezil and galantamine differentially affect isolation rearing-induced prepulse inhibition (PPI) deficits and that this might be due to differential effects on brain muscarinic acetylcholine (mACh) receptor function in mice. We examined the effects of rivastigmine on isolation rearing-induced PPI deficits, brain ACh levels, and mACh receptor function in mice. Acoustic startle responses were measured in a startle chamber. Microdialysis was performed, and the levels of dopamine and ACh in the prefrontal cortex were measured. Rivastigmine (0.3 mg/kg) improved PPI deficits, and this improvement was antagonized by the mACh receptor antagonist telenzepine but not by the nicotinic ACh receptor antagonist mecamylamine. Rivastigmine increased extracellular ACh levels by approximately 2-3-fold, less than the increase produced by galantamine. Rivastigmine enhanced the effect of the mACh receptor agonist N-desmethylclozapine on prefrontal dopamine release, a marker of mACh receptor function, and this increase was blocked by telenzepine. In contrast, galantamine did not affect N-desmethylclozapine-induced dopamine release. Furthermore, rivastigmine did not affect cortical dopamine release induced by the serotonin1A receptor agonist osemozotan, suggesting that the effect of rivastigmine has specificity for mACh receptors. Taken together with our previous finding that marked increases in ACh levels are required for the PPI deficit improvement induced by galantamine, our present results suggest that rivastigmine improves isolation rearing-induced PPI deficits by increasing ACh levels and by concomitantly enhancing mACh receptor function.

The effect of CA1 dopaminergic system on amnesia induced by harmane in mice.

PubMed

Nasehi, Mohammad; Hasanvand, Simin; Khakpai, Fatemeh; Zarrindast, Mohammad-Reza

2018-05-16

In the present study, the effects of bilateral injections of dopaminergic drugs into the hippocampal CA1 regions (intra-CA1) on harmane-induced amnesia were examined in mice. We used a single-trial step-down inhibitory avoidance task for the assessment of memory acquisition in adult male mice. Our data indicated that pre-training intra-peritoneal (i.p.) administration of harmane (12 mg/kg) impaired memory acquisition. Moreover, intra-CA1 administration of dopamine D1 receptor agonist, SKF38393 (0.25 µg/mouse), dopamine D1 receptor antagonist, SCH23390 (0.25 µg/mouse), dopamine D2 receptor agonist, quinpirole (0.125 and 0.25 µg/mouse) and dopamine D2 receptor antagonist, sulpiride (0.2 and 0.4 µg/mouse) decreased the learning of a single-trial inhibitory avoidance task. Furthermore, pre-training intra-CA1 injection of sub-threshold doses of SKF38393 (0.0625 µg/mouse) or sulpiride (0.1 µg/mouse) increased pre-training harmane (4 and 8 mg/kg, i.p.)-induced amnesia. On the other hand, pre-training intra-CA1 injection of a sub-threshold dose of SCH23390 (0.0625 µg/mouse) reversed amnesia induced by an effective dose of harmane (12 mg/kg; i.p.). In addition, Pre-training intra-CA1 injection of quinpirole (0.0625 µg/mouse) had no effect on memory impairment induced by harmane. These findings indicate the involvement of CA1 dopaminergic system on harmane-induced impairment of memory acquisition.

The latest development of antihypertensive medication

NASA Astrophysics Data System (ADS)

Nasution, S.; Rey, I.; Effendi-YS, R.

2018-03-01

Hypertension is the most common risk factor for cardiovascular disease, stroke, renal failure, and death. Recent drug monitoring studies found non-adherence to BP lowering therapy in 25% to 65% of patients with apparent treatment-resistant hypertension (TRH). This review focuses on the latest development of antihypertensive medication, such as vasopeptidase inhibitors, aldosterone synthase inhibitors, Soluble Epoxide Hydrolase Inhibitors, agonists of natriuretic peptide receptor, Vasoactive Intestinal Peptide Receptor Agonist, a novel mineralocorticoid receptor antagonist, inhibitors of aminopeptidase A, dopamine β-hydroxylase inhibitor, intestinal Na+/H+ exchanger 3 inhibitor and other agents.

A solid-phase combinatorial approach for indoloquinolizidine-peptides with high affinity at D(1) and D(2) dopamine receptors.

PubMed

Molero, Anabel; Vendrell, Marc; Bonaventura, Jordi; Zachmann, Julian; López, Laura; Pardo, Leonardo; Lluis, Carme; Cortés, Antoni; Albericio, Fernando; Casadó, Vicent; Royo, Miriam

2015-06-05

Ligands acting at multiple dopamine receptors hold potential as therapeutic agents for a number of neurodegenerative disorders. Specifically, compounds able to bind at D1R and D2R with high affinity could restore the effects of dopamine depletion and enhance motor activation on degenerated nigrostriatal dopaminergic systems. We have directed our research towards the synthesis and characterisation of heterocycle-peptide hybrids based on the indolo[2,3-a]quinolizidine core. This privileged structure is a water-soluble and synthetically accessible scaffold with affinity for diverse GPCRs. Herein we have prepared a solid-phase combinatorial library of 80 indoloquinolizidine-peptides to identify compounds with enhanced binding affinity at D2R, a receptor that is crucial to re-establish activity on dopamine-depleted degenerated GABAergic neurons. We applied computational tools and high-throughput screening assays to identify 9a{1,3,3} as a ligand for dopamine receptors with nanomolar affinity and agonist activity at D2R. Our results validate the application of indoloquinolizidine-peptide combinatorial libraries to fine-tune the pharmacological profiles of multiple ligands at D1 and D2 dopamine receptors. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Physician response to a medication alert system in inpatients with levodopa-treated diseases

PubMed Central

Morris, Marie; Willis, Allison W.; Searles Nielsen, Susan; McCann, Franklin; Birke, Angela

2015-01-01

Objective: To evaluate the appropriateness of dopamine receptor antagonist prescriptions in hospitalized patients with dopamine-requiring diseases after implementation of an automated prescription alert system. Methods: We examined dopamine receptor antagonist prescriptions in hospitalized patients with dopamine-requiring diseases and physician response to an automated drug contraindication alert system at Barnes-Jewish Hospital from 2009 to 2013. A detailed review of patient medical records was performed for all alert events generated when a physician prescribed a dopamine receptor antagonist concurrently with a dopamine receptor agonist in hospitalized patients. Two movement disorders neurologists determined the appropriateness of each prescription, based on patient medical history, through consensus. Physician response to alert was compared by indication for the prescription and physician specialty. Results: Of 237 orders, 197 (83.1%) prescriptions for dopamine receptor antagonists were considered inappropriate. The prevalence of inappropriate dopamine receptor antagonist prescriptions per levodopa prescriptions was 16.10% (95% confidence interval 9.47, 22.73) in psychiatry, 7.51% (6.16, 8.86) in general medicine, 6.14% (4.49, 7.79) in the surgical specialties, and 0.85% (0.46, 1.25) in the neurologic/neurosurgical specialties. Of the inappropriate prescriptions, 146 (74.1%) were continued despite the alert. The strongest predictor of discontinuation of dopamine receptor antagonist medications was use of the medication to treat nausea or emesis (p < 0.001). Conclusions: Despite successfully identifying instances when dopamine antagonists were prescribed to patients with dopamine-requiring diseases, the alert system modestly affected physician prescribing behavior, highlighting the need for improved education of health care providers. PMID:26092916

Radiosynthesis and in vitro evaluation of 2-(N-alkyl-N-1'-11C-propyl)amino-5-hydroxytetralin analogs as high affinity agonists for dopamine D-2 receptors.

PubMed

Shi, B; Narayanan, T K; Yang, Z Y; Christian, B T; Mukherjee, J

1999-10-01

We have developed radiotracers based on agonists that may potentially allow the in vivo assessment of the high affinity (HA) state of the dopamine D-2 receptors. The population of HA state, which is likely the functional state of the receptor, may be altered in certain diseases. We carried out radiosyntheses and evaluated the binding affinities, lipophilicity, and in vitro autoradiographic binding characteristics of three dopamine D-2 receptor agonists: (+/-)-2-(N,N-dipropyl)amino-5-hydroxytetralin (5-OH-DPAT), (+/-)-2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin (PPHT), and (+/-)-2-(N-cyclohexylethyl-N-propyl)amino-5-hydroxytetralin (ZYY-339). In 3H-spiperone assays using rat striata, ZYY-339 exhibited subnanomolar affinity for D-2 receptor sites (IC50 = 0.010 nM), PPHT was somewhat weaker (IC50 = 0.65 nM), and 5-OH-DPAT exhibited the weakest affinity (IC50 = 2.5 nM) of the three compounds. Radiosynthesis of these derivatives, 2-(N-propyl-N-1'-11C-propyl)amino-5-hydroxytetralin (11C-5-OH-DPAT), 2-(N-phenethyl-N-1'-11C-propyl)amino-5-hydroxytetralin (11C-PPHT), and 2-(N-cyclohexylethyl-N-1'-11C-propyl)amino-5-hydroxytetralin (11C-ZYY-339) was achieved by first synthesizing 11C-1-propionyl chloride and subsequent coupling with the appropriate secondary amine precursor to form the respective amide, which was then reduced to provide the desired tertiary amine products. The final products were obtained by reverse-phase high performance liquid chromatography (HPLC) purification in radiochemical yields of 5-10% after 60-75 min from the end of 11CO2 trapping and with specific activities in the range of 250-1,000 Ci/mmol. In vitro autoradiographs in rat brain slices with 11C-5-OH-DPAT, 11C-PPHT, and 11C-ZYY-339 revealed selective binding of the three radiotracers to the dopamine D-2 receptors in the striata.

Medial prefrontal cortex dopamine controls the persistent storage of aversive memories

PubMed Central

Gonzalez, María C.; Kramar, Cecilia P.; Tomaiuolo, Micol; Katche, Cynthia; Weisstaub, Noelia; Cammarota, Martín; Medina, Jorge H.

2014-01-01

Medial prefrontal cortex (mPFC) is essential for initial memory processing and expression but its involvement in persistent memory storage has seldom been studied. Using the hippocampus dependent inhibitory avoidance learning task and the hippocampus-independent conditioned taste aversion paradigm together with specific dopamine receptor agonists and antagonists we found that persistence but not formation of long-term aversive memories requires dopamine D1/D5 receptors activation in mPFC immediately after training and, depending on the task, between 6 and 12 h later. Our results indicate that besides its well-known participation in retrieval and early consolidation, mPFC also modulates the endurance of long-lasting aversive memories regardless of whether formation of the aversive mnemonic trace requires the participation of the hippocampus. PMID:25506318

An Anatomical Basis for Opponent Process Mechanisms of Opiate Withdrawal

PubMed Central

Radke, Anna K.; Rothwell, Patrick E.; Gewirtz, Jonathan C.

2011-01-01

Opponent process theory predicts that the first step in the induction of drug withdrawal is the activation of reward-related circuitry. Using the acoustic startle reflex as a model of anxiety-like behavior in rats, we show the emergence of a negative affective state during withdrawal after direct infusion of morphine into the ventral tegmental area (VTA), the origin of the mesolimbic dopamine system. Potentiation of startle during withdrawal from systemic morphine exposure requires a decrease in opiate receptor stimulation in the VTA and can be relieved by administration of the dopamine receptor agonist apomorphine. Together, our results suggest that the emergence of anxiety during withdrawal from acute opiate exposure begins with activation of VTA mesolimbic dopamine circuitry, providing a mechanism for the opponent process view of withdrawal. PMID:21593338

Dopamine Release and Uptake Impairments and Behavioral Alterations Observed in Mice that Model Fragile X Mental Retardation Syndrome.

PubMed

Fulks, Jenny L; O'Bryhim, Bliss E; Wenzel, Sara K; Fowler, Stephen C; Vorontsova, Elena; Pinkston, Jonathan W; Ortiz, Andrea N; Johnson, Michael A

2010-10-20

In this study we evaluated the relationship between amphetamine-induced behavioral alterations and dopamine release and uptake characteristics in Fmr1 knockout (Fmr1 KO) mice, which model fragile X syndrome. The behavioral analyses, obtained at millisecond temporal resolution and 2 mm spatial resolution using a force-plate actometer, revealed that Fmr1 KO mice express a lower degree of focused stereotypy compared to wild type (WT) control mice after injection with 10 mg/kg (ip) amphetamine. To identify potentially related neurochemical mechanisms underlying this phenomenon, we measured electrically-evoked dopamine release and uptake using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal brain slices. At 10 weeks of age, dopamine release per pulse, which is dopamine release corrected for differences in uptake, was unchanged. However, at 15 (the age of behavioral testing) and 20 weeks of age, dopamine per pulse and the maximum rate of dopamine uptake was diminished in Fmr1 KO mice compared to WT mice. Dopamine uptake measurements, obtained at different amphetamine concentrations, indicated that dopamine transporters in both genotypes have equal affinities for amphetamine. Moreover, dopamine release measurements from slices treated with quinpirole, a D2-family receptor agonist, rule out enhanced D2 autoreceptor sensitivity as a mechanism of release inhibition. However, dopamine release, uncorrected for uptake and normalized against the corresponding pre-drug release peaks, increased in Fmr1 KO mice, but not in WT mice. Collectively, these data are consistent with a scenario in which a decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in Fmr1 KO mice.

Reduced dopamine transporter binding predates impulse control disorders in Parkinson's disease.

PubMed

Vriend, Chris; Nordbeck, Anna H; Booij, Jan; van der Werf, Ysbrand D; Pattij, Tommy; Voorn, Pieter; Raijmakers, Pieter; Foncke, Elisabeth M J; van de Giessen, Elsmarieke; Berendse, Henk W; van den Heuvel, Odile A

2014-06-01

Impulse control disorders (ICD) are relatively common in Parkinson's disease (PD) and generally are regarded as adverse effects of dopamine replacement therapy, although certain demographic and clinical risk factors are also involved. Previous single-photon emission computed tomography (SPECT) studies showed reduced ventral striatal dopamine transporter binding in Parkinson patients with ICD compared with patients without. Nevertheless, these studies were performed in patients with preexisting impulse control impairments, which impedes clear-cut interpretation of these findings. We retrospectively procured follow-up data from 31 medication-naïve PD patients who underwent dopamine transporter SPECT imaging at baseline and were subsequently treated with dopamine replacement therapy. We used questionnaires and a telephone interview to assess medication status and ICD symptom development during the follow-up period (31.5 ± 12.0 months). Eleven patients developed ICD symptoms during the follow-up period, eight of which were taking dopamine agonists. The PD patients with ICD symptoms at follow-up had higher baseline depressive scores and lower baseline dopamine transporter availability in the right ventral striatum, anterior-dorsal striatum, and posterior putamen compared with PD patients without ICD symptoms. No baseline between-group differences in age and disease stage or duration were found. The ICD symptom severity correlated negatively with baseline dopamine transporter availability in the right ventral and anterior-dorsal striatum. The results of this preliminary study show that reduced striatal dopamine transporter availability predates the development of ICD symptoms after dopamine replacement therapy and may constitute a neurobiological risk factor related to a lower premorbid dopamine transporter availability or a more pronounced dopamine denervation in PD patients susceptible to ICD. © 2014 International Parkinson and Movement Disorder Society.

Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core.

PubMed

Fortin, Samantha M; Roitman, Mitchell F

2017-07-01

Drugs of abuse increase the frequency and magnitude of brief (1-3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release - possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse. Copyright © 2017 Elsevier Inc. All rights reserved.

Actions of novel antipsychotic agents on apomorphine-induced PPI disruption: influence of combined serotonin 5-HT1A receptor activation and dopamine D2 receptor blockade.

PubMed

Auclair, Agnès L; Kleven, Mark S; Besnard, Joël; Depoortère, Ronan; Newman-Tancredi, Adrian

2006-09-01

The dopamine D1/D2 agonist apomorphine (0.63 mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D2 antagonist property, various levels of 5-HT1A agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HT1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT1A agonist, did not. New generation antipsychotics with marked 5-HT1A agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HT1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D2 and 5-HT1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.

[MODERN PROKINETICS AND THEIR ROLE IN THE TREATMENT OF GASTROENTEROLOGICAL PATHOLOGY].

PubMed

Sheptulin, A A; Belousova, I B

2016-01-01

The importance of prokinetics (drugs stimulating motor function of the gastrointestinal tract) arises from the high prevalence of gastroenterological pathology associated with primary or secondary disturbances of this function in esophagus, stomach, and intestines. The main groups of prokinetics are beta-blockers of dopamine receptors, inhibitors of acetylcholine esterase (or their combination with dopamine receptor blockers), 5-HT4-receptor agonists. They find wide application for the treatment of gastroesophgeal reflux disease, functional dyspepsia and constipation, obstipational form of irritable bowel syndrome, and other conditions accompanied by motor function disorders of the gastrointestinal tract.

Switching to aripiprazole for the treatment of residual mutism resulted in distinct clinical courses in two catatonic schizophrenia cases.

PubMed

Muneoka, Katsumasa; Kanahara, Nobuhisa; Kimura, Shou

2017-01-01

The efficacy of a partial agonist for the dopamine D 2 receptor, aripiprazole, for catatonia in schizophrenia has been reported. We report distinct clinical courses in challenging aripiprazole to treat residual mutism after severe catatonic symptoms improved. In the first case, mutism was successfully treated when the patient was switched from olanzapine to aripiprazole. In contract, switching to aripiprazole from risperidone aggravated auditory hallucinations in the second case. We will discuss the benefits and risks of using aripiprazole for the treatment of catatonic schizophrenia and the possibility of dopamine supersensitivity psychosis.

The awakening of artistic creativity and Parkinson's disease.

PubMed

Inzelberg, Rivka

2013-04-01

Despite the prominent loss of motor skills, artistic capacities remain preserved in Parkinson's disease (PD). Furthermore, artistic creativity may emerge in art-naïve PD patients treated with levodopa and dopamine agonists. The present review discusses reported PD patients who developed enhanced artistic skills under anti-Parkinsonian therapy and the course of this phenomenon in the clinical context. It is unclear whether creative drive is related to dopamine dysregulation, and the mechanisms remain speculative. The delineation of the particular constellation that enables this emergence in PD patients may shed light on the comprehension of the concept of creativity in general.

New functional activity of aripiprazole revealed: robust antagonism of D2 dopamine receptor-stimulated Gβγ signaling

PubMed Central

Brust, Tarsis F.; Hayes, Michael P.; Roman, David L.; Watts, Val J.

2014-01-01

The dopamine D2 receptor (DRD2) is a G protein-coupled receptor (GPCR) that is generally considered to be a primary target in the treatment of schizophrenia. First generation antipsychotic drugs (e.g. haloperidol) are antagonists of the DRD2, while second generation antipsychotic drugs (e.g. olanzapine) antagonize DRD2 and 5HT2A receptors. Notably, both these classes of drugs may cause side effects associated with D2 receptor antagonism (e.g. hyperprolactemia and extrapyramidal symptoms). The novel, “third generation” antipsychotic drug, aripiprazole is also used to treat schizophrenia, with the remarkable advantage that its tendency to cause extrapyramidal symptoms is minimal. Aripiprazole is considered a partial agonist of the DRD2, but it also has partial agonist/antagonist activity for other GPCRs. Further, aripiprazole has been reported to have a unique activity profile in functional assays with the DRD2. In the present study the molecular pharmacology of aripiprazole was further examined in HEK cell models stably expressing the DRD2 and specific isoforms of adenylyl cyclase to assess functional responses of Gα and Gβγ subunits. Additional studies examined the activity of aripiprazole in DRD2-mediated heterologous sensitization of adenylyl cyclase and cell-based dynamic mass redistribution (DMR). Aripiprazole displayed a unique functional profile for modulation of G proteins, being a partial agonist for Gαi/o and a robust antagonist for Gβγ signaling. Additionally, aripiprazole was a weak partial agonist for both heterologous sensitization and dynamic mass redistribution. PMID:25449598

Substance P and dopamine interact to modulate the distribution of delta-opioid receptors on cholinergic interneurons in the striatum.

PubMed

Heath, Emily; Chieng, Billy; Christie, Macdonald J; Balleine, Bernard W

2018-05-01

It has been recently demonstrated that predictive learning induces a persistent accumulation of delta-opioid receptors (DOPrs) at the somatic membrane of cholinergic interneurons (CINs) in the nucleus accumbens shell (Nac-S). This accumulation is required for predictive learning to influence subsequent choice between goal-directed actions. The current experiments investigated the local neurochemical events responsible for this translocation. We found that (1) local administration of substance P into multiple striatal sub-territories induced DOPr translocation and (2) that this effect was mediated by the NK1 receptor, likely through its expression on CINs. Interestingly, whereas intrastriatal infusion of the D1 agonist chloro-APB reduced the DOPr translocation on CINs and infusion of the D2 agonist quinpirole had no effect, co-administration of both agonists again generated DOPr translocation, suggesting the effect of the D1 agonist alone was due to receptor internalisation. In support of this, local administration of cocaine was found to increase DOPr translocation as was chloro-APB when co-administered with the DOPr antagonist naltrindole. These studies provide the first evidence of delta-opioid receptor translocation in striatal cholinergic interneurons outside of the accumbens shell and suggest that, despite differences in local striatal neurochemical microenvironments, a similar molecular mechanism - involving an interaction between dopamine and SP signalling via NK1R - regulates DOPr translocation in multiple striatal regions. To our knowledge, this represents a novel mechanism by which DOPr distribution is regulated that may be particularly relevant to learning-induced DOPr trafficking. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Can Exercise Help Women with PMS?

ERIC Educational Resources Information Center

Cowart, Virginia S.

1989-01-01

Various treatments for premenstrual syndrome (PMS) are described, focusing on the role of exercise. Some physicians prefer to try exercise and others, lifestyle changes before turning to such treatment as psychoactive drugs, vitamin B complex, dopamine agonists, and immunotherapy. Regular exercise has been shown to relieve symptoms of PMS. (SM)

Assessing the Comprehensive Soldier Fitness Program: Measuring Startle Response and Prepulse Inhibition

DTIC Science & Technology

2011-04-01

increase PPI, but dopamine agonists can have the opposite effect by reducing PPI. Fortunately, caffeine appears to have no significant effect on PPI...violent behavior, and sexual risk behavior. Landis, C., & Hunt, W.A. (1939). The Startle Pattern. New York: Farrar. An example of early research on

Effects of Nicotine Administration and Stress on Sensory-Gating Depend on Rat Strain and Sex

DTIC Science & Technology

1998-01-01

and cocaine (Harty & Davis, 1985), and decrease in response to ethanol (Pohorecky, Cagan, Brick, & Jaffe, 1976) and haloperidol (Mansbach, Geyer...dopamine agonists. Specifically, increased PPI has been found after treatment with haloperidol , raclopride, and buspirone (antagonists at the D2 receptor

Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study.

PubMed

Florio, Tullio; Barbieri, Federica; Spaziante, Renato; Zona, Gianluigi; Hofland, Leo J; van Koetsveld, Peter M; Feelders, Richard A; Stalla, Günter K; Theodoropoulou, Marily; Culler, Michael D; Dong, Jesse; Taylor, John E; Moreau, Jacques-Pierre; Saveanu, Alexandru; Gunz, Ginette; Dufour, Henry; Jaquet, Philippe

2008-06-01

Dopamine D2 and somatostatin receptors (sstrs) were reported to affect non-functioning pituitary adenoma (NFPA) proliferation in vitro. However, the reported results differ according to the experimental conditions used. We established an experimental protocol allowing reproducible evaluation of NFPA cell proliferation in vitro, to test and compare the antiproliferative effects of dopamine and somatostatin analogs (alone or in combination) with the activity of the dopamine-somatostatin chimeric molecule BIM-23A760. The protocol was utilized by four independent laboratories, studying 38 fibroblast-deprived NFPA cell cultures. Cells were characterized for GH, POMC, sstr1-sstr5, total dopamine D2 receptor (D2R) (in all cases), and D2 receptor long and short isoforms (in 15 out of 38 cases) mRNA expression and for alpha-subunit, LH, and FSH release. D2R, sstr3, and sstr2 mRNAs were consistently observed, with the dominant expression of D2R (2.9+/-2.6 copy/copy beta-glucuronidase; mean+/-s.e.m.), when compared with sstr3 and sstr2 (0.6+/-1.0 and 0.3+/-0.6 respectively). BIM-23A760, a molecule with high affinity for D2R and sstr2, significantly inhibited [3H]thymidine incorporation in 23 out of 38 (60%) NFPA cultures (EC50=1.2 pM and Emax=-33.6+/-3.7%). BIM-23A760 effects were similar to those induced by the selective D2R agonist cabergoline that showed a statistically significant inhibition in 18 out of 27 tumors (compared with a significant inhibition obtained in 17 out of 27 tumors using BIM-23A760, in the same subgroup of adenomas analyzed), while octreotide was effective in 13 out of 27 cases. In conclusion, superimposable data generated in four independent laboratories using a standardized protocol demonstrate that, in vitro, chimeric dopamine/sstr agonists are effective in inhibiting cell proliferation in two-thirds of NFPAs.

Consequence of dopamine D2 receptor blockade on the hyperphagic effect induced by cannabinoid CB1 and CB2 receptors in layers.

PubMed

Khodadadi, M; Zendehdel, M; Baghbanzadeh, A; Babapour, V

2017-10-01

1. Endocannabinoids (ECBs) and their receptors play a regulatory function on several physiological processes such as feed-intake behaviour, mainly in the brain. This study was carried out in order to investigate the effects of the dopaminergic D1 and D2 receptors on CB1/CB2 ECB receptor-induced hyperphagia in 3-h feed-deprived neonatal layer chickens. 2. A total of 8 experiments were designed to explore the interplay of these two modulatory systems on feed intake in neonatal chickens. In Experiment 1, chickens were intracerebroventricular (ICV) injected with control solution, l-DOPA (levo-dihydroxyphenylalanine as precursor of dopamine; 125 nmol), 2-AG (2-arachidonoylglycerol as CB 1 receptor agonist; 2 µg) and co-administration of l-DOPA (125 nmol) plus 2-AG (2 µg). Experiments 2-4 were similar to Experiment 1 except birds were injected with either 6-OHDA (6-hydroxydopamine as dopamine synthesis inhibitor; 150 nmol), SCH23390 (D1 receptor antagonist; 5 nmol) and AMI-193 (D2 receptor antagonist; 5 nmol) instead of l-DOPA, respectively. Additionally, Experiments 5-8 followed the previous ones using the same dose of l-DOPA, 6-OHDA and dopamine antagonists except that birds were injected with CB65 (CB2 receptor agonist; 5 µg) instead of 2-AG. Coadministrations were at the same dose for each experiment. Cumulative feed intakes were measured until 120 min after each injection. 3. ICV administration of 6-OHDA and AMI-193 significantly attenuated 2-AG-induced hyperphagia. Interestingly, the hyperphagic effect of CB65 was significantly attenuated by administration of l-DOPA, whereas the administration of 6-OHDA and AMI-193 together amplified the hyperphagic effect of CB65. 4. It was concluded that cannabinoid-induced feeding behaviour is probably modulated by dopamine receptors in neonatal layer-type chickens. It seems that their interaction may be mediated by the D2-dopamine receptor.

Striatal Dopamine Transporter Modulation After Rotigotine: Results From a Pilot Single-Photon Emission Computed Tomography Study in a Group of Early Stage Parkinson Disease Patients.

PubMed

Rossi, Carlo; Genovesi, Dario; Marzullo, Paolo; Giorgetti, Assuero; Filidei, Elena; Corsini, Giovanni Umberto; Bonuccelli, Ubaldo; Ceravolo, Roberto

Several in vitro data have reported negative interference by dopamine-agonists on the expression of dopamine transporter (DAT), whereas the majority of imaging studies have shown that neither L-dopa nor dopamine-agonists interfere with DAT availability. As yet, there are no in vivo studies on DAT expression after treatment with rotigotine. We evaluated presynaptic nigrostriatal function in 8 patients with de novo Parkinson disease (age, 59 ± 6.2 years; male/female sex, 5/3) using 123-I- N-ω-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophenyl)nortropane (FP-CIT) single-photon emission computed tomography before and after 3 months of treatment with rotigotine (mean dose, 7.75 ± 1.98 mg). For data analysis, specific (left and right caudate, left and right putamen) to nonspecific (occipital cortex) binding ratios, putamen-to-caudate ratios, and asymmetry indices were calculated. After rotigotine, motor symptoms improved in all patients (Unified Parkinson Disease Rating Scale III mean score, 11.88 ± 2.59 vs 7.63 ± 1.92 on therapy; P = 0.0022). Striatal FP-CIT levels showed a significant improvement in every patient at the follow-up scan. Comparisons between before and after treatment in the whole group revealed a significant improvement in FP-CIT uptake in both caudate and putamen (P < 0.001 in each nucleus). Putamen-to-caudate ratio and asymmetry indices did not show any significant difference before and after treatment. Although the study population was small, we found DAT overexpression after chronic treatment with rotigotine, presumably related to its pharmacological profile. The DAT upregulation by rotigotine in an opposite direction with respect to early Parkinson disease compensatory mechanisms might reduce the risk of dyskinesia, but it could imply less motor benefit because of less stimulation by the dopamine itself on dopaminergic receptors.

Circadian perinatal photoperiod has enduring effects on retinal dopamine and visual function.

PubMed

Jackson, Chad R; Capozzi, Megan; Dai, Heng; McMahon, Douglas G

2014-03-26

Visual system development depends on neural activity, driven by intrinsic and light-sensitive mechanisms. Here, we examined the effects on retinal function due to exposure to summer- and winter-like circadian light cycles during development and adulthood. Retinal light responses, visual behaviors, dopamine content, retinal morphology, and gene expression were assessed in mice reared in seasonal photoperiods consisting of light/dark cycles of 8:16, 16:8, and 12:12 h, respectively. Mice exposed to short, winter-like, light cycles showed enduring deficits in photopic retinal light responses and visual contrast sensitivity, but only transient changes were observed for scotopic measures. Dopamine levels were significantly lower in short photoperiod mice, and dopaminergic agonist treatment rescued the photopic light response deficits. Tyrosine hydroxylase and Early Growth Response factor-1 mRNA expression were reduced in short photoperiod retinas. Therefore, seasonal light cycles experienced during retinal development and maturation have lasting influence on retinal and visual function, likely through developmental programming of retinal dopamine.

Adjuvant therapies for Parkinson's disease: critical evaluation of safinamide.

PubMed

Stocchi, Fabrizio; Torti, Margherita

2016-01-01

Safinamide (SAF) is a new drug developed for the treatment of Parkinson's disease (PD). It is a benzylamino derivative with multiple mechanisms of action and antiparkinsonian, anticonvulsant, and neuroprotective properties. SAF inhibits monoamine oxidase B and dopamine reuptake and glutamate release, blocks voltage-dependent sodium channels, and modulates calcium channels. Although the antiparkinsonian effect can be ascribed in part to the inhibition of the monoamine oxidase B, which is complete at 50 mg, the enhanced benefit seen at the 100 mg dose is probably due to nondopaminergic mechanisms. SAF will represent an important option for patients with both early and advanced PD. In early PD patients, the addition of SAF to dopamine agonists may be an effective treatment strategy to improve motor function, prolong the use of dopamine agonists, and/or delay the introduction of levodopa. In advanced parkinsonian patients, SAF has been demonstrated to significantly increase on time with no, or nontroublesome dyskinesias. All studies performed have demonstrated its efficacy in benefiting both short-term and long-term quality-of-life outcomes in both early and advanced PD patients. SAF has been investigated in long-term (24 months), double-blind, placebo-controlled studies, where it showed a very good safety profile. SAF has not been studied in de novo PD patients, and its potential positive effect on dyskinesia deserves further dedicated studies.

Adjuvant therapies for Parkinson’s disease: critical evaluation of safinamide

PubMed Central

Stocchi, Fabrizio; Torti, Margherita

2016-01-01

Safinamide (SAF) is a new drug developed for the treatment of Parkinson’s disease (PD). It is a benzylamino derivative with multiple mechanisms of action and antiparkinsonian, anticonvulsant, and neuroprotective properties. SAF inhibits monoamine oxidase B and dopamine reuptake and glutamate release, blocks voltage-dependent sodium channels, and modulates calcium channels. Although the antiparkinsonian effect can be ascribed in part to the inhibition of the monoamine oxidase B, which is complete at 50 mg, the enhanced benefit seen at the 100 mg dose is probably due to nondopaminergic mechanisms. SAF will represent an important option for patients with both early and advanced PD. In early PD patients, the addition of SAF to dopamine agonists may be an effective treatment strategy to improve motor function, prolong the use of dopamine agonists, and/or delay the introduction of levodopa. In advanced parkinsonian patients, SAF has been demonstrated to significantly increase on time with no, or nontroublesome dyskinesias. All studies performed have demonstrated its efficacy in benefiting both short-term and long-term quality-of-life outcomes in both early and advanced PD patients. SAF has been investigated in long-term (24 months), double-blind, placebo-controlled studies, where it showed a very good safety profile. SAF has not been studied in de novo PD patients, and its potential positive effect on dyskinesia deserves further dedicated studies. PMID:26917951

The dopamine-D2-receptor agonist ropinirole dose-dependently blocks the Ca2+-triggered permeability transition of mitochondria.

PubMed

Parvez, Suhel; Winkler-Stuck, Kirstin; Hertel, Silvia; Schönfeld, Peter; Siemen, Detlef

2010-01-01

Ropinirole, an agonist of the post-synaptic dopamine D2-receptor, exerts neuroprotective activity. The mechanism is still under discussion. Assuming that this neuroprotection might be associated with inhibition of the apoptotic cascade underlying cell death, we examined a possible effect of ropinirole on the permeability transition pore (mtPTP) in the mitochondrial inner membrane. Using isolated rat liver mitochondria, the effect of ropinirole was studied on Ca2+-triggered large amplitude swelling, membrane depolarization and cytochrome c release. In addition, the effect of ropinirole on oxidation of added, membrane-impermeable NADH was investigated. The results revealed doubtlessly, that ropinirole can inhibit permeability transition. In patch-clamp experiments on mitoplasts, we show directly that ropinirole interacts with the mtPTP. Thus, ropinirole reversibly inhibits the opening of mtPTP with an IC50 of 3.4 microM and a Hill coefficient of 1.3. In both systems (i.e. energized mitochondria and mitoplasts) the inhibitory effect on permeability transition was attenuated by increasing concentrations of inorganic phosphate. In addition, we showed with antimycin A-treated mitochondria that ropinirole failed to suppress respiratory chain-linked reactive oxygen species release. In conclusion, our data suggest that the neuroprotective activity of ropinirole is due to the blockade of the Ca2+-triggered permeability transition. Copyright © 2010 Elsevier B.V. All rights reserved.

B-HT 920, a dopamine D2 agonist, in the treatment of negative symptoms of chronic schizophrenia.

PubMed

Ohmori, T; Koyama, T; Inoue, T; Matsubara, S; Yamashita, I

1993-05-15

A prospective, nonblind 8-week trial of talipexole dihydrochloride (B-HT 920), a dopamine D2 agonist, was conducted in 15 schizophrenic patients with predominantly negative symptoms. B-HT 920 was initiated at 0.15 mg/day and then adjusted at 0.15-2.4 mg/day on the basis of clinical response and side effects. Dosage of concurrent neuroleptics was fixed at least 3 weeks prior to the trial and was unchanged throughout the study period. In addition to clinical assessment, levels of plasma homovanillic acid (pHVA), a potential index of central dopamine turnover, were measured. There was a small but significant (p < 0.01, Wilcoxon test) reduction in total scores of the Scale for the Assessment of Negative Symptoms or in a cluster score of three negative items (Emotional Withdrawal, Blunted Affect, and Psychomotor Retardation) of the Brief Psychiatric Rating Scale (BPRS). No change was observed in cluster scores of positive items of BPRS. There was a weak negative correlation between pHVA levels and the cluster scores of negative items of BPRS both at weeks 0 and 8 of the trial. The clinical results suggest that activation of D2 receptors was related to partial amelioration of the negative symptoms. The clinical and biochemical findings are consistent with a hypothesis that decreased dopaminergic activity may be related to the etiology of negative symptoms of schizophrenia.

A photoaffinity ligand for dopamine D2 receptors: azidoclebopride.

PubMed

Niznik, H B; Guan, J H; Neumeyer, J L; Seeman, P

1985-02-01

In order to label D2 dopamine receptors selectively and covalently by means of a photosensitive compound, azidoclebopride was synthesized directly from clebopride. The dissociation constant (KD) of clebopride for the D2 dopamine receptor (canine brain striatum) was 1.5 nM, while that for azidoclebopride was 21 nM. The affinities of both clebopride and azidoclebopride were markedly reduced in the absence of sodium chloride. In the presence of ultraviolet light, azidoclebopride inactivated D2 dopamine receptors irreversibly, as indicated by the inability of the receptors to bind [3H]spiperone. Maximal photoinactivation of about 60% of the D2 dopamine receptors occurred at 1 microM azidoclebopride; 30% of the receptors were inactivated at 80 nM azidoclebopride (pseudo-IC50). Dopamine agonists selectively protected the D2 receptors from being inactivated by azidoclebopride, the order of potency being (-)-N-n-propylnorapomorphine greater than apomorphine greater than (+/-)-6,7-dihydroxy-2-aminotetralin greater than (+)-N-n-propylnorapomorphine greater than dopamine greater than noradrenaline greater than serotonin. Similarly, dopaminergic antagonists prevented the photoinactivation of D2 receptors by azidoclebopride with the following order of potency: spiperone greater than (+)-butaclamol greater than haloperidol greater than clebopride greater than (-)-sulpiride greater than (-)-butaclamol. The degree of D2 dopamine receptor photoinduced inactivation by azidoclebopride was not significantly affected by scavengers such as p-aminobenzoic acid and dithiothreitol. Furthermore, irradiation of striatal membranes with a concentration of azidoclebopride sufficient to inactivate dopamine D2 receptors by 60% did not significantly reduce dopamine D1, serotonin (S2), benzodiazepine, alpha 1- or beta-noradrenergic receptors. This study describes the use of a novel and selective photoaffinity ligand for brain dopamine D2 receptors. The molecule, in radiolabeled form, may aid in the molecular characterization of these receptors.

Investigational agents in the treatment of Parkinson’s disease: focus on safinamide

PubMed Central

Malek, Naveed M; Grosset, Donald G

2012-01-01

The authors review management issues in Parkinson’s disease (PD) and provide an overview of the current pharmacological management strategies, with a specific focus on safinamide. Current therapeutic management of PD largely involves strategies to optimize the replacement of deficient dopamine, using levodopa, dopamine agonists, and inhibitors of dopamine-metabolizing enzymes. Currently under investigation for use in the treatment of PD, safinamide has multiple modes of action including monoamine oxidase B inhibition. It is well absorbed orally, has a long plasma half-life, and does not have liver enzyme-inducing or liver enzyme-inhibiting activity. Peak plasma concentration occurs 2–4 hours after single oral doses. Safinamide as monotherapy and as an adjunct to dopamine agonists improves Unified Parkinson’s Disease Rating Scale motor scores. One randomized, placebo-controlled trial involving 168 patients given a median safinamide dose of 70 mg/day (range 40–90 mg/day) significantly increased the proportion of responders – defined as patients improving their Unified Parkinson’s Disease Rating Scale motor scores by 30% or more from baseline – after 3 months (37.5% for safinamide versus 21.4% for placebo; P < 0.05). Safinamide increased “on” time with no or minor dyskinesia compared with the placebo in another trial, but dyskinesia severity was not reduced. Safinamide was well tolerated, with an adverse effect profile similar to that of the placebo. Further Phase III trial data for safinamide efficacy is awaited, and will be of interest in a comparison with other developments in PD therapeutics: modified formulations of available compounds, new drug classes such as adenosine receptor antagonists, and gene-based therapies. PMID:27186120

Influence of body weight and type of chow on the sensitivity of rats to the behavioral effects of the direct-acting dopamine receptor agonist quinpirole

PubMed Central

Baladi, Michelle G; Newman, Amy H; France, Charles P

2013-01-01

Rationale Amount and type of food can alter dopamine systems and sensitivity to drugs acting on those systems. Objectives This study examined whether changes in body weight, food type, or both body weight and food type contribute to these effects. Methods Rats had free or restricted access (increasing, decreasing, or maintaining body weight) to standard (5.7% fat) or high fat (34.3%) chow. Results In rats gaining weight with restricted or free access to high fat chow, both limbs of the quinpirole yawning dose-response curve (0.0032–0.32 mg/kg) shifted leftward compared with rats eating standard chow. Restricting access to standard or high fat chow (maintaining or decreasing body weight) decreased or eliminated quinpirole-induced yawning; within one week of resuming free feeding, sensitivity to quinpirole was restored, although the descending limb of the dose-response curve was shifted leftward in rats eating high fat chow. These are not likely pharmacokinetic differences because quinpirole-induced hypothermia was not different among groups. PG01037 and L-741,626 antagonized the ascending and descending limbs of the quinpirole dose-response curve in rats eating high fat chow, indicating D3 and D2 receptor mediation, respectively. Rats eating high fat chow also developed insulin resistance. Conclusions These results show that amount and type of chow alter sensitivity to a direct-acting dopamine receptor agonist with the impact of each factor depending on whether body weight increases, decreases, or is maintained. These data demonstrate that feeding conditions, perhaps related to insulin and insulin sensitivity, profoundly impact the actions of drugs acting on dopamine systems. PMID:21544521

Influence of body weight and type of chow on the sensitivity of rats to the behavioral effects of the direct-acting dopamine-receptor agonist quinpirole.

PubMed

Baladi, Michelle G; Newman, Amy H; France, Charles P

2011-10-01

Amount and type of food can alter dopamine systems and sensitivity to drugs acting on those systems. This study examined whether changes in body weight, food type, or both body weight and food type contribute to these effects. Rats had free or restricted access (increasing, decreasing, or maintaining body weight) to standard (5.7% fat) or high-fat (34.3%) chow. In rats gaining weight with restricted or free access to high-fat chow, both limbs of the quinpirole yawning dose-response curve (0.0032-0.32 mg/kg) shifted leftward compared with rats eating standard chow. Restricting access to standard or high-fat chow (maintaining or decreasing body weight) decreased or eliminated quinpirole-induced yawning; within 1 week of resuming free feeding, sensitivity to quinpirole was restored, although the descending limb of the dose-response curve was shifted leftward in rats eating high-fat chow. These are not likely pharmacokinetic differences because quinpirole-induced hypothermia was not different among groups. PG01037 and L-741,626 antagonized the ascending and descending limbs of the quinpirole dose-response curve in rats eating high-fat chow, indicating D3 and D2 receptor mediation, respectively. Rats eating high-fat chow also developed insulin resistance. These results show that amount and type of chow alter sensitivity to a direct-acting dopamine-receptor agonist with the impact of each factor depending on whether body weight increases, decreases, or is maintained. These data demonstrate that feeding conditions, perhaps related to insulin and insulin sensitivity, profoundly impact the actions of drugs acting on dopamine systems.

The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine.

PubMed

Karkhanis, Anushree N; Beveridge, Thomas J R; Blough, Bruce E; Jones, Sara R; Ferris, Mark J

2016-09-01

The US Food and Drug Administration has not approved a treatment for cocaine addiction, possibly due in part to the fact that repeated cocaine use results in dysregulation of multiple neurotransmitter systems, including glutamate and dopamine, and an emergence of increased negative affective states and heightening motivation to take cocaine despite negative consequences. We used a combination therapy approach to assess whether modulation of both glutamate and dopamine transmission would reduce the motivation to self- administer cocaine compared to modulation of either system alone. The metabotropic glutamate 2/3 receptor agonist, LY379268, and the monoamine releaser, phenmetrazine, were used to assess their individual and combined ability to decrease the reinforcing efficacy of cocaine because they modulate glutamate and dopamine levels, respectively. Cocaine breakpoints and cocaine intake was assessed, using a progressive ratio schedule, at baseline in three groups based on dose of cocaine (0.19, 0.38, 0.75mg/kg/infusion), and following LY379268 (0.03 or 0.30mg/kg; i.p.), phenmetrazine (25mg/kg/day; osmotic minipump), and a combination of the two drugs. LY379268 and phenmetrazine alone reduced breakpoints for all doses of cocaine. The combination of the two drugs showed a concerted effect in reducing breakpoints for all doses of cocaine, with the lowest dose of cocaine reduced by as much as 70%. These data support combination therapy of dopamine and glutamate systems as an effective means to reduce the motivation to take cocaine since a combination of drugs can address neurobiological dysfunction in multiple neurotransmitter systems compared to therapies using single drugs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro.

PubMed

Giacomelli, S; Palmery, M; Romanelli, L; Cheng, C Y; Silvestrini, B

1998-01-01

The hallucinogenic effects of lysergic acid diethylamide (LSD) have mainly been attributed to the interaction of this drug with the serotoninergic system, but it seems more likely that they are the result of the complex interactions of the drug with both the serotoninergic and dopaminergic systems. The aim of the present study was to investigate the functional actions of LSD at dopaminergic receptors using prolactin secretion by primary cultures of rat pituitary cells as a model. LSD produced a dose-dependent inhibition of prolactin secretion in vitro with an IC50 at 1.7x10(-9) M. This action was antagonized by spiperone but not by SKF83566 or cyproheptadine, which indicates that LSD has a specific effect on D2 dopaminergic receptors. The maximum inhibition of prolactin secretion achieved by LSD was lower than that by dopamine (60% versus 80%). Moreover, the fact that LSD at 10(-8)-10(-6) M antagonized the inhibitory effect of dopamine (10(-7) M) and bromocriptine (10(-11) M) suggests that LSD acts as a partial agonist at D2 receptors on lactotrophs in vitro. Interestingly, LSD at 10(-13)-10(-10) M, the concentrations which are 10-1000-fold lower than those required to induce direct inhibition on pituitary prolactin secretion, potentiated the dopamine (10(-10)-2.5x10(-9) M)-mediated prolactin secretion by pituitary cells in vitro. These results suggest that LSD not only interacts with dopaminergic receptors but also has a unique capacity for modulating dopaminergic transmission. These findings may offer new insights into the hallucinogenic effect of LSD.

Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats

PubMed Central

Oliveras, Ignasi; Sánchez-González, Ana; Sampedro-Viana, Daniel; Piludu, Maria Antonietta; Río-Alamos, Cristóbal; Giorgi, Osvaldo; Corda, Maria G.; Aznar, Susana; González-Maeso, Javier; Gerbolés, Cristina; Blázquez, Gloria; Cañete, Toni; Tobeña, Adolf

2017-01-01

Rationale Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders. Objectives We have carried out a pharmacological characterization of the Roman high-(RHA-I) and low-avoidance (RLA-I) rat strains with different acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages). Results RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 70 dB prepulse intensities) and reduced locomotion in both strains. The atypical antipsychotic clozapine (serotonin/dopamine receptor antagonist) did not affect PPI in either strain, but decreased locomotion in a dose-dependent manner in both rat strains. The mixed dopamine D1/D2 agonist, apomorphine, at the dose of 0.05 mg/kg, decreased PPI in RHA-I, but not RLA-I rats. The hallucinogen drug DOI (5-HT2A agonist; 0.1–1.0 mg/kg) disrupted PPI in RLA-I rats in a dose-dependent manner at the 70 dB prepulse intensity, while in RHA-Irats, only the 0.5 mg/kg dose impaired PPI at the 80 dB prepulse intensity. DOI slightly decreased locomotion in both strains. Finally, clozapine attenuated the PPI impairment induced by the NMDA receptor antagonist MK-801 only in RLA-I rats. Conclusions These results add experimental evidence to the view that RHA-I rats represent a model with predictive and construct validity of some dopamine and 5-HT2A receptor-related features of schizophrenia. PMID:28154892

Reversal of dopamine-mediated firing inhibition through activation of the dopamine transporter in substantia nigra pars compacta neurons.

PubMed

Aversa, Daniela; Martini, Alessandro; Guatteo, Ezia; Pisani, Antonio; Mercuri, Nicola Biagio; Berretta, Nicola

2018-06-22

One of the hallmarks of ventral midbrain dopamine (DA)-releasing neurons is membrane hyperpolarization in response to somato-dendritic D 2 receptors (D 2 Rs) stimulation. At early postnatal age, under sustained DA, this inhibitory response is followed by a slow recovery, resulting in dopamine inhibition reversal (DIR). In the present investigation we aimed to get a better insight onto the cellular mechanisms underlying DIR. We performed single unit extracellular recordings with a multi-electrode array (MEA) device and conventional patch-clamp recordings on midbrain mouse slices. While continuous DA (100 μM) perfusion gave rise to firing inhibition that recovered in 10 to 15 min, the same effect was not obtained with the D 2 R agonist quinpirole (100 nM). Moreover, firing inhibition caused by the GABA B receptor agonist baclofen (300 nM), was reverted by DA (100 μM), albeit D 2 Rs had been blocked by sulpiride (10 μM). Conversely, the block of the DA transporter (DAT) with cocaine (30 μM) prevented firing recovery by DA under GABA B receptor stimulation. Accordingly, in whole cell recordings from single cells the baclofen-induced outward current was counteracted by DA (100 μM) in the presence of sulpiride (10 μM), and this effect was prevented by the DAT antagonists cocaine (30 μM) and GBR12909 (2 μM). Our results indicate a major role played by DAT in causing DIR under conditions of sustained DA exposure and point to DAT as an important target for pharmacological therapies leading to prolonged enhancement of the DAergic signal. This article is protected by copyright. All rights reserved.

Transdermal Patch of Rotigotine Attenuates Freezing of Gait in Patients with Parkinson's Disease: An Open-Label Comparative Study of Three Non-Ergot Dopamine Receptor Agonists.

PubMed

Ikeda, Ken; Hirayama, Takehisa; Takazawa, Takanori; Kawabe, Kiyokazu; Iwasaki, Yasuo

Objective Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic neurons. Rotigotine is a non-ergot dopamine receptor agonist (DA). Its transdermal patch maintains the effective concentrations for 24 hours. Freezing of gait (FOG) is a common and devastating symptom in PD patients. Little is known about therapeutic effects of rotigotine on FOG in PD patients. Herein we compared how three non-ergot DAs of rotigotine, pramipexole LA and ropinirole CR influence FOG, besides classical motor deficits in PD patients. Methods Rotigotine (maintenance doses of 9-27 mg/day) was administered in 51 patients, 36 patients received pramipexole LA (1.5-4.5 mg/day) and 35 patients received ropinirole CR (8-16 mg/day). The Unified PD Rating Scale (UPDRS) parts I-IV, FOG questionnaire (16 items) and wearing off time were examined from baseline to 7 months after DA administration. UPDRS parts I-IV were evaluated during on time and FOG was recorded during off time if patients experienced wearing off. Results A total of 111 patients completed the study. UPDRS parts II-III scores and wearing off time were significantly reduced after each DA treatment compared to baseline. FOG was found in 54 patients (49%). Most patients developed FOG during off time only. FOG scores were significantly decreased at 2 months after rotigotine treatment whereas pramipexole LA and ropinirole treatment did not alter FOG scores. Conclusion The present study indicates that transdermal patch of rotigotine attenuated the FOG off time. The similar binding affinities to dopamine receptors between rotigotine and dopamine, and 24 hours steady hemodynamics could contribute to the therapeutic mechanism of rotigotine on FOG in PD patients with wearing off.

Transdermal Patch of Rotigotine Attenuates Freezing of Gait in Patients with Parkinson's Disease: An Open-Label Comparative Study of Three Non-Ergot Dopamine Receptor Agonists

PubMed Central

Ikeda, Ken; Hirayama, Takehisa; Takazawa, Takanori; Kawabe, Kiyokazu; Iwasaki, Yasuo

2016-01-01

Objective Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic neurons. Rotigotine is a non-ergot dopamine receptor agonist (DA). Its transdermal patch maintains the effective concentrations for 24 hours. Freezing of gait (FOG) is a common and devastating symptom in PD patients. Little is known about therapeutic effects of rotigotine on FOG in PD patients. Herein we compared how three non-ergot DAs of rotigotine, pramipexole LA and ropinirole CR influence FOG, besides classical motor deficits in PD patients. Methods Rotigotine (maintenance doses of 9-27 mg/day) was administered in 51 patients, 36 patients received pramipexole LA (1.5-4.5 mg/day) and 35 patients received ropinirole CR (8-16 mg/day). The Unified PD Rating Scale (UPDRS) parts I-IV, FOG questionnaire (16 items) and wearing off time were examined from baseline to 7 months after DA administration. UPDRS parts I-IV were evaluated during on time and FOG was recorded during off time if patients experienced wearing off. Results A total of 111 patients completed the study. UPDRS parts II-III scores and wearing off time were significantly reduced after each DA treatment compared to baseline. FOG was found in 54 patients (49%). Most patients developed FOG during off time only. FOG scores were significantly decreased at 2 months after rotigotine treatment whereas pramipexole LA and ropinirole treatment did not alter FOG scores. Conclusion The present study indicates that transdermal patch of rotigotine attenuated the FOG off time. The similar binding affinities to dopamine receptors between rotigotine and dopamine, and 24 hours steady hemodynamics could contribute to the therapeutic mechanism of rotigotine on FOG in PD patients with wearing off. PMID:27725534

Experimental basis for a role for sulfhydryls and dopamine in ulcerogenesis: a primer for cytoprotection--organoprotection.

PubMed

Szabo, S

1986-01-01

This brief review presents the evolution of the concept of cytoprotection which was originally described by Robert (1979) to represent prevention of chemically induced hemorrhagic gastric erosions without inhibiting acid secretion. Prostaglandins (PG) and sulfhydryls (SH) protect only against deep hemorrhagic necrosis in the mucosa without altering the initial damage to surface epithelial cells. Organ integrity and function are thus maintained (i.e., organoprotection) despite the loss of several layers of mucosal cells. While both PG and SH are natural products it must be stressed that only SH compounds can enter directly into protective reactions (e.g., free radical scavenging, modification of receptor SH groups, oxidation of certain structural and enzyme proteins). In addition, SH compounds also stimulate PG synthesis. A major target of gastroprotection by either PG or SH is the preservation of mucosal microvasculature to maintain blood flow for rapid restitution and cell proliferation. Dopamine-related compounds are reviewed because of their possible role in duodenal ulceration. Dopamine and dopamine agonists are antiulcerogens in duodenal ulcer models. Dopamine antagonists are proulcerogens and the dopamine neurotoxin MPTP causes duodenal ulcer in experimental animals. The mechanism of duodenal antiulcerogenic effect involves inhibition of gastric acid and pepsin secretion, stimulation of duodenal bicarbonate secretion, correction of duodenal dysmotility, and maybe increased blood flow. Because of their multiple beneficial effects, SH compounds and dopamine drugs are good models for gastroenteroprotection.

Pramipexole enhances disadvantageous decision-making: Lack of relation to changes in phasic dopamine release.

PubMed

Pes, Romina; Godar, Sean C; Fox, Andrew T; Burgeno, Lauren M; Strathman, Hunter J; Jarmolowicz, David P; Devoto, Paola; Levant, Beth; Phillips, Paul E; Fowler, Stephen C; Bortolato, Marco

2017-03-01

Pramipexole (PPX) is a high-affinity D 2 -like dopamine receptor agonist, used in the treatment of Parkinson's disease (PD) and restless leg syndrome. Recent evidence indicates that PPX increases the risk of problem gambling and impulse-control disorders in vulnerable patients. Although the molecular bases of these complications remain unclear, several authors have theorized that PPX may increase risk propensity by activating presynaptic dopamine receptors in the mesolimbic system, resulting in the reduction of dopamine release in the nucleus accumbens (NAcc). To test this possibility, we subjected rats to a probability-discounting task specifically designed to capture the response to disadvantageous options. PPX enhanced disadvantageous decision-making at a dose (0.3 mg/kg/day, SC) that reduced phasic dopamine release in the NAcc. To test whether these modifications in dopamine efflux were responsible for the observed neuroeconomic deficits, PPX was administered in combination with the monoamine-depleting agent reserpine (RES), at a low dose (1 mg/kg/day, SC) that did not affect baseline locomotor and operant responses. Contrary to our predictions, RES surprisingly exacerbated the effects of PPX on disadvantageous decision-making, even though it failed to augment PPX-induced decreases in phasic dopamine release. These results collectively suggest that PPX impairs the discounting of probabilistic losses and that the enhancement in risk-taking behaviors secondary to this drug may be dissociated from dynamic changes in mesolimbic dopamine release. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum.

PubMed

Mattsson, Anna; Olson, Lars; Svensson, Torgny H; Schilström, Björn

2007-11-01

Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine-induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine-induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission.

D-amino acid oxidase is expressed in the ventral tegmental area and modulates cortical dopamine

PubMed Central

Betts, Jill F.; Schweimer, Judith V.; Burnham, Katherine E.; Burnet, Philip W. J.; Sharp, Trevor; Harrison, Paul J.

2014-01-01

D-amino acid oxidase (DAO, DAAO) degrades the NMDA receptor co-agonist D-serine, modulating D-serine levels and thence NMDA receptor function. DAO inhibitors are under development as a therapy for schizophrenia, a disorder involving both NMDA receptor and dopaminergic dysfunction. However, a direct role for DAO in dopamine regulation has not been demonstrated. Here, we address this question in two ways. First, using in situ hybridization and immunohistochemistry, we show that DAO mRNA and immunoreactivity are present in the ventral tegmental area (VTA) of the rat, in tyrosine hydroxylase (TH)-positive and -negative neurons, and in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Second, we show that injection into the VTA of sodium benzoate, a DAO inhibitor, increases frontal cortex extracellular dopamine, as measured by in vivo microdialysis and high performance liquid chromatography. Combining sodium benzoate and D-serine did not enhance this effect, and injection of D-serine alone affected dopamine metabolites but not dopamine. These data show that DAO is expressed in the VTA, and suggest that it impacts on the mesocortical dopamine system. The mechanism by which the observed effects occur, and the implications of these findings for schizophrenia therapy, require further study. PMID:24822045

Cortical Regulation of Striatal Medium Spiny Neuron Dendritic Remodeling in Parkinsonism: Modulation of Glutamate Release Reverses Dopamine Depletion–Induced Dendritic Spine Loss

PubMed Central

Garcia, Bonnie G.; Neely, M. Diana

2010-01-01

Striatal medium spiny neurons (MSNs) receive glutamatergic afferents from the cerebral cortex and dopaminergic inputs from the substantia nigra (SN). Striatal dopamine loss decreases the number of MSN dendritic spines. This loss of spines has been suggested to reflect the removal of tonic dopamine inhibitory control over corticostriatal glutamatergic drive, with increased glutamate release culminating in MSN spine loss. We tested this hypothesis in two ways. We first determined in vivo if decortication reverses or prevents dopamine depletion–induced spine loss by placing motor cortex lesions 4 weeks after, or at the time of, 6-hydroxydopamine lesions of the SN. Animals were sacrificed 4 weeks after cortical lesions. Motor cortex lesions significantly reversed the loss of MSN spines elicited by dopamine denervation; a similar effect was observed in the prevention experiment. We then determined if modulating glutamate release in organotypic cocultures prevented spine loss. Treatment of the cultures with the mGluR2/3 agonist LY379268 to suppress corticostriatal glutamate release completely blocked spine loss in dopamine-denervated cultures. These studies provide the first evidence to show that MSN spine loss associated with parkinsonism can be reversed and point to suppression of corticostriatal glutamate release as a means of slowing progression in Parkinson's disease. PMID:20118184

Reinforcer Magnitude Attenuates Apomorphine's Effects on Operant Pecking

ERIC Educational Resources Information Center

Pinkston, Jonathan W.; Lamb, R. J.

2012-01-01

When given to pigeons, the direct-acting dopamine agonist apomorphine elicits pecking. The response has been likened to foraging pecking because it bears remarkable similarity to foraging behavior, and it is enhanced by food deprivation. On the other hand, other data suggest the response is not related to foraging behavior and may even interfere…

Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis

PubMed Central

2016-01-01

The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools for cell-based studies that have been translated to in vivo models of drug abuse. D3R antagonists and partial agonists have shown especially promising results in rodent models of relapse-like behavior, including stress-, drug-, and cue-induced reinstatement of drug seeking. However, to date, translation to human studies has been limited. Herein, we present an overview and illustrate some of the pitfalls and challenges of developing novel D3R-selective compounds toward clinical utility, especially for treatment of cocaine abuse. Future research and development of D3R-selective antagonists and partial agonists for substance abuse remains critically important but will also require further evaluation and development of translational animal models to determine the best time in the addiction cycle to target D3Rs for optimal therapeutic efficacy. PMID:25826710

Pharmacokinetic drug evaluation of safinamide mesylate for the treatment of mid-to-late stage Parkinson's disease.

PubMed

Müller, Thomas

2017-06-01

Patients with Parkinson's disease suffer from a heterogeneous expression of neurotransmitter deficits. They cause an individual variable expression of motor and non-motor symptoms. Thus, drugs with various mechanisms of actions are suitable to counteract these disease related neurotransmitter alterations. Areas covered: This invited review suggests safinamide as an ideal compound for therapy of Parkinson's disease, as its pharmacological profile includes reversible monoamine oxidase B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and abnormal glutamate release. Safinamide may provide benefits effects on non-motor symptoms in addition to the demonstrated amelioration of motor impairment in levodopa treated patients with Parkinson's disease. Safinamide was well tolerated and safe when administered in dose of 50 or 100 mg daily in pivotal trials. Expert opinion: Clinical handling, safety and tolerability of Safinamide are better than of dopamine agonists or levodopa. Safinamide supplements the existing armamentarium of drugs for Parkinson's disease. Safinamide will help to reduce dosing of levodopa but also of dopamine agonists during long term treatment in patients with Parkinson's disease.

Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters.

PubMed

Tosh, Dilip K; Janowsky, Aaron; Eshleman, Amy J; Warnick, Eugene; Gao, Zhan-Guo; Chen, Zhoumou; Gizewski, Elizabeth; Auchampach, John A; Salvemini, Daniela; Jacobson, Kenneth A

2017-04-13

We have repurposed (N)-methanocarba adenosine derivatives (A 3 adenosine receptor (AR) agonists) to enhance radioligand binding allosterically at the human dopamine (DA) transporter (DAT) and inhibit DA uptake. We extended the structure-activity relationship of this series with small N 6 -alkyl substitution, 5'-esters, deaza modifications of adenine, and ribose restored in place of methanocarba. C2-(5-Halothien-2-yl)-ethynyl 5'-methyl 9 (MRS7292) and 5'-ethyl 10 (MRS7232) esters enhanced binding at DAT (EC 50 ∼ 35 nM) and at the norepinephrine transporter (NET). 9 and 10 were selective for DAT compared to A 3 AR in the mouse but not in humans. At DAT, the binding of two structurally dissimilar radioligands was enhanced; NET binding of only one radioligand was enhanced; SERT radioligand binding was minimally affected. 10 was more potent than cocaine at inhibiting DA uptake (IC 50 = 107 nM). Ribose analogues were weaker in DAT interaction than the corresponding bicyclics. Thus, we enhanced the neurotransmitter transporter activity of rigid nucleosides while reducing A 3 AR affinity.

GABA(A) and dopamine receptors in the nucleus accumbens shell differentially influence performance of a water-reinforced progressive ratio task.

PubMed

Covelo, Ignacio R; Wirtshafter, David; Stratford, Thomas R

2012-03-01

Several authors have shown that injections of the GABA(A) agonist muscimol into the medial shell region of the nucleus accumbens (AcbSh) result in large increases in food, but not water, intake. In previous studies we demonstrated that intra-AcbSh injections of either muscimol or of the indirect dopamine agonist amphetamine increase response output on a food-reinforced progressive ratio schedule. In the current experiment we extended these observations by examining the effects of muscimol and amphetamine injections on the performance of a water-reinforced progressive ratio task in mildly deprived animals. We found that muscimol did not affect the number of responses made in the water-reinforced task, even though a marked increase in responding was observed after amphetamine. Muscimol did, however, significantly increase food intake in the same animals. The results suggest that the enhancing effects of intra-AcbSh muscimol differ from those of amphetamine in that they are selective for food-reinforced behaviors. Copyright © 2011. Published by Elsevier Inc.

Apomorphine and the dopamine hypothesis of schizophrenia: a dilemma?

PubMed Central

Dépatie, L; Lal, S

2001-01-01

The dopamine (DA) hypothesis of schizophrenia implicates an enhancement of DA function in the pathophysiology of the disorder, at least in the genesis of positive symptoms. Accordingly, apomorphine, a directly acting DA receptor agonist, should display psychotomimetic properties. A review of the literature shows little or no evidence that apomorphine, in doses that stimulate postsynaptic DA receptors, induces psychosis in non-schizophrenic subjects or a relapse or exacerbation of psychotic symptoms in patients with schizophrenia. After a detailed review of the literature reporting psychotogenic effects of apomorphine in patients with Parkinson's disease, an interpretation of these data is difficult, in part because of several confounding factors, such as the concomitant use of drugs known to induce psychosis and the advanced state of the progressive neurological disorder. In the context of the DA hypothesis of schizophrenia, the limited ability of apomorphine to induce psychosis, in contrast to indirectly acting DA agonists that increase synaptic DA, may be explained by the relatively weak affinity of apomorphine for the D3 receptor compared with DA. Alternatively, enhancement of DA function, though necessary, may be insufficient by itself to induce psychosis. PMID:11394190

Activation of serotonin 2C receptors in dopamine neurons inhibits binge-like eating in mice

PubMed Central

Xu, Pingwen; He, Yanlin; Cao, Xuehong; Valencia-Torres, Lourdes; Yan, Xiaofeng; Saito, Kenji; Wang, Chunmei; Yang, Yongjie; Hinton, Antentor; Zhu, Liangru; Shu, Gang; Myers, Martin G.; Wu, Qi; Tong, Qingchun; Heisler, Lora K.; Xu, Yong

2016-01-01

Background Neural networks that regulate binge eating remain to be identified, and effective treatments for binge eating are limited. Methods We combined neuroanatomical, pharmacological, electrophysiological, Cre-lox, and chemogenetic approaches to investigate the functions of 5-HT 2C receptor (5-HT2CR) expressed by dopamine (DA) neurons in the regulation of binge-like eating behavior in mice. Results We showed that 5-HT stimulates DA neural activity through a 5-HT2CR-mediated mechansim, and activation of this midbrain 5-HT-DA neural circuit effectively inhibits binge-like eating behavior in mice. Notably, 5-HT medications, including fluoxetine, d-Fenfluramine, and lorcaserin (a selective 5-HT2CR agonist), act upon 5-HT2CRs expressed by DA neurons to inhibit binge-like eating in mice. Conclusions We identified the 5-HT2CR population in DA neurons as one potential target for anti-binge therapies, and provided pre-clinical evidence that 5-HT2CR agonists could be used to treat binge eating. PMID:27516377

Pretreatment with nomifensine or nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline augments methamphetamine-induced stereotypical behavior in mice

PubMed Central

Hall, F. Scott; Uhl, George R.; Asano, Hiromi; Chatani, Ryuki; Hayata, Sachiko; Yokoyama, Hiroko; Tanaka, Koh-ichi; Nishiyama, Nobuyoshi; Takemura, Motohiko

2014-01-01

Nomifensine is a dopamine/norepinephrine reuptake inhibitor. Nomifensine and some of its structural analogues produce behavioral effects indicative of indirect dopaminergic agonist properties, such as hyperlocomotion. By contrast, the deaminated and demethylated nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) is reported to have amphetamine-antagonistic properties, as demonstrated by inhibition of methamphetamine (METH)-induced dopamine release in the nucleus accumbens and METH-induced hyperlocomotion in rats. In the present study, we examined the effect of PTIQ (10 mg/kg, i.p.) and nomifensine (3 mg/kg, i.p.) on METH (5 or 10 mg/kg ,i.p.)-induced stereotypical behavior in mice in order to determine whether PTIQ and nomifensine inhibit and augment, respectively, METH-induced stereotypical behavior. Unexpectedly, our observations demonstrated that both PTIQ and nomifensine significantly augmented METH-induced stereotypical behavior and locomotion in mice. This augmentation is likely the result of additive effects on dopaminergic function by METH in combination with PTIQ or nomifensine. These results suggest that, contrary to some reports, PTIQ may display dopaminergic agonist properties in mice. PMID:22265332

Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells.

PubMed

Heusler, Peter; Newman-Tancredi, Adrian; Loock, Timothé; Cussac, Didier

2008-02-26

Antipsychotic drugs act preferentially via dopamine D(2) receptor blockade, but interaction with serotonin 5-HT(1A) receptors has attracted interest as additional target for antipsychotic treatment. As receptor internalisation is considered crucial for drug action, we tested the propensity of antipsychotics to internalise human (h)D(2S) receptors and h5-HT(1A) receptors. Agonist-induced internalisation of hemaglutinin (HA)-tagged hD(2S) and HA-h5-HT(1A) receptors expressed in HEK293 cells was increased by coexpression of G-protein coupled receptor kinase 2 and beta-arrestin2. At the HA-hD(2S) receptor, dopamine, quinpirole and bromocriptine behaved as full agonists, while S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3PPP] and sarizotan were partial agonists. The typical antipsychotic, haloperidol, and the atypical compounds, olanzapine, nemonapride, ziprasidone and clozapine did not internalise HA-hD(2S) receptors, whereas aripiprazole potently internalised these receptors (>50% relative efficacy). Among antipsychotics with combined D(2)/5-HT(1A) properties, bifeprunox and (3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo-[3.2.1]octane-3-methanamine (SSR181507) partially internalised HA-hD(2S) receptors, piperazine, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-[[5-(4-fluorophenyl)-3-pyridinyl]methyl (SLV313) and N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine (F15063) were inactive. At the HA-h5-HT(1A) receptor, serotonin, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] and sarizotan were full agonists, buspirone acted as partial agonist. (-)-Pindolol showed little activity and no internalising properties were manifested for the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY100635). Most antipsychotics induced HA-h5-HT(1A) receptor internalisation, with an efficacy rank order: nemonapride>F15063>SSR181507>bifeprunox approximately SLV313 approximately ziprasidone>aripiprazole and potencies: SLV313>SSR181507 approximately F15063>bifeprunox approximately nemonapride approximately aripiprazole>ziprasidone. Interestingly, the internalisation induced by clozapine was only minimal, whereas aripirazole and bifeprunox were more potent for internalisation than for G-protein activation. These different profiles of antipsychotics for receptor internalisation may help to evaluate their potential therapeutic impact in the treatment of schizophrenia.

Feasibility of a randomized single-blind crossover trial to assess the effects of the second-generation slow-release dopamine agonists pramipexole and ropinirole on cued recall memory in idiopathic mild or moderate Parkinson's disease without cognitive impairment.

PubMed

Shepherd, Thomas A; Edelstyn, Nicola M J; Longshaw, Laura; Sim, Julius; Watts, Keira; Mayes, Andrew R; Murray, Michael; Ellis, Simon J

2018-01-01

The aim was to assess the feasibility of a single-centre, single-blind, randomized, crossover design to explore the effects of two slow-release dopamine agonists, ropinirole and pramipexole, on cued recall in Parkinson's disease. As the design required a switch from the prescribed agonist (pramipexole-to-ropinirole, or ropinirole-to-pramipexole), the primary objectives were to (a) examine the efficacy of processes and procedures used to manage symptoms during the washout period and (b) to use cued recall estimates to inform a power calculation for a definitive trial. Secondary objectives were to assess consent and missing data rates, acceptability of clinical support for the OFF sessions, experience of the OFF sessions and of agonist switching, barriers-to-participation for patients and informal caregivers. Patients were randomized in a 1:1 ratio to two treatment arms and stabilized on each agonist for 6 weeks. The arms differed only in the sequence in which the agonists were administered. Cued recall was assessed ON medication and, following a washout period resulting in 93.75% agonist elimination, OFF medication. A total of 220 patients were screened: 145 were excluded and 75 invitations to participate were sent to eligible patients. Fifty-three patients declined, 22 consented and 16 completed the study. There were no serious adverse events, and rates of non-serious adverse events were equivalent between the agonists. Using the largest standard deviation (SD) of the ON-OFF difference cued recall score (inflated by ~25% to give a conservative estimate of the SD in a definitive trial) and assuming an effect of at least 10% of the observed range of OFF medication cued recall scores for either agonist to be clinically important, a main trial requires a sample size of just under 150 patients. The consent and missing data rates were 29 and 27% respectively. The washout period and the preparation for the OFF sessions were acceptable, and the sessions were manageable. The experience of switching was also manageable. Barriers to participation included concerns about disease stability, side effects, research process, carer workload and accessibility of the information sheet. This study presented challenges to recruitment both in design and execution, and while it was a major aim of the study to assess this, evaluation of these challenges provided the opportunity to explore how they could be overcome for future studies. EudraCT 2012-000801-64.

Dopamine modulates reward system activity during subconscious processing of sexual stimuli.

PubMed

Oei, Nicole Y L; Rombouts, Serge Arb; Soeter, Roelof P; van Gerven, Joop M; Both, Stephanie

2012-06-01

Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive-compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the 'reward system'. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. Young healthy males (n=53) were randomly assigned to two experimental groups or a control group, and were administered a dopamine antagonist (haloperidol), a dopamine agonist (levodopa), or placebo. Brain activation was assessed during a backward-masking task with subliminally presented sexual stimuli. Results showed that levodopa significantly enhanced the activation in the nucleus accumbens and dorsal anterior cingulate when subliminal sexual stimuli were shown, whereas haloperidol decreased activations in those areas. Dopamine thus enhances activations in regions thought to regulate 'wanting' in response to potentially rewarding sexual stimuli that are not consciously perceived. This running start of the reward system might explain the pull of rewards in individuals with compulsive reward-seeking behaviors such as hypersexuality and patients who receive dopaminergic medication.

Agnus castus extracts inhibit prolactin secretion of rat pituitary cells.

PubMed

Sliutz, G; Speiser, P; Schultz, A M; Spona, J; Zeillinger, R

1993-05-01

In our studies on prolactin inhibition by plant extracts we focused on the effects of extracts of Vitex agnus castus and its preparations on rat pituitary cells under basal and stimulated conditions in primary cell culture. Both extracts from Vitex agnus castus as well as synthetic dopamine agonists (Lisuride) significantly inhibit basal as well as TRH-stimulated prolactin secretion of rat pituitary cells in vitro and as a consequence inhibition of prolactin secretion could be blocked by adding a dopamine receptor blocker. Therefore because of its dopaminergic effect Agnus castus could be considered as an efficient alternative phytotherapeutic drug in the treatment of slight hyperprolactinaemia.

In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with\\ increased motor disability.

PubMed

Iravani, Mahmoud M; Tayarani-Binazir, Kayhan; Chu, Wing B; Jackson, Michael J; Jenner, Peter

2006-12-01

5-Hydroxytryptamine 1a (5-HT(1a)) receptor agonists, such as sarizotan and tandospirone, are reported to reduce levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques and in Parkinson's disease without worsening motor disability. However, these compounds are not specific for 5-HT(1a) receptors and also possess dopamine antagonist actions. We now report on the effects of (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-(+)-8-OHDPAT], a selective 5-HT(1a) agonist lacking dopaminergic activity, on motor disability and dyskinesia (chorea and dystonia) in levodopa-primed MPTP-treated common marmosets. Administration of (R)-(+)-8-OHDPAT (0.2, 0.6, and 2.0 mg/kg s.c), in conjunction with levodopa/carbidopa (12.5 mg/kg each p.o.) to levodopa-primed animals, dose-dependently reduced levodopa-induced chorea but did not affect dystonic movements. However, (R)-(+)-8-OHDPAT treatment also reduced locomotor activity and the reversal of motor disability. Administration of (R)-(+)-8-OHDPAT alone had no effects of motor behaviors. The effects of (R)-(+)-8-OHDPAT on levodopa-induced motor behaviors were antagonized by the 5-HT(1a) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY-100635) (1.0 mg/kg s.c.). Administration of (R)-(+)-8-OHDPAT (0.6 mg/kg s.c.) also reduced chorea produced by the administration of the D(2)/D(3) dopamine receptor agonist pramipexole (0.06 mg/kg p.o.) to levodopa-primed MPTP-treated animals. However, again the increase in locomotor activity and reversal of motor disability produced by pramipexole were also inhibited. These data suggest that selective 5-HT(1a) agonists do not provide an effective means of suppressing levodopa-induced dyskinesia, except with worsening of parkinsonism.

An intracellular loop 2 amino acid residue determines differential binding of arrestin to the dopamine D2 and D3 receptors.

PubMed

Lan, Hongxiang; Teeter, Martha M; Gurevich, Vsevolod V; Neve, Kim A

2009-01-01

Dopamine D(2) and D(3) receptors are similar subtypes with distinct interactions with arrestins; the D(3) receptor mediates less agonist-induced translocation of arrestins than the D(2) receptor. The goals of this study were to compare nonphosphorylated arrestin-binding determinants in the second intracellular domain (IC2) of the D(2) and D(3) receptors to identify residues that contribute to the differential binding of arrestin to the subtypes. Arrestin 3 bound to glutathione transferase (GST) fusion proteins of the D(2) receptor IC2 more avidly than to the D(3) receptor IC2. Mutagenesis of the fusion proteins identified a residue at the C terminus of IC2, Lys149, that was important for the preferential binding of arrestin 3 to D(2)-IC2; arrestin binding to D(2)-IC2-K149C was greatly decreased compared with wild-type D(2)-IC2, whereas binding to the reciprocal mutant D(3)-IC2-C147K was enhanced compared with wild-type D(3)-IC2. Mutating this lysine in the full-length D(2) receptor to cysteine decreased the ability of the D(2) receptor to mediate agonist-induced arrestin 3 translocation to the membrane and decreased agonist-induced receptor internalization in human embryonic kidney 293 cells. The reciprocal mutation in the D(3) receptor increased receptor-mediated translocation of arrestin 3 without affecting agonist-induced receptor internalization. G protein-coupled receptor crystal structures suggest that Lys149, at the junction of IC2 and the fourth membrane-spanning helix, has intramolecular interactions that contribute to maintaining an inactive receptor state. It is suggested that the preferential agonist-induced binding of arrestin3 to the D(2) receptor over the D(3) receptor is due in part to Lys149, which could be exposed as a result of receptor activation.

Functional Selectivity of Allosteric Interactions within G Protein–Coupled Receptor Oligomers: The Dopamine D1-D3 Receptor Heterotetramer

PubMed Central

Guitart, Xavier; Navarro, Gemma; Moreno, Estefania; Yano, Hideaki; Cai, Ning-Sheng; Sánchez-Soto, Marta; Kumar-Barodia, Sandeep; Naidu, Yamini T.; Mallol, Josefa; Cortés, Antoni; Lluís, Carme; Canela, Enric I.; Casadó, Vicent; McCormick, Peter J.

2014-01-01

The dopamine D1 receptor–D3 receptor (D1R-D3R) heteromer is being considered as a potential therapeutic target for neuropsychiatric disorders. Previous studies suggested that this heteromer could be involved in the ability of D3R agonists to potentiate locomotor activation induced by D1R agonists. It has also been postulated that its overexpression plays a role in L-dopa–induced dyskinesia and in drug addiction. However, little is known about its biochemical properties. By combining bioluminescence resonance energy transfer, bimolecular complementation techniques, and cell-signaling experiments in transfected cells, evidence was obtained for a tetrameric stoichiometry of the D1R–D3R heteromer, constituted by two interacting D1R and D3R homodimers coupled to Gs and Gi proteins, respectively. Coactivation of both receptors led to the canonical negative interaction at the level of adenylyl cyclase signaling, to a strong recruitment of β-arrestin-1, and to a positive cross talk of D1R and D3R agonists at the level of mitogen-activated protein kinase (MAPK) signaling. Furthermore, D1R or D3R antagonists counteracted β-arrestin-1 recruitment and MAPK activation induced by D3R and D1R agonists, respectively (cross-antagonism). Positive cross talk and cross-antagonism at the MAPK level were counteracted by specific synthetic peptides with amino acid sequences corresponding to D1R transmembrane (TM) domains TM5 and TM6, which also selectively modified the quaternary structure of the D1R-D3R heteromer, as demonstrated by complementation of hemiproteins of yellow fluorescence protein fused to D1R and D3R. These results demonstrate functional selectivity of allosteric modulations within the D1R-D3R heteromer, which can be involved with the reported behavioral synergism of D1R and D3R agonists. PMID:25097189

You are what you eat: influence of type and amount of food consumed on central dopamine systems and the behavioral effects of direct- and indirect-acting dopamine receptor agonists.

PubMed

Baladi, Michelle G; Daws, Lynette C; France, Charles P

2012-07-01

The important role of dopamine (DA) in mediating feeding behavior and the positive reinforcing effects of some drugs is well recognized. Less widely studied is how feeding conditions might impact the sensitivity of drugs acting on DA systems. Food restriction, for example, has often been the focus of aging and longevity studies; however, other studies have demonstrated that mild food restriction markedly increases sensitivity to direct- and indirect-acting DA receptor agonists. Moreover, it is becoming clear that not only the amount of food, but the type of food, is an important factor in modifying the effects of drugs. Given the increased consumption of high fat and sugary foods, studies are exploring how consumption of highly palatable food impacts DA neurochemistry and the effects of drugs acting on these systems. For example, eating high fat chow increases sensitivity to some behavioral effects of direct- as well as indirect-acting DA receptor agonists. A compelling mechanistic possibility is that central DA pathways that mediate the effects of some drugs are regulated by one or more of the endocrine hormones (e.g. insulin) that undergo marked changes during food restriction or after consuming high fat or sugary foods. Although traditionally recognized as an important signaling molecule in regulating energy homeostasis, insulin can also regulate DA neurochemistry. Because direct- and indirect-acting DA receptor drugs are used therapeutically and some are abused, a better understanding of how food intake impacts response to these drugs would likely facilitate improved treatment of clinical disorders and provide information that would be relevant to the causes of vulnerability to abuse drugs. This article is part of a Special Issue entitled 'Central Control of Food Intake'. Copyright © 2012 Elsevier Ltd. All rights reserved.

The serotonin 5-HT₁A receptor agonist tandospirone improves executive function in common marmosets.

PubMed

Baba, Satoko; Murai, Takeshi; Nakako, Tomokazu; Enomoto, Takeshi; Ono, Michiko; Shimizu, Isao; Ikeda, Kazuhito

2015-01-01

Previous pilot clinical studies have shown that the serotonin 5-HT1A receptor agonist tandospirone has beneficial effect on cognitive deficits associated with schizophrenia. In the present study, we evaluated the cognitive efficacy of tandospirone, given alone or in combination with the antipsychotic blonanserin, risperidone or haloperidol, on executive function in marmosets using the object retrieval with detour (ORD) task. Treatment with tandospirone alone at 20 and 40 mg/kg increased the number of correct responses in the difficult trial, while risperidone (0.3mg/kg) and haloperidol (0.3mg/kg) decreased the number of correct responses in this trial. On the other hand, blonanserin (0.1-0.3mg/kg), an atypical antipsychotic highly selective for dopamine D2/D3 and serotonin 5-HT2A receptors, did not affect the number of correct responses in both the easy and difficult trials. Co-treatment with tandospirone (20mg/kg) and risperidone (0.1-0.3mg/kg) or haloperidol (0.1-0.3mg/kg) did not improve animals' performance in the difficult trial. However, co-treatment with tandospirone and blonanserin (0.1-0.3mg/kg) increased the number of correct responses in the difficult trial. In addition, treatment with the dopamine D1 receptor agonist SKF-81297 at 1mg/kg increased marmosets correct responses in the difficult trial. These results suggest that tandospirone is a promising candidate for the treatment of cognitive deficits associated with schizophrenia and that adjunctive treatment with tandospirone and blonanserin is more appropriate for cognitive deficits than combination therapy with tandospirone and risperidone or haloperidol. The results of this study also indicate that the putative mechanism of action of tandospirone might be related to enhancement of dopamine neurotransmission via activation of the 5-HT1A receptor. Copyright © 2015 Elsevier B.V. All rights reserved.

Dopamine acting at D1-like, D2-like and α1-adrenergic receptors differentially modulates theta and gamma oscillatory activity in primary motor cortex.

PubMed

Özkan, Mazhar; Johnson, Nicholas W; Sehirli, Umit S; Woodhall, Gavin L; Stanford, Ian M

2017-01-01

The loss of dopamine (DA) in Parkinson's is accompanied by the emergence of exaggerated theta and beta frequency neuronal oscillatory activity in the primary motor cortex (M1) and basal ganglia. DA replacement therapy or deep brain stimulation reduces the power of these oscillations and this is coincident with an improvement in motor performance implying a causal relationship. Here we provide in vitro evidence for the differential modulation of theta and gamma activity in M1 by DA acting at receptors exhibiting conventional and non-conventional DA pharmacology. Recording local field potentials in deep layer V of rat M1, co-application of carbachol (CCh, 5 μM) and kainic acid (KA, 150 nM) elicited simultaneous oscillations at a frequency of 6.49 ± 0.18 Hz (theta, n = 84) and 34.97 ± 0.39 Hz (gamma, n = 84). Bath application of DA resulted in a decrease in gamma power with no change in theta power. However, application of either the D1-like receptor agonist SKF38393 or the D2-like agonist quinpirole increased the power of both theta and gamma suggesting that the DA-mediated inhibition of oscillatory power is by action at other sites other than classical DA receptors. Application of amphetamine, which promotes endogenous amine neurotransmitter release, or the adrenergic α1-selective agonist phenylephrine mimicked the action of DA and reduced gamma power, a result unaffected by prior co-application of D1 and D2 receptor antagonists SCH23390 and sulpiride. Finally, application of the α1-adrenergic receptor antagonist prazosin blocked the action of DA on gamma power suggestive of interaction between α1 and DA receptors. These results show that DA mediates complex actions acting at dopamine D1-like and D2-like receptors, α1 adrenergic receptors and possibly DA/α1 heteromultimeric receptors to differentially modulate theta and gamma activity in M1.

Randomized, controlled trial of rasagiline as an add-on to dopamine agonists in Parkinson's disease.

PubMed

Hauser, Robert A; Silver, Dee; Choudhry, Azhar; Eyal, Eli; Isaacson, Stuart

2014-07-01

Dopamine agonists (DA) are often used as first-line monotherapy for the symptomatic control of Parkinson's disease (PD). However, DA monotherapy typically becomes inadequate within a few years, at which time the DA dosage must be increased or other antiparkinsonian medications added. Adding a monoamine oxidase-B (MAO-B) inhibitor to DA monotherapy might improve symptomatic control while maintaining good safety and tolerability. We conducted an 18-week, randomized, double-blind, placebo-controlled trial of rasagiline 1 mg/d as an add-on to DA therapy (ropinirole ≥ 6 mg/d or pramipexole ≥ 1.0 mg/d) in early PD patients whose conditions were not adequately controlled on their current treatment regimen. The primary efficacy variable was the change in total Unified Parkinson Disease Rating Scale (UPDRS) score (sum of parts I, II, and III) from baseline to week 18, comparing rasagiline and placebo groups. The modified intent-to-treat (ITT) population included 321 subjects whose mean ± SD age was 62.6 ± 9.7, and duration of PD was 2.1 ± 2.1 years. Results demonstrated a significantly greater improvement in total UPDRS scores from baseline to week 18 in the rasagiline group compared with the placebo group (least squares [LS] mean difference ± SE, -2.4 ± 0.95; 95% confidence interval [CI], -4.3, -0.5; P = 0.012). Mean improvement (LS mean ± SE) was -3.6 ± 0.68 in the rasagiline group and -1.2 ± 0.68 in the placebo group. Rasagiline was well tolerated, and the most common adverse events (AEs; rasagiline vs. placebo) were dizziness (7.4% vs. 6.1%), somnolence (6.8% vs. 6.7%), and headache (6.2% vs. 4.3%). Rasagiline 1 mg/d provided statistically significant improvement when added to dopamine agonist therapy and was well tolerated. © 2014 International Parkinson and Movement Disorder Society.

A method to switch from oral dopamine agonists to rotigotine in patients with restless legs syndrome and mild augmentation.

PubMed

Winkelman, John W; Mackie, Susan E; Mei, Leslie A; Platt, Samuel; Schoerning, Laura

2016-08-01

We examined the short- and long-term efficacy and tolerability of a cross-titration algorithm from oral dopamine agonists to the rotigotine transdermal patch in patients dissatisfied with their restless legs syndrome (RLS) treatment, predominantly with mild augmentation. Patients with RLS (n = 20) were recruited at a single site. The cross-titration consisted of decreasing oral dopaminergic agents (ropinirole by 1 mg or pramipexole by 0.25 mg) and increasing rotigotine by 1 mg every two days. Efficacy and adverse events (AEs) were assessed at one, three, six and 12 months after the switch. Patients had moderate-severe RLS symptoms at the baseline (mean international restless legs syndrome (IRLS) score 19.4 ± 5.5); 85% had augmentation and 45% reported afternoon RLS symptoms. The baseline mean pramipexole equivalent dose was 0.6 ± 0.3 mg. At Week 5, 85% (17/20) had successfully switched from their oral dopamine agonist to rotigotine (mean dose 2.5 ± 0.6 mg; change in IRLS score: -6.7 ± 8.4, p = 0.002); 14 patients were CGI-I responders (much or very much improved). Three patients withdrew due to lack of efficacy. Twelve months after cross-titration, 10 patients continued on rotigotine, of whom four required either higher doses of rotigotine or supplemental RLS medication compared with their optimal Week 5 dose; five patients withdrew due to AEs and two due to lack of efficacy. A cross-titration to rotigotine was efficacious after five weeks in 70% of patients dissatisfied with RLS treatment, most of whom had mild augmentation. At one year following the medication switch, 50% had discontinued rotigotine due to lack of continued efficacy or side effects. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of dopamine D2/D3 receptor ligands on food-cocaine choice in socially housed male cynomolgus monkeys.

PubMed

Czoty, Paul W; Nader, Michael A

2013-02-01

Dopamine D2/D3 receptor partial agonists have been suggested as medications for cocaine dependence. The present experiments examined the effect of acute and repeated administration of drugs with varying intrinsic efficacy at D2/D3 receptors on the relative reinforcing strength of cocaine. Use of socially housed cynomolgus monkeys permitted the assessment of whether social status, known to alter D2/D3 receptor availability, influenced the behavioral effects of D2/D3 receptor compounds. The high-efficacy agonist R(-)-norpropylapomorphine [(-)-NPA], low-efficacy agonist aripiprazole (ARI), and antagonist eticlopride (ETIC) were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine self-administration dose-effect curve was determined daily. The effects of 5-day treatment with ARI and (-)-NPA were characterized under conditions in which monkeys did (ARI) or did not [ARI and (-)-NPA] self-administer cocaine during treatment. When administered acutely, ARI and ETIC increased the choice of low cocaine doses, and only (-)-NPA decreased the choice of higher cocaine doses and cocaine intake; effects were similar across social ranks. When administered repeatedly while self administration occurred only on days 1 and 5 of treatment, ARI, but not (-)-NPA, decreased cocaine choice in dominant monkeys, whereas (-)-NPA, but not ARI, did so in subordinates. When dominant monkeys self-administered cocaine on all five days of ARI treatment, however, these effects were not observed. The results indicate that the behavioral effects of D2/D3 receptor agonists can differ according to intrinsic efficacy and subject characteristics. Moreover, these results suggest that exposure to cocaine during treatment can counteract treatment-induced reductions in the reinforcing effects of cocaine.

Long-Term Citalopram Treatment Alters the Stress Responses of the Cortical Dopamine and Noradrenaline Systems: the Role of Cortical 5-HT1A Receptors

PubMed Central

Kaneko, Fumi; Kishikawa, Yuki; Hanada, Yuuki; Yamada, Makiko; Kakuma, Tatsuyuki; Kawahara, Hiroshi; Nishi, Akinori

2016-01-01

Background: Cortical dopamine and noradrenaline are involved in the stress response. Citalopram, a selective serotonin reuptake inhibitor, has direct and indirect effects on the serotonergic system. Furthermore, long-term treatment with citalopram affects the dopamine and noradrenaline systems, which could contribute to the therapeutic action of antidepressants. Methods: The effects of long-term treatment with citalopram on the responses of the dopamine and noradrenaline systems in the rat prefrontal cortex to acute handling stress were evaluated using in vivo microdialysis. Results: Acute handling stress increased dopamine and noradrenaline levels in the prefrontal cortex. The dopamine and noradrenaline responses were suppressed by local infusion of a 5-HT1A receptor agonist, 7-(Dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol;hydrobromide, into the prefrontal cortex. The dopamine response was abolished by long-term treatment with citalopram, and the abolished dopamine response was reversed by local infusion of a 5-HT1A receptor antagonist, (Z)-but-2-enedioic acid;N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-ylcyclohexanecarboxamide into the prefrontal cortex. On the other hand, long-term treatment with citalopram reduced the basal noradrenaline levels (approximately 40% of the controls), but not the basal dopamine levels. The noradrenaline response was maintained despite the low basal noradrenaline levels. Signaling from the 5-HT1A receptors and α2-adrenoceptors was not involved in the decrease in the basal noradrenaline levels but partially affected the noradrenaline response. Conclusions: Chronic citalopram treatment differentially suppresses the dopamine and noradrenaline systems in the prefrontal cortex, and the dopamine stress response was preferentially controlled by upregulating 5-HT1A receptor signaling. Our findings provide insight into how antidepressants modulate the dopamine and noradrenaline systems to overcome acute stress. PMID:27029212

Molecular imaging and neural networks in impulse control disorders in Parkinson's disease.

PubMed

Aracil-Bolaños, I; Strafella, A P

2016-01-01

Impulse control disorders (ICDs) may arise in Parkinson's disease (PD) in relation to the use of dopamine agonists (DA). A dysfunction of reward circuits is considered the main underlying mechanism. Neuroimaging has been largely used in this setting to understand the structure of the reward system and its abnormalities brought by exogenous stimulation in PD. Dopaminergic changes, such as increased dopamine release, reduced dopamine transporter activity and other changes, have been shown to be a consistent feature of ICDs in PD. Beyond the striatum, alterations of prefrontal cortical function may also impact an individuals' propensity for impulsivity. Neuroimaging is advancing our knowledge of the mechanisms involved in the development of these behavioral addictions. An increased understanding of these disorders may lead to the discovery of new therapeutic targets, or the identification of risk factors for the development of these disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release.

PubMed

Foster, Daniel J; Wilson, Jermaine M; Remke, Daniel H; Mahmood, M Suhaib; Uddin, M Jashim; Wess, Jürgen; Patel, Sachin; Marnett, Lawrence J; Niswender, Colleen M; Jones, Carrie K; Xiang, Zixiu; Lindsley, Craig W; Rook, Jerri M; Conn, P Jeffrey

2016-09-21

Muscarinic receptors represent a promising therapeutic target for schizophrenia, but the mechanisms underlying the antipsychotic efficacy of muscarinic modulators are not well understood. Here, we report that activation of M4 receptors on striatal spiny projection neurons results in a novel form of dopaminergic regulation resulting in a sustained depression of striatal dopamine release that is observed more than 30 min after removal of the muscarinic receptor agonist. Furthermore, both the M4-mediated sustained inhibition of dopamine release and the antipsychotic-like efficacy of M4 activators were found to require intact signaling through CB2 cannabinoid receptors. These findings highlight a novel mechanism by which striatal cholinergic and cannabinoid signaling leads to sustained reductions in dopaminergic transmission and concurrent behavioral effects predictive of antipsychotic efficacy. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhibition of the sympathetic nervous system by a series of heterocyclic congeners of dopamine.

PubMed

Sharabi, F M; Long, J P; Cannon, J G; Hatheway, G J

1976-12-01

A series of heterocyclic congeners of dopamine (GJH-series) with different positions of phenolic oxygens and with the possibility of cis and trans isomerism at the 4a-10b ring juncture was evaluated in vitro and in vivo for dopaminergic activity. Two compounds, GJH-166 and GJH-171, were found to suppress the positive chronotropic response induced by stimulation of the right cardioaccelerator nerves. These effects were antagonized by haloperidol. GJH-166, in doses as low as 9.5 x 10(-4) mugmol/kg reduced the resting heart rate in cats anesthetized with alpha-chloralose. GJH-166 and GJH-171 antagonized pressor responses induced by bilateral carotid occlusion and stimulation of the central stump of the sciatic nerve. The results outlined in this manuscript support the hypothesis that the extended conformation of the dihydroxyhenylethylamine moiety of dopamine with a trans isomeric form is favorable for dopaminergic agonist activity.

Dopamine D2 receptor-mediated G-protein activation in rat striatum: functional autoradiography and influence of unilateral 6-hydroxydopamine lesions of the substantia nigra.

PubMed

Newman-Tancredi, A; Cussac, D; Brocco, M; Rivet, J M; Chaput, C; Touzard, M; Pasteau, V; Millan, M J

2001-11-30

Unilateral 6-hydroxydopamine (6-OHDA) lesions of substantia nigra pars compacta (SNPC) neurons in rats induce behavioural hypersensitivity to dopaminergic agonists. However, the role of specific dopamine receptors is unclear, and potential alterations in their transduction mechanisms remain to be evaluated. The present study addressed these issues employing the dopaminergic agonist, quinelorane, which efficaciously stimulated G-protein activation (as assessed by [35S]GTPgammaS binding) at cloned hD2 (and hD3) receptors. At rat striatal membranes, dopamine stimulated [35S]GTPgammaS binding by 1.9-fold over basal, but its actions were only partially reversed by the selective D2/D3 receptor antagonist, raclopride, indicating the involvement of other receptor subtypes. In contrast, quinelorane-induced stimulation (48% of the effect of dopamine) was abolished by raclopride, and by the D2 receptor antagonist, L741,626. Further, novel antagonists selective for D3 and D4 receptors, S33084 and S18126, respectively, blocked the actions of quinelorane at concentrations corresponding to their affinities for D2 receptors. Quinelorane potently induced contralateral rotation in unilaterally 6-OHDA-lesioned rats, an effect abolished by raclopride and L741,626, but not by D3 and D4 receptor-selective doses of S33084 and S18126, respectively. In functional ([35S]GTPgammaS) autoradiography experiments, quinelorane stimulated G-protein activation in caudate putamen and, to a lesser extent, in nucleus accumbens and cingulate cortex of naive rats. In unilaterally SNPC-lesioned rats, quinelorane-induced G-protein activation in the caudate putamen on the non-lesioned side was similar to that seen in naive animals (approximately 50% stimulation), but significantly greater on the lesioned side (approximately 80%). This increase was both pharmacologically and regionally specific since it was reversed by raclopride, and was not observed in nucleus accumbens or cingulate cortex. In conclusion, the present data indicate that, in rat striatum, the actions of quinelorane are mediated primarily by D2 receptors, and suggest that behavioural hypersensitivity to this agonist, induced by unilateral SNPC lesions, is associated with an increase in D2, but not D3 or D4, receptor-mediated G-protein activation.

Eating high fat chow increases the sensitivity of rats to 8-OH-DPAT-induced lower lip retraction.

PubMed

Li, Jun-Xu; Ju, Shutian; Baladi, Michelle G; Koek, Wouter; France, Charles P

2011-12-01

Eating high fat food can alter sensitivity to drugs acting on dopamine systems; this study examined whether eating high fat food alters sensitivity to a drug acting on serotonin (5-HT) systems. Sensitivity to (+)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide (8-OH-DPAT; 5-HT1A receptor agonist)-induced lower lip retraction was examined in separate groups (n=8-9) of rats with free access to standard (5.7% fat) or high fat (34.3% fat) chow; sensitivity to quinpirole (dopamine D3/D2 receptor agonist)-induced yawning was also examined. Rats eating high fat chow gained more body weight than rats eating standard chow and, after 6 weeks of eating high fat chow, they were more sensitive to 8-OH-DPAT (0.01-0.1 mg/kg)-induced lower lip retraction and quinpirole (0.0032-0.32 mg/kg)-induced yawning. These changes were not reversed when rats that previously ate high fat chow were switched to eating standard chow and sensitivity to 8-OH-DPAT and quinpirole increased when rats that previously ate standard chow ate high fat chow. These data extend previous results showing changes in sensitivity to drugs acting on dopamine systems in animals eating high fat chow to a drug acting at 5-HT1A receptors and they provide support for the notion that eating certain foods impacts sensitivity to drugs acting on monoamine systems.

Eating high fat chow increases the sensitivity of rats to 8-OH-DPAT-induced lower lip retraction

PubMed Central

Li, Jun-Xu; Ju, Shutian; Baladi, Michelle G; Koek, Wouter; France, Charles P

2011-01-01

Eating high fat food can alter sensitivity to drugs acting on dopamine systems; this study examined whether eating high fat food alters sensitivity to a drug acting on serotonin (5-HT) systems. Sensitivity to (+)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide (8-OH-DPAT; 5-HT1A receptor agonist)-induced lower lip retraction was examined in separate groups (n=8-9) of rats with free access to standard (5.7% fat) or high fat (34.3% fat) chow; sensitivity to quinpirole (dopamine D3/D2 receptor agonist)-induced yawning was also examined. Rats eating high fat chow gained more body weight than rats eating standard chow and, after 6 weeks of eating high fat chow, they were more sensitive to 8-OH-DPAT (0.01-0.1 mg/kg)-induced lower lip retraction and quinpirole (0.0032-0.32 mg/kg)-induced yawning. These changes were not reversed when rats that previously ate high fat chow were switched to eating standard chow and sensitivity to 8-OH-DPAT and quinpirole increased when rats that previously ate standard chow ate high fat chow. These data extend previous results showing changes in sensitivity to drugs acting on dopamine systems in animals eating high fat chow to a drug acting at 5-HT1A receptors and they provide support for the notion that eating certain foods impacts sensitivity to drugs acting on monoamine systems. PMID:21979831

Determinants of cocaine self-administration by laboratory animals.

PubMed

Woolverton, W L

1992-01-01

The reinforcing effect of a drug is that effect that increases the probability that the drug will be self-administered again. Like other drug effects, a reinforcing effect is the result of an interaction between organism, drug and environment. Laboratory research using animal subjects has helped elucidate the contribution of each of these factors to the self-administration of cocaine. A substantial amount of research indicates that increased dopamine neurotransmission in the brain, particularly in mesolimbic and mesocortical regions, plays a major role in cocaine self-administration. Both indirect and direct dopamine agonists can function as positive reinforcers in animals, whereas noradrenergic and serotonergic (5-HT, 5-hydroxytryptamine) agonists have not been found to do so. In addition, evidence suggests that dopamine but not noradrenaline (norepinephrine) or serotonin antagonists can attenuate the reinforcing effect of cocaine. Environmental factors have also been shown to be critical determinants of the reinforcing effect of cocaine. The schedule of reinforcement essentially determines the rate and pattern of drug-maintained behaviour. In addition, punishing self-administration, increasing the value of alternative reinforcers that are available, and increasing the cost of cocaine have all been shown to decrease the reinforcing effect of cocaine. With regard to organismic factors, recent research has suggested that there are significant genetic determinants of cocaine consumption. Taken together these research findings in animals imply that certain individuals may be more sensitive to the reinforcing effect of cocaine but that cocaine abuse can be decreased by pharmacological or behavioural means or by a combination of the two.

The role of multiple dopamine receptors in apomorphine and N-n-propylnorapomorphine-induced climbing and hypothermia.

PubMed

Moore, N A; Axton, M S

1990-03-20

Apomorphine and N-n-propylnorapomorphine (NPA) were compared for their ability to induce stereotyped cage climbing and hypothermia in mice. Climbing behavior was produced by similar doses of apomorphine and NPA (0.625-2.5 mg/kg s.c.), whereas NPA was 43 times more potent than apomorphine in inducing a hypothermic response. SKF38393 caused a shift to the left in the dose-response curve for NPA-induced climbing, the ED50 changing from 0.98 to 0.014 mg/kg. SKF38393 had no effect on apomorphine-induced climbing behaviour. The climbing response produced by apomorphine was antagonised by both D-1 and D-2 antagonists. Climbing behaviour induced by NPA (2.5 mg/kg) could be antagonised by SCH23390 but not by clebopride, however climbing behaviour induced by a low dose of NPA (0.06 mg/kg) plus SKF38393 could be blocked by both D-1 and D-2 receptor antagonists. The hypothermic responses produced by either apomorphine or NPA could only be reversed by the selective D-2 antagonist, clebopride. These results demonstrate that dopamine agonist-induced stereotyped cage climbing requires both D-1 and D-2 receptor stimulation, whereas the hypothermic response is D-2-mediated. The results also show that it is possible to assess the relative activity of a dopamine agonist at D-1 or D-2 receptors in vivo by comparing the ability of the compound to induce hypothermia and climbing behaviour.

Rotigotine transdermal patch for the treatment of Parkinson's Disease.

PubMed

Perez-Lloret, Santiago; Rey, María Verónica; Ratti, Pietro Lucca; Rascol, Olivier

2013-02-01

Rotigotine, a non-ergot dopamine agonist, has been developed as a novel transdermal formulation. The rotigotine transdermal patch has received EMEA marketing authorization for the treatment of adult patients with early or advanced Parkinson's disease (PD) or with moderate to severe restless legs syndrome (RLS). FDA originally granted a marketing authorization for early PD, which was later suspended, and is now studying the authorization for RLS. The aim of this review is to review the pharmacokinetics, pharmacodynamics as well as the clinical efficacy and tolerability of the rotigotine transdermal patch in PD. Source material was identified using a PubMed search for the term 'rotigotine' and PD. Articles published up to January 2011 or abstract submitted to most relevant international neurology congresses were reviewed. The rotigotine transdermal patch is efficacious for the treatment of PD. Tolerability profile appears to be well within the range of that observed with other non-ergot dopamine agonists in PD. Application-site reactions were the most frequent adverse event, and they were considered mild to moderate in the majority of cases. The rotigotine transdermal patch offers a safe and efficacious alternative for the treatment of PD. Further studies should focus on the possibility that continuous dopamine stimulation by means of the transdermal patch has any influence on levodopa-related motor complications. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.

Pilot clinical observations between food and drug seeking derived from fifty cases attending an eating disorder clinic.

PubMed

Beitscher-Campbell, Harriet; Blum, Kenneth; Febo, Marcelo; Madigan, Margaret A; Giordano, John; Badgaiyan, Rajendra D; Braverman, Eric R; Dushaj, Kristina; Li, Mona; Gold, Mark S

2016-09-01

Background The reward deficiency syndrome hypothesis posits that genes are responsible for reward dependence and related behaviors. There is evidence that both bulimia and anorexia nervosa, especially in women, have been linked to a lifetime history of substance use disorder (SUD). There are difficulties in accepting food as an addiction similar to drugs; however, increasingly neuroimaging studies favor such an assertion. Case presentations We are reporting the evidence of comorbidity of eating disorders with SUD found within these case presentations. We show 50 case reports derived from two independent treatment centers in Florida that suggest the commonality between food and drug addictions. In an attempt to provide data from this cohort, many participants did not adequately respond to our questionnaire. Discussion We propose that dopamine agonist therapy may be of common benefit. Failure in the past may reside in too powerful D2 agonist activity leading to D2 receptor downregulation, while the new methodology may cause a reduction of "dopamine resistance" by inducing "dopamine homeostasis." While this is not a definitive study, it does provide some additional clinical evidence that these two addictions are not mutually exclusive. Conclusion Certainly, it is our position that there is an overlap between food- and drug-seeking behavior. We propose that the studies focused on an effort to produce natural activation of dopaminergic reward circuitry as a type of common therapy may certainly be reasonable. Additional research is warranted.

Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature

PubMed Central

Lute, Beth; Jou, William; Lateef, Dalya M.; Goldgof, Margalit; Xiao, Cuiying; Piñol, Ramón A.; Kravitz, Alexxai V.; Miller, Nicole R.; Huang, Yuning George; Girardet, Clemence; Butler, Andrew A.; Gavrilova, Oksana; Reitman, Marc L.

2014-01-01

Summary The melanocortin system regulates metabolic homeostasis and inflammation. Melanocortin agonists have contradictorily been reported to both increase and decrease metabolic rate and body temperature. We find two distinct physiologic responses occurring at similar doses. Intraperitoneal administration of the nonselective melanocortin agonist MTII causes a melanocortin-4 receptor (Mc4r) mediated hypermetabolism/hyperthermia. This is preceded by a profound, transient hypometabolism/hypothermia that is preserved in mice lacking any one of Mc1r, Mc3r, Mc4r, or Mc5r. Three other melanocortin agonists also caused hypothermia, which is actively achieved via seeking a cool environment, vasodilation, and inhibition of brown adipose tissue thermogenesis. These results suggest that the hypometabolic/hypothermic effect of MTII is not due to a failure of thermoregulation. The hypometabolism/hypothermia was prevented by dopamine antagonists and MTII selectively activated arcuate nucleus dopaminergic neurons; these neurons may contribute to the hypometabolism/hypothermia. We propose that the hypometabolism/hypothermia is a regulated response, potentially beneficial during extreme physiologic stress. PMID:24981835

Octopamine partially restores walking in hypokinetic cockroaches stung by the parasitoid wasp Ampulex compressa.

PubMed

Rosenberg, Lior Ann; Glusman, Jose Gustavo; Libersat, Frederic

2007-12-01

When stung by the parasitoid wasp Ampulex compressa, cockroaches Periplaneta americana enter a hypokinetic state that is characterized by little, if any, spontaneous locomotor activity. In the present study we investigate the effect of an octopamine receptor agonist and an antagonist on the locomotor behavior of stung and control cockroaches. We show that in cockroaches stung by a wasp the octopamine receptor agonist chlordimeform induces a significant increase in spontaneous walking. In good agreement, in control individuals an octopamine receptor antagonist significantly reduces walking activity. Adipokinetic hormone I (AKH-I) promotes spontaneous walking in controls but does not do so in stung individuals, which suggests that the venom effect is most probably not mediated by AKH-I. Dopamine receptor agonists or antagonists had no significant effect on the spontaneous walking of stung or control cockroaches, respectively. The effect of the octopamine receptor agonist was maximal when injected into the brain, suggesting that the wasp venom interferes with octopaminergic modulation of walking initiation in central structures of the cockroach brain.

Carbachol induces burst firing of dopamine cells in the ventral tegmental area by promoting calcium entry through L-type channels in the rat

PubMed Central

Zhang, Lei; Liu, Yudan; Chen, Xihua

2005-01-01

Enhanced activity of the central dopamine system has been implicated in many psychiatric disorders including schizophrenia and addiction. Besides terminal mechanisms that boost dopamine levels at the synapse, the cell body of dopamine cells enhances terminal dopamine concentration through encoding action potentials in bursts. This paper presents evidence that burst firing of dopamine cells in the ventral tegmental area was under cholinergic control using nystatin-perforated patch clamp recording from slice preparations. The non-selective cholinergic agonist carbachol excited the majority of recorded neurones, an action that was not affected by blocking glutamate and GABA ionotropic receptors. Twenty per cent of dopamine cells responded to carbachol with robust bursting, an effect mediated by both muscarinic and nicotinic cholinoceptors postsynaptically. Burst firing induced as such was completely dependent on calcium entry as it could be blocked by cadmium and more specifically the L-type blocker nifedipine. In the presence of the sodium channel blocker tetrodotoxin, carbachol induced membrane potential oscillation that had similar kinetics and frequency as burst firing cycles and could also be blocked by cadmium and nifedipine. Direct activation of the L-type channel with Bay K8644 induced strong bursting which could be blocked by nifedipine but not by depleting internal calcium stores. These results indicate that carbachol increases calcium entry into the postsynaptic cell through L-type channels to generate calcium-dependent membrane potential oscillation and burst firing. This could establish the L-type channel as a target for modulating the function of the central dopamine system in disease conditions. PMID:16081481

The effects of administration of monoamine oxidase-B inhibitors on rat striatal neurone responses to dopamine.

PubMed Central

Berry, M D; Scarr, E; Zhu, M Y; Paterson, I A; Juorio, A V

1994-01-01

1. (-)-Deprenyl has been shown to potentiate rat striatal neurone responses to dopamine agonists at doses not altering dopamine metabolism. Since there are a number of effects of (-)-deprenyl which could result in this phenomenon, we have investigated the effects of MDL 72,145 and Ro 19-6327, whose only common effect with (-)-deprenyl is an inhibition of monoamine oxidase-B (MAO-B), on rat striatal neurone responses to dopamine and on striatal dopamine metabolism. 2. Using in vivo electrophysiology, i.p. injection of either MDL 72,145 or Ro 19-6327 was found to produce a dose-dependent potentiation of striatal neurone responses to dopamine but not gamma-aminobutyric acid. 3. Neurochemical investigations revealed that this occurred at doses (0.25-1 mg kg-1) which, while not affecting levels of dopamine or its metabolites, 3,4-dihydroxyphenylacetic acid or homovanillic acid, did cause a significant, dose-dependent, elevation in striatal levels of the putative neuromodulator, 2-phenylethylamine (PE). 4. Inhibition of PE synthesis by i.p. injection of the aromatic L-amino acid decarboxylase inhibitor, NSD 1015, produced a reversal of the effects of MDL 72,145 and Ro 19-6327. 5. Neurochemical analysis revealed this to occur at a dose of NSD 1015 (10 mg kg-1) selective for reduction of elevated PE levels. 6. These results suggest that PE can act as a neuromodulator of dopaminergic responses and that MAO-B inhibitors may potentiate neuronal responses to dopamine via the indirect mechanism of elevation of PE following MAO-B inhibition. PMID:7889269

Dopamine treatment does not need speed recovery of newborns from transient tachypnea.

PubMed

Guzoglu, Nilufer; Uras, Nurdan; Aksoy, Hatice T; Eras, Zeynep; Oguz, Serife S; Dilmen, Ugur

2016-05-01

Transient tachypnea of the newborn (TTN) results from inadequate neonatal lung fluid clearance. Low-dose dopamine induces natriuresis in the kidneys and it has been assumed that, at this low dosage, dopamine increases renal perfusion in critically ill patients. Medium doses have positive inotropic and chronotropic effects via increased β-receptor activation. Recent studies have demonstrated that dopamine stimulates the clearance of pulmonary edema. Furthermore, β-adrenergic agonists regulate Na+ channels and Na-K-ATPase activity in the pulmonary epithelium. This study investigated the effect of dopamine at different dosages on TTN treatment. A prospective controlled study examined 60 infants with TTN older than 34 weeks of gestation who required at least 24 h of O2 and nasal continuous positive airway pressure (nCPAP) treatment. The infants were randomized into three groups of 20: controls, infants treated with low-dose dopamine (3 μg/kg/min), and infants treated with a medium dose (5 μg/kg/min). The control and study groups were compared in terms of the requirement for mechanical ventilation, and the durations of nCPAP, oxygen requirement, and hospitalization. The requirement for mechanical ventilation, and durations of nCPAP, oxygen requirement, and hospitalization did not differ significantly among the three groups (P=0.54, 0.16 and 0.11, respectively). Dopamine treatment in low-moderate doses does not improve the outcome in TTN. Thus, further studies in this area are needed.

Nucleus accumbens opioid, GABaergic, and dopaminergic modulation of palatable food motivation: contrasting effects revealed by a progressive ratio study in the rat.

PubMed

Zhang, Min; Balmadrid, Christian; Kelley, Ann E

2003-04-01

The current studies were designed to evaluate whether incentive motivation for palatable food is altered after manipulations of opioid, GABAergic, and dopaminergic transmission within the nucleus accumbens. A progressive ratio schedule was used to measure lever-pressing for sugar pellets after microinfusion of drugs into the nucleus accumbens in non-food-deprived rats. The mu opioid agonist D-Ala2, NMe-Phe4, Glyo15-enkephalin and the indirect dopamine agonist amphetamine induced a marked increase in break point and correct lever-presses; the GABA(A) agonist muscimol did not affect breakpoint or lever-presses. The data suggest that opioid, dopaminergic, and GABAergic systems within the accumbens differentially modulate food-seeking behavior through mechanisms related to hedonic evaluation of food, incentive salience, and control of motor feeding circuits, respectively.

Metabotropic glutamate receptor modulation of dopamine release in the nucleus accumbens shell is unaffected by phencyclidine pretreatment: In vitro assessment using fast-scan cyclic voltammetry rat brain slices.

PubMed

Gupta, Ishan; Young, Andrew M J

2018-05-15

The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release. We showed that the orthosteric mGluR2 agonist LY379268 (0.1 µM, 1 µM and 10 µM) and mGluR5 positive allosteric modulator CDPPB (1 µM and 10 µM) both attenuated potassium-evoked dopamine release, underscoring their role in modulating dopamine neurotransmission in the nucleus accumbens. Sub-chronic PCP treatment, which caused cognitive deficits measured by performance in the novel object recognition task, modelling aspects of behavioral deficits seen in schizophrenia, induced neurobiological changes that enhanced dopamine release in the nucleus accumbens, but had no effect on mGluR2 or mGluR5 mediated changes in dopamine release. Therefore it is unlikely that schizophrenia-related behavioural changes seen after sub-chronic phencyclidine pre-treatment are mediated through mGluR modulation of dopamine release. Copyright © 2018 Elsevier B.V. All rights reserved.

The D1 family dopamine receptor, DopR, potentiates hind leg grooming behavior in Drosophila

PubMed Central

Pitmon, E.; Stephens, G.; Parkhurst, S. J.; Wolf, F. W.; Kehne, G.; Taylor, M.

2016-01-01

Drosophila groom away debris and pathogens from the body using their legs in a stereotyped sequence of innate motor behaviors. Here, we investigated one aspect of the grooming repertoire by characterizing the D1 family dopamine receptor, DopR. Removal of DopR results in decreased hind leg grooming, as substantiated by quantitation of dye remaining on mutant and RNAi animals vs. controls and direct scoring of behavioral events. These data are also supported by pharmacological results that D1 receptor agonists fail to potentiate grooming behaviors in headless DopR flies. DopR protein is broadly expressed in the neuropil of the thoracic ganglion and overlaps with TH‐positive dopaminergic neurons. Broad neuronal expression of dopamine receptor in mutant animals restored normal grooming behaviors. These data provide evidence for the role of DopR in potentiating hind leg grooming behaviors in the thoracic ganglion of adult Drosophila. This is a remarkable juxtaposition to the considerable role of D1 family dopamine receptors in rodent grooming, and future investigations of evolutionary relationships of circuitry may be warranted. PMID:26749475

PCBs Alter Dopamine Mediated Function in Aging Workers

DTIC Science & Technology

2010-01-01

sympathomimetic agents, beta-adrenergic blocking agents, angiotensin-converting enzyme inhibitors, COX-2 inhibitors, other non - steroidal anti - inflammatory ...other non - steroidal anti - inflammatory agents, opiate agonists, miscellaneous analgesics and antipyretics, thyroid agents and antithyroid agents. ⁎ p...fold from peak values during occupational PCB use but remain elevated (two-fold) compared to a similar-aged non -occupationally exposed population

Pramipexole and compulsive masturbation.

PubMed

Sansone, Randy A; Ferlan, Mark

2007-09-01

Exploration of a possible relationship between pramipexole and compulsive masturbation. We present a case report. Given the temporal overlap between pramipexole prescription and its discontinuation, and the onset and cessation of the patient's hypersexual behavior, there appears to be a strong likelihood of association. Like other dopamine agonists, pramipexole may precipitate compulsive behaviors, including hypersexual behavior in the form of compulsive masturbation.

Neurogentics of Dopaminergic Receptor Super-sensitivity in Activation of Brain Reward Circuitry and Relapse: Proposing “Deprivation-Amplification Relapse Therapy” (DART)

PubMed Central

Downs, B. William; Bowirrat, Abdalla; Waite, Roger L.; Braverman, Eric R.; Madigan, Margaret; Oscar-Berman, Marlene; DiNubile, Nicholas; Gold, Mark

2013-01-01

Background and Hypothesis It is well known that after prolonged abstinence, individuals who imbibe or use their drug of choice experience a powerful euphoria that precipitates serious relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed “super sensitivity” might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared to DRD2 A2 allele carriers. Based upon the fact that carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine agonist bromocriptine. Moreover, under chronic or long-term therapy, the potential proliferation of D2 receptors with bromocriptine has been shown in vitro. This seems to lead to a positive outcome and significantly better treatment compliance only in A1 carriers. Proposal and Conclusion We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: “denervation supersensitivity.” Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing the amino-acid neurotransmitter precursors, enkephalinase and catechol-O-methyl-transferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in Reward Deficiency Syndrome (RDS) probands. Future warranted translational research with positive outcome showing prevented or lower relapse in RDS will ultimately support the proposed concept, which we term “Deprivation-Amplification Relapse Therapy (DART).” PMID:19940429

The endocannabinoid 2-arachidonoylglycerol mediates D1 and D2 receptor cooperative enhancement of rat nucleus accumbens core neuron firing.

PubMed

Seif, T; Makriyannis, A; Kunos, G; Bonci, A; Hopf, F W

2011-10-13

Many motivated and addiction-related behaviors are sustained by activity of both dopamine D1- and D2-type receptors (D1Rs and D2Rs) as well as CB1 receptors (CB1Rs) in the nucleus accumbens (NAc). Here, we use in vitro whole-cell patch-clamp electrophysiology to describe an endocannabinoid (eCB)-dopamine receptor interaction in adult rat NAc core neurons. D1R and D2R agonists in combination enhanced firing, with no effect of a D1R or D2R agonist alone. This D1R+D2R-mediated firing increase required CB1Rs, since it was prevented by the CB1R antagonists AM251 and Rimonabant. The D1R+D2R firing increase also required phospholipase C (PLC), the major synthesis pathway for the eCB 2-arachidonoylglycerol (2-AG) and one of several pathways for anandamide. Further, inhibition of 2-AG hydrolysis with the monoglyceride lipase (MGL) inhibitor JZL184 allowed subthreshold levels of D1R+D2R receptor agonists to enhance firing, while inhibition of anandamide hydrolysis with the fatty acid amide hydrolase (FAAH) inhibitors URB597 or AM3506 did not. Filling the postsynaptic neuron with 2-AG enabled subthreshold D1R+D2R agonists to increase firing, and the 2AG+D1R+D2R increase in firing was prevented by a CB1R antagonist. Also, the metabotropic glutamate receptor 5 (mGluR5) blocker MPEP prevented the ability of JZL184 to promote subthreshold D1R+D2R enhancement of firing, while the 2-AG+D1R+D2R increase in firing was not prevented by the mGluR5 blocker, suggesting that mGluR5s acted upstream of 2-AG production. Thus, our results taken together are consistent with the hypothesis that NAc core eCBs mediate dopamine receptor (DAR) enhancement of firing, perhaps providing a cellular mechanism underlying the central role of NAc core D1Rs, D2Rs, CB1Rs, and mGluR5s during many drug-seeking behaviors. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

THE ENDOCANNABINOID 2-ARACHIDONOYLGLYCEROL MEDIATES D1 AND D2 RECEPTOR COOPERATIVE ENHANCEMENT OF RAT NUCLEUS ACCUMBENS CORE NEURON FIRING

PubMed Central

Seif, T.; Makriyannis, A.; Kunos, G.; Bonci, A.; Hopf, F. W.

2011-01-01

Many motivated and addiction-related behaviors are sustained by activity of both dopamine D1- and D2-type receptors (D1Rs and D2Rs) as well as CB1 receptors (CB1Rs) in the nucleus accumbens (NAc). Here, we use in vitro whole-cell patch-clamp electrophysiology to describe an endocannabinoid (eCB)–dopamine receptor interaction in adult rat NAc core neurons. D1R and D2R agonists in combination enhanced firing, with no effect of a D1R or D2R agonist alone. This D1R+D2R-mediated firing increase required CB1Rs, since it was prevented by the CB1R antagonists AM251 and Rimonabant. The D1R+D2R firing increase also required phospholipase C (PLC), the major synthesis pathway for the eCB 2-arachidonoylglycerol (2-AG) and one of several pathways for anandamide. Further, inhibition of 2-AG hydrolysis with the monoglyceride lipase (MGL) inhibitor JZL184 allowed subthreshold levels of D1R+D2R receptor agonists to enhance firing, while inhibition of anandamide hydrolysis with the fatty acid amide hydrolase (FAAH) inhibitors URB597 or AM3506 did not. Filling the postsynaptic neuron with 2-AG enabled subthreshold D1R+D2R agonists to increase firing, and the 2AG+D1R+D2R increase in firing was prevented by a CB1R antagonist. Also, the metabotropic glutamate receptor 5 (mGluR5) blocker MPEP prevented the ability of JZL184 to promote subthreshold D1R+D2R enhancement of firing, while the 2-AG+D1R+D2R increase in firing was not prevented by the mGluR5 blocker, suggesting that mGluR5s acted upstream of 2-AG production. Thus, our results taken together are consistent with the hypothesis that NAc core eCBs mediate dopamine receptor (DAR) enhancement of firing, perhaps providing a cellular mechanism underlying the central role of NAc core D1Rs, D2Rs, CB1Rs, and mGluR5s during many drug-seeking behaviors. PMID:21821098

Dopaminergic modulation of locomotor network activity in the neonatal mouse spinal cord

PubMed Central

Sharples, Simon A.; Humphreys, Jennifer M.; Jensen, A. Marley; Dhoopar, Sunny; Delaloye, Nicole; Clemens, Stefan

2015-01-01

Dopamine is now well established as a modulator of locomotor rhythms in a variety of developing and adult vertebrates. However, in mice, while all five dopamine receptor subtypes are present in the spinal cord, it is unclear which receptor subtypes modulate the rhythm. Dopamine receptors can be grouped into two families—the D1/5 receptor group and the D2/3/4 group, which have excitatory and inhibitory effects, respectively. Our data suggest that dopamine exerts contrasting dose-dependent modulatory effects via the two receptor families. Our data show that administration of dopamine at concentrations >35 μM slowed and increased the regularity of a locomotor rhythm evoked by bath application of 5-hydroxytryptamine (5-HT) and N-methyl-d(l)-aspartic acid (NMA). This effect was independent of the baseline frequency of the rhythm that was manipulated by altering the NMA concentration. We next examined the contribution of the D1- and D2-like receptor families on the rhythm. Our data suggest that the D1-like receptor contributes to enhancement of the stability of the rhythm. Overall, the D2-like family had a pronounced slowing effect on the rhythm; however, quinpirole, the D2-like agonist, also enhanced rhythm stability. These data indicate a receptor-dependent delegation of the modulatory effects of dopamine on the spinal locomotor pattern generator. PMID:25652925

Contrasting contribution of 5-hydroxytryptamine 1A receptor activation to neurochemical profile of novel antipsychotics: frontocortical dopamine and hippocampal serotonin release in rat brain.

PubMed

Assié, Marie-Bernadette; Ravailhe, Véronique; Faucillon, Valérie; Newman-Tancredi, Adrian

2005-10-01

Several novel antipsychotics, such as aripiprazole, bifeprunox, SSR181507 [(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine], and SLV313 [1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine], activate serotonin 5-hydroxytryptamine (5-HT)1A receptors. Such activity is associated with enhanced treatment of negative symptoms and cognitive deficits, which may be mediated by modulation of cerebral dopamine and serotonin levels. We employed microdialysis coupled to high pressure liquid chromatography with electrochemical detection to examine 5-HT1A receptor activation in the modulation of extracellular dopamine in medial prefrontal cortex and serotonin in hippocampus of freely moving rats. The above compounds were compared with drugs that have less interaction with 5-HT1A receptors (clozapine, nemonapride, ziprasidone, olanzapine, risperidone, and haloperidol). Hippocampal 5-HT was decreased by bifeprunox, SSR181507, SLV313, sarizotan, and nemonapride, effects similar to those seen with the 5-HT1A agonist, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)8-OH-DPAT], consistent with activation of 5-HT1A autoreceptors. These decreases were reversed by the selective 5-HT1A antagonist, WAY100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide]. In contrast, haloperidol, risperidone, clozapine, olanzapine, ziprasidone, and aripiprazole did not significantly modify hippocampal serotonin levels. In medial prefrontal cortex, dopamine levels were increased by SSR181507, SLV313, sarizotan, and (+)8-OH-DPAT. These effects were reversed by WAY100635, indicating mediation by 5-HT1A receptors. In contrast, the increases in dopamine levels induced by clozapine, risperidone, olanzapine, and ziprasidone were not blocked by WAY100635, consistent with predominant influence of other mechanisms in the actions of these drugs. Haloperidol, nemonapride, and the D2 partial agonists, aripiprazole and bifeprunox, did not significantly alter dopamine release. Taken together, these data demonstrate the diverse contribution of 5-HT1A receptor activation to the profile of antipsychotics and suggest that novel drugs selectively targeting D2 and 5-HT1A receptors may present distinctive therapeutic properties.

A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses α-syn- and MPTP-induced toxicities in vivo.

PubMed

Das, Banibrata; Rajagopalan, Subramanian; Joshi, Gnanada S; Xu, Liping; Luo, Dan; Andersen, Julie K; Todi, Sokol V; Dutta, Aloke K

2017-09-01

Here, we report the characterization of a novel hybrid D 2 /D 3 agonist and iron (II) specific chelator, D-607, as a multi-target-directed ligand against Parkinson's disease (PD). In our previously published report, we showed that D-607 is a potent agonist of dopamine (DA) D 2 /D 3 receptors, exhibits efficacy in a reserpinized PD animal model and preferentially chelates to iron (II). As further evidence of its potential as a neuroprotective agent in PD, the present study reveals D-607 to be protective in neuronal PC12 cells against 6-OHDA toxicity. In an in vivo Drosophila melanogaster model expressing a disease-causing variant of α-synuclein (α-Syn) protein in fly eyes, the compound was found to significantly suppress toxicity compared to controls, concomitant with reduced levels of aggregated α-Syn. Furthermore, D-607 was able to rescue DAergic neurons from MPTP toxicity in mice, a well-known PD neurotoxicity model, following both sub-chronic and chronic MPTP administration. Mechanistic studies indicated that possible protection of mitochondria, up-regulation of hypoxia-inducible factor, reduction in formation of α-Syn aggregates and antioxidant activity may underlie the observed neuroprotection effects. These observations strongly suggest that D-607 has potential as a promising multifunctional lead molecule for viable symptomatic and disease-modifying therapy for PD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors

PubMed Central

Karkhanis, Anushree N.; Huggins, Kimberly N.; Rose, Jamie H.; Jones, Sara R.

2016-01-01

Acute ethanol exposure is known to stimulate the dopamine system; however, chronic exposure has been shown to downregulate the dopamine system. In rodents, chronic intermittent exposure (CIE) to ethanol also increases negative affect during withdrawal, such as, increases in anxiety- and depressive-like behavior. Moreover, CIE exposure results in increased ethanol drinking and preference during withdrawal. Previous literature documents reductions in CIE-induced anxiety-, depressive-like behaviors and ethanol intake in response to kappa opioid receptor (KOR) blockade. KORs are located on presynaptic dopamine terminals in the nucleus accumbens (NAc) and inhibit release, an effect which has been linked to negative affective behaviors. Previous reports show an upregulation in KOR function following extended CIE exposure; however it is not clear whether there is a direct link between KOR upregulation and dopamine downregulation during withdrawal from CIE. This study aimed to examine the effects of KOR modulation on dopamine responses to ethanol of behaving mice exposed to air or ethanol vapor in a repeated intermittent pattern. First, we showed that KORs have a greater response to an agonist after moderate CIE compared to air exposed mice using ex vivo fast scan cyclic voltammetry. Second, using in vivo microdialysis, we showed that, in contrast to the expected increase in extracellular levels of dopamine following an acute ethanol challenge in air exposed mice, CIE exposed mice exhibited a robust decrease in dopamine levels. Third, we showed that blockade of KORs reversed the aberrant inhibitory dopamine response to ethanol in CIE exposed mice while not affecting the air exposed mice demonstrating that inhibition of KORs “rescued” dopamine responses in CIE exposed mice. Taken together, these findings indicate that augmentation of dynorphin/KOR system activity drives the reduction in stimulated (electrical and ethanol) dopamine release in the NAc. Thus, blockade of KORs is a promising avenue for developing pharmacotherapies for alcoholism. PMID:27450094

Differential agonist and inverse agonist profile of antipsychotics at D2L receptors coupled to GIRK potassium channels.

PubMed

Heusler, Peter; Newman-Tancredi, Adrian; Castro-Fernandez, Annabelle; Cussac, Didier

2007-03-01

The D(2) dopaminergic receptor represents a major target of antipsychotic drugs. Using the coupling of the human D(2long) (hD(2L)) receptor to G protein-coupled inward rectifier potassium (GIRK) channels in Xenopus laevis oocytes, we examined the activity of antipsychotic agents of different classes - typical, atypical, and a "new generation" of compounds, exhibiting a preferential D(2) and 5-HT(1A) receptor profile. When the hD(2L) receptor was coexpressed with GIRK channels, a series of reference compounds exhibited full agonist (dopamine, and quinpirole), partial agonist (apomorphine, (-)3-PPP, and (+)-UH232) or inverse agonist (raclopride, and L741626) properties. Sarizotan exhibited only very weak partial agonist action. At higher levels of receptor cRNA injected per oocyte, both partial agonist activity and inverse agonist properties were generally more pronounced. The inverse agonist action of L741626 was reversed by interaction with sarizotan, thus confirming the constitutive activity of wild-type hD(2L) receptors in the oocyte expression system. When antipsychotic agents were tested for their actions at the hD(2L) receptor, typical (haloperidol) as well as atypical (nemonapride, ziprasidone, and clozapine) compounds acted as inverse agonists. In contrast, among D(2)/5-HT(1A) antipsychotics, only SLV313 and F15063 behaved as inverse agonists, whilst the other members of this group (bifeprunox, SSR181507 and the recently marketed antipsychotic, aripiprazole) exhibited partial agonist properties. Thus, the X. laevis oocyte expression system highlights markedly different activity of antipsychotics at the hD(2L) receptor. These differential properties may translate to distinct therapeutic potential of these compounds.

Medical management of levodopa-associated motor complications in patients with Parkinson's disease.

PubMed

Jankovic, Joseph; Stacy, Mark

2007-01-01

Parkinson's disease is a neurodegenerative disorder that affects approximately 1% of people over the age of 60 years. Levodopa is standard, and often initial, therapy for patients with this condition; however, with continued treatment and as the disease progresses, up to 80% of patients experience 'wearing-off' symptoms, dyskinesias and other motor complications. These levodopa-associated problems may become disabling and profoundly affect quality of life. Medications commonly used to manage these symptoms include monoamine oxidase type B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, the NMDA receptor antagonist amantadine and dopamine receptor agonists. Agents that block MAO-B, such as rasagiline and selegiline, are used as both initial and adjunctive therapy in patients with Parkinson's disease. These medications increase concentrations of dopamine in the brain by blocking its reuptake from the synaptic cleft, a mechanism that can slow motor decline, increase 'on' time and improve symptoms of Parkinson's disease. Adverse events with these agents can include confusion, hallucination and orthostatic hypotension. MAO-B inhibition may elicit drug-drug interactions if administered with TCAs, SSRIs or SNRIs. Conventional oral selegiline is associated with potentially harmful plasma concentrations of three major amphetamine metabolites, although metabolite concentrations are significantly lower with a new orally disintegrating tablet (ODT) selegiline formulation. Selegiline ODT is also absorbed more efficiently and shows less pharmacokinetic variability than conventional oral selegiline.COMT mediates peripheral catabolism of levodopa. Therefore, agents that block COMT, such as tolcapone and entacapone, increase the elimination half-life of levodopa. Given adjunctively with levodopa, COMT inhibitors can decrease 'off' time and increase 'on' time, as well as lower the daily levodopa dose. Although more potent than entacapone, tolcapone requires monitoring for hepatotoxicity. Amantadine is a noncompetitive NMDA receptor antagonist shown to lower dyskinesia scores and improve motor complications in patients with Parkinson's disease when given adjunctively with levodopa. Dopamine agonists, also used as initial and adjunctive therapy in Parkinson's disease, improve motor response and decrease 'off' time purportedly through direct stimulation of dopamine receptors. Current dopamine agonists include bromocriptine, pergolide, cabergoline, lisuride, apomorphine, pramipexole, ropinirole and rotigotine. Although effective, this class of medications can be associated with cardiovascular and psychiatric adverse effects that can limit their utility. All medications used to manage levodopa-associated motor complications in patients with Parkinson's disease have had differing degrees of success. Although head-to-head comparisons of drugs within classes are rare, some differences have emerged related to effects on motor fluctuations, dyskinesias and on/off times, as well as to adverse effects. When choosing a drug to treat levodopa-induced complications, it is important to consider the risks and benefits of the different classes and of the specific agents within each class, given the different efficacy and safety profiles of each.

Multiple functionalization of fluorescent nanoparticles for specific biolabeling and drug delivery of dopamine

NASA Astrophysics Data System (ADS)

Malvindi, Maria Ada; di Corato, Riccardo; Curcio, Annalisa; Melisi, Daniela; Rimoli, Maria Grazia; Tortiglione, Claudia; Tino, Angela; George, Chandramohan; Brunetti, Virgilio; Cingolani, Roberto; Pellegrino, Teresa; Ragusa, Andrea

2011-12-01

The development of fluorescent biolabels for specific targeting and controlled drug release is of paramount importance in biological applications due to their potential in the generation of novel tools for simultaneous diagnosis and treatment of diseases. Dopamine is a neurotransmitter involved in several neurological diseases, such as Parkinson's disease and attention deficit hyperactivity disorder (ADHD), and the controlled delivery of its agonists already proved to have beneficial effects both in vitro and in vivo. Here, we report the synthesis and multiple functionalization of highly fluorescent CdSe/CdS quantum rods for specific biolabeling and controlled drug release. After being transferred into aqueous media, the nanocrystals were made highly biocompatible through PEG conjugation and covered by a carbohydrate shell, which allowed specific GLUT-1 recognition. Controlled attachment of dopamine through an ester bond also allowed hydrolysis by esterases, yielding a smart nanotool for specific biolabeling and controlled drug release.The development of fluorescent biolabels for specific targeting and controlled drug release is of paramount importance in biological applications due to their potential in the generation of novel tools for simultaneous diagnosis and treatment of diseases. Dopamine is a neurotransmitter involved in several neurological diseases, such as Parkinson's disease and attention deficit hyperactivity disorder (ADHD), and the controlled delivery of its agonists already proved to have beneficial effects both in vitro and in vivo. Here, we report the synthesis and multiple functionalization of highly fluorescent CdSe/CdS quantum rods for specific biolabeling and controlled drug release. After being transferred into aqueous media, the nanocrystals were made highly biocompatible through PEG conjugation and covered by a carbohydrate shell, which allowed specific GLUT-1 recognition. Controlled attachment of dopamine through an ester bond also allowed hydrolysis by esterases, yielding a smart nanotool for specific biolabeling and controlled drug release. Electronic supplementary information (ESI) available: TEM images, absorption and emission spectra, ζ-potential and DLS graphics, gel electrophoresis images, cyclic voltammograms, western blot and RT-PCR data. See DOI: 10.1039/c1nr10797f

Dopaminergic sensitivity and cocaine abuse: response to apomorphine.

PubMed

Hollander, E; Nunes, E; DeCaria, C M; Quitkin, F M; Cooper, T; Wager, S; Klein, D F

1990-08-01

Ten male patients with chronic cocaine abuse received a single dose of the dopamine agonist apomorphine. Self-ratings of cocaine craving, depression, and anxiety decreased in response to apomorphine. Neuroendocrine response was consistent with central dopaminergic stimulation. Patients in the "craving" phase of the cocaine abuse cycle differed in behavioral but not neuroendocrine response to apomorphine from patients in the "crash" phase. Decrease in cocaine craving correlated with decrease in plasma homovanillic acid (pHVA). Total cocaine consumption correlated negatively with baseline prolactin and pHVA levels and inversely with peak change in prolactin following apomorphine. Patients had blunted neuroendocrine response to apomorphine in comparison to historical normal controls. Implications for the "dopamine" hypothesis of cocaine abuse are discussed.

Sexual-incentive motivation and paced sexual behavior in female rats after treatment with drugs modifying dopaminergic neurotransmission.

PubMed

Ellingsen, Ellinor; Agmo, Anders

2004-03-01

The effects of the dopamine receptor agonist apomorphine, the dopamine releaser amphetamine, and the dopamine receptor antagonist cis(Z)-flupenthixol on sexual-incentive motivation and on paced-mating behavior were studied in female rats. Apomorphine, in the doses of 0.125 and 0.5 mg/kg, showed a tendency to reduce incentive motivation. Ambulatory activity was inhibited, evidenced both by diminished distance moved and reduced velocity of movement. Amphetamine (0.25 and 1 mg/kg) and flupenthixol (0.25 and 0.5 mg/kg) failed to modify incentive motivation while stimulating and reducing ambulatory activity, respectively. In the mating test, apomorphine enhanced the latency to enter the male's half and reduced the number of proceptive behaviors. However, these effects were associated with the appearance of stereotyped sniffing. Amphetamine increased the propensity to escape from the male after a mount without having other effects. Flupenthixol augmented the duration of the lordosis posture. Neither amphetamine nor flupenthixol affected sniffing. These data show that facilitated dopaminergic neurotransmission stimulates neither paced female sexual behavior nor sexual-incentive motivation. Dopamine receptor blockade has slight consequences. It is concluded that dopamine is not a transmitter of major importance for unconditioned female sexual motivation and behavior.

Dopamine Increases CD14+CD16+ Monocyte Migration and Adhesion in the Context of Substance Abuse and HIV Neuropathogenesis

PubMed Central

Coley, Jacqueline S.; Calderon, Tina M.; Gaskill, Peter J.; Eugenin, Eliseo A.; Berman, Joan W.

2015-01-01

Drug abuse is a major comorbidity of HIV infection and cognitive disorders are often more severe in the drug abusing HIV infected population. CD14+CD16+ monocytes, a mature subpopulation of peripheral blood monocytes, are key mediators of HIV neuropathogenesis. Infected CD14+CD16+ monocyte transmigration across the blood brain barrier mediates HIV entry into the brain and establishes a viral reservoir within the CNS. Despite successful antiretroviral therapy, continued influx of CD14+CD16+ monocytes, both infected and uninfected, contributes to chronic neuroinflammation and the development of HIV associated neurocognitive disorders (HAND). Drug abuse increases extracellular dopamine in the CNS. Once in the brain, CD14+CD16+ monocytes can be exposed to extracellular dopamine due to drug abuse. The direct effects of dopamine on CD14+CD16+ monocytes and their contribution to HIV neuropathogenesis are not known. In this study, we showed that CD14+CD16+ monocytes express mRNA for all five dopamine receptors by qRT-PCR and D1R, D5R and D4R surface protein by flow cytometry. Dopamine and the D1-like dopamine receptor agonist, SKF38393, increased CD14+CD16+ monocyte migration that was characterized as chemokinesis. To determine whether dopamine affected cell motility and adhesion, live cell imaging was used to monitor the accumulation of CD14+CD16+ monocytes on the surface of a tissue culture dish. Dopamine increased the number and the rate at which CD14+CD16+ monocytes in suspension settled to the dish surface. In a spreading assay, dopamine increased the area of CD14+CD16+ monocytes during the early stages of cell adhesion. In addition, adhesion assays showed that the overall total number of adherent CD14+CD16+ monocytes increased in the presence of dopamine. These data suggest that elevated extracellular dopamine in the CNS of HIV infected drug abusers contributes to HIV neuropathogenesis by increasing the accumulation of CD14+CD16+ monocytes in dopamine rich brain regions. PMID:25647501

Inhibition of tetrodotoxin-resistant sodium current in dorsal root ganglia neurons mediated by D1/D5 dopamine receptors

PubMed Central

2013-01-01

Background Dopaminergic fibers originating from area A11 of the hypothalamus project to different levels of the spinal cord and represent the major source of dopamine. In addition, tyrosine hydroxylase, the rate-limiting enzyme for the synthesis of catecholamines, is expressed in 8-10% of dorsal root ganglia (DRG) neurons, suggesting that dopamine may be released in the dorsal root ganglia. Dopamine has been shown to modulate calcium current in DRG neurons, but the effects of dopamine on sodium current and on the firing properties of small DRG neurons are poorly understood. Results The effects of dopamine and dopamine receptor agonists were tested on the tetrodotoxin-resistant (TTX-R) sodium current recorded from acutely dissociated small (diameter ≤ 25 μm) DRG neurons. Dopamine (20 μM) and SKF 81297 (10 μM) caused inhibition of TTX-R sodium current in small DRG neurons by 23% and 37%, respectively. In contrast, quinpirole (20 μM) had no effects on the TTX-R sodium current. Inhibition by SKF 81297 of the TTX-R sodium current was not affected when the protein kinase A (PKA) activity was blocked with the PKA inhibitory peptide (6–22), but was greatly reduced when the protein kinase C (PKC) activity was blocked with the PKC inhibitory peptide (19–36), suggesting that activation of D1/D5 dopamine receptors is linked to PKC activity. Expression of D1and D5 dopamine receptors in small DRG neurons, but not D2 dopamine receptors, was confirmed by Western blotting and immunofluorescence analysis. In current clamp experiments, the number of action potentials elicited in small DRG neurons by current injection was reduced by ~ 30% by SKF 81297. Conclusions We conclude that activation of D1/D5 dopamine receptors inhibits TTX-R sodium current in unmyelinated nociceptive neurons and dampens their intrinsic excitability by reducing the number of action potentials in response to stimulus. Increasing or decreasing levels of dopamine in the dorsal root ganglia may serve to adjust the sensitivity of nociceptors to noxious stimuli. PMID:24283218

Gene Expression of Serotonin and Dopamine Receptors and Monoamine Oxidase-A in the Brain of Dominant and Subordinate Pubertal Pigs Fed a ß-Adrenoreceptor Agonist

USDA-ARS?s Scientific Manuscript database

Aggression is a major source of social stress and injuries, negatively affecting the health and well-being of those involved in the fight. The serotonergic and dopaminergic systems are widely implicated in aggression regulation in several animal species, but information on molecular mechanisms media...

Ionization pattern obtained in electrospray ionization or atmospheric pressure chemical ionization interfaces for authorized antidepressants in Romania

NASA Astrophysics Data System (ADS)

Grecu, Iulia; Ionicǎ, Mihai; Vlǎdescu, Marian; Truţǎ, Elena; Sultan, Carmen; Viscol, Oana; Horhotǎ, Luminiţa; Radu, Simona

2016-12-01

Antidepressants were found in 1950. In the 1990s there was a new generation of antidepressants. They act on the level of certain neurotransmitters extrasinpatic by its growth. After their mode of action antidepressants may be: SSRIs (Selective Serotonin Reuptake Inhibitors); (Serotonin-Norepinephrine Reuptake Inhibitors); SARIs (Serotonin Antagonist Reuptake Inhibitors); NRIs (Norepinephrine Reuptake Inhibitors); NDRIs (Norepinephrine-Dopamine Reuptake Inhibitors) NDRAs (Norepinephrine-Dopamine Releasing Agents); TCAs (Tricyclic Antidepressants); TeCAs (Tetracyclic Antidepressants); MAOIs (Monoamine Oxidase Inhibitors); agonist receptor 5-HT1A (5- hydroxytryptamine); antagonist receptor 5-HT2; SSREs (Selective Serotonin Reuptake Enhancers) and Sigma agonist receptor. To determine the presence of antidepressants in biological products, it has been used a system HPLC-MS (High Performance Liquid Chromatography - Mass Spectrometry) Varian 12001. The system is equipped with APCI (Atmospheric Pressure Chemical Ionization) or ESI (ElectroSpray Ionization) interface. To find antidepressants in unknown samples is necessary to recognize them after mass spectrum. Because the mass spectrum it is dependent on obtaining private parameters work of HPLC-MS system, and control interfaces, the mass spectra library was filled with the mass spectra of all approved antidepressants in Romania. The paper shows the mass spectra obtained in the HPLCMS system.

Patch clamp reveals powerful blockade of the mitochondrial permeability transition pore by the D2-receptor agonist pramipexole.

PubMed

Sayeed, Iqbal; Parvez, Suhel; Winkler-Stuck, Kirstin; Seitz, Gordon; Trieu, Isabelle; Wallesch, Claus-Werner; Schönfeld, Peter; Siemen, Detlef

2006-03-01

The dopamine-D2-agonist pramipexole (PPX) was tested for blocking mitochondrial permeability transition (PT) in order to give a possible explanation for its neuroprotective effect seen in PPX-treated Parkinson's disease patients. Patch-clamp techniques for studying single-channel currents in the inner mitochondrial membrane and large-amplitude swelling of energized mitochondria were used to study PPX action on the permeability transition pore (PTP), a key player in the mitochondrial route of the apoptotic cascade. Identity of the PTP was proven by measuring the concentration-response relation for cyclosporin A-blockade (IC50=26 nM). PPX inhibits the PTP reversibly with an IC50 of 500 nM, which is close to the values determined earlier as plasma concentrations after PPX medication in patients. Interaction of PPX with the PTP is further supported by demonstrating that it abolished Ca2+-triggered swelling in functionally intact mitochondria. Blockade of the PTP by PPX was attenuated by increasing concentrations of inorganic phosphate and by acidification. We suggest that PPX could exert part of its neuroprotective effect by inhibition of the PTP and thus, probably, blocking of the mitochondrial pathway of the apoptosis cascade.

Ergotamine-derived dopamine agonists and left ventricular function in Parkinson patients: systolic and diastolic function studied by conventional echocardiography, tissue Doppler imaging, and two-dimensional speckle tracking.

PubMed

Rasmussen, Vibeke Guldbrand; Poulsen, Steen Hvitfeldt; Dupont, Erik; Ostergaard, Karen; Safikhany, Gholamhossein; Egeblad, Henrik

2008-11-01

Ergot-derived dopamine agonists (EDDA) induce fibrotic heart valve disease. We aimed to investigate whether EDDA treatment also affects left ventricular (LV) function. Myocardial function was evaluated in 110 Parkinson patients [mean age (63.4 +/- 9.0 years)] treated for at least 6 months with either EDDA (n = 71) or non-EDDA (n = 39). LV ejection fraction did not differ between EDDA and non-EDDA patients [63 +/- 4% vs. 65 +/- 4% (ns)]. There was no difference in prevalence of diastolic dysfunction between EDDA and non-EDDA patients [7% vs. 8% (ns)]. Finally, averaged LV systolic myocardial strain and longitudinal displacement analysed by means of two-dimensional speckle tracking showed no difference between EDDA and non-EDDA patients [strain: 19 +/- 3% vs. 19 +/- 2% (ns) and longitudinal displacement: 12 +/- 2 mm vs. 12 +/- 2 mm (ns)]. Elevated p-NT-proBNP was found in 38% of EDDA patients and in 59% of non-EDDA patients (ns). In contrast to the well-established association between EDDA treatment and valvular fibrosis, EDDA did not have a detectable adverse impact on myocardial systolic and diastolic function.

AC-186, a Selective Nonsteroidal Estrogen Receptor β Agonist, Shows Gender Specific Neuroprotection in a Parkinson’s Disease Rat Model

PubMed Central

2013-01-01

Drugs that selectively activate estrogen receptor β (ERβ) are potentially safer than the nonselective estrogens currently used in hormonal replacement treatments that activate both ERβ and ERα. The selective ERβ agonist AC-186 was evaluated in a rat model of Parkinson’s disease induced through bilateral 6-hydroxydopamine lesions of the substantia nigra. In this model, AC-186 prevented motor, cognitive, and sensorimotor gating deficits and mitigated the loss of dopamine neurons in the substantia nigra, in males, but not in females. Furthermore, in male rats, 17β-estradiol, which activates ERβ and ERα with equal potency, did not show the same neuroprotective benefits as AC-186. Hence, in addition to a beneficial safety profile for use in both males and females, a selective ERβ agonist has a differentiated pharmacological profile compared to 17β-estradiol in males. PMID:23898966

Dopamine Receptors and Parkinson's Disease

PubMed Central

Hisahara, Shin; Shimohama, Shun

2011-01-01

Parkinson's disease (PD) is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa) significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first choice to delay the starting of L-dopa therapy. In advanced stage of PD, they are also used as adjunct therapy together with L-dopa. DA receptor agonists act by stimulation of presynaptic and postsynaptic DA receptors. Despite the usefulness, they could be causative drugs for valvulopathy and nonmotor complication such as DA dysregulation syndrome (DDS). In this paper, physiological characteristics of DA receptor familyare discussed. We also discuss the validity, benefits, and specific adverse effects of pharmaceutical DA receptor agonist. PMID:25954517

The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment

PubMed Central

Ashok, A H; Marques, T R; Jauhar, S; Nour, M M; Goodwin, G M; Young, A H; Howes, O D

2017-01-01

Bipolar affective disorder is a common neuropsychiatric disorder. Although its neurobiological underpinnings are incompletely understood, the dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. The increased use of antidopaminergics in the treatment of this disorder and new in vivo neuroimaging and post-mortem studies makes it timely to review this theory. To do this, we conducted a systematic search for post-mortem, pharmacological, functional magnetic resonance and molecular imaging studies of dopamine function in bipolar disorder. Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. In bipolar depression imaging studies show increased dopamine transporter levels, but changes in other aspects of dopaminergic function are inconsistent. Puzzlingly, pharmacological evidence shows that both dopamine agonists and antidopaminergics can improve bipolar depressive symptoms and perhaps actions at other receptors may reconcile these findings. Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania and DAT blockade in bipolar depression. PMID:28289283

Reduced dopamine and glutamate neurotransmission in the nucleus accumbens of quinpirole-sensitized rats hints at inhibitory D2 autoreceptor function.

PubMed

Escobar, Angélica P; Cornejo, Francisca A; Olivares-Costa, Montserrat; González, Marcela; Fuentealba, José A; Gysling, Katia; España, Rodrigo A; Andrés, María E

2015-09-01

Dopamine from the ventral tegmental area and glutamate from several brain nuclei converge in the nucleus accumbens (NAc) to drive motivated behaviors. Repeated activation of D2 receptors with quinpirole (QNP) induces locomotor sensitization and compulsive behaviors, but the mechanisms are unknown. In this study, in vivo microdialysis and fast scan cyclic voltammetry in adult anesthetized rats were used to investigate the effect of repeated QNP on dopamine and glutamate neurotransmission within the NAc. Following eight injections of QNP, a significant decrease in phasic and tonic dopamine release was observed in rats that displayed locomotor sensitization. Either a systemic injection or the infusion of QNP into the NAc decreased dopamine release, and the extent of this effect was similar in QNP-sensitized and control rats, indicating that inhibitory D2 autoreceptor function is maintained despite repeated activation of D2 receptors and decreased dopamine extracellular levels. Basal extracellular levels of glutamate in the NAc were also significantly lower in QNP-treated rats than in controls. Moreover, the increase in NAc glutamate release induced by direct stimulation of medial prefrontal cortex was significantly lower in QNP-sensitized rats. Together, these results indicate that repeated activation of D2 receptors disconnects NAc from medial prefrontal cortex and ventral tegmental area. Repeated administration of the dopamine D2 receptor agonist quinpirole (QNP) induces locomotor sensitization. We found that the NAc of QNP-sensitized rats has reduced glutamate levels coming from prefrontal cortex together with a decreased phasic and tonic dopamine neurotransmission but a conserved presynaptic D2 receptor function. We suggest that locomotor sensitization is because of increased affinity state of D2 post-synaptic receptors. © 2015 International Society for Neurochemistry.

Dopamine D3 Receptor Availability Is Associated with Inflexible Decision Making.

PubMed

Groman, Stephanie M; Smith, Nathaniel J; Petrullli, J Ryan; Massi, Bart; Chen, Lihui; Ropchan, Jim; Huang, Yiyun; Lee, Daeyeol; Morris, Evan D; Taylor, Jane R

2016-06-22

Dopamine D2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D2, D3, or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [(11)C]-(+)-PHNO was used to quantify individual differences in putative D3 receptor availability in rodents trained on a novel three-choice spatial acquisition and reversal-learning task with probabilistic reinforcement. Binding of [(11)C]-(+)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [(11)C]-(+)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D3-preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D3 receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D3 receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D3 receptor in decision-making processes that are altered in psychiatric disorders. Flexible decision-making behavior is dependent upon dopamine D2/3 signaling in corticostriatal brain regions. However, the role of D3 receptors in adaptive, goal-directed behavior has not been thoroughly investigated. By combining PET imaging with the D3-preferring radioligand [(11)C]-(+)-PHNO, pharmacology, a novel three-choice probabilistic discrimination and reversal task and computational modeling of behavior in rats, we report that naturally occurring variation in [(11)C]-(+)-PHNO receptor availability relates to specific aspects of flexible decision making. We confirm these relationships using a D3-preferring agonist, thus identifying a unique role of midbrain D3 receptors in decision-making processes. Copyright © 2016 the authors 0270-6474/16/366732-10$15.00/0.

Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(+)-PHNO.

PubMed

Girgis, Ragy R; Slifstein, Mark; D'Souza, Deepak; Lee, Yih; Periclou, Antonia; Ghahramani, Parviz; Laszlovszky, István; Durgam, Suresh; Adham, Nika; Nabulsi, Nabeel; Huang, Yiyun; Carson, Richard E; Kiss, Béla; Kapás, Margit; Abi-Dargham, Anissa; Rakhit, Ashok

2016-10-01

Second-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia. The purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia. Using [(11)C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations. A monotonic dose-occupancy relationship was observed for both receptor types. After 2 weeks of treatment, near complete (∼100 %) occupancies were observed for both receptors at a dose of 12 mg/day. At the lowest cariprazine dose (1 mg/day), mean D3 and D2 receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma after 2 weeks of dosing. This PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.

Control of the subthalamic innervation of substantia nigra pars reticulata by D1 and D2 dopamine receptors.

PubMed

Ibañez-Sandoval, Osvaldo; Hernández, Adán; Florán, Benjamin; Galarraga, Elvira; Tapia, Dagoberto; Valdiosera, Rene; Erlij, David; Aceves, Jorge; Bargas, José

2006-03-01

The effects of activating dopaminergic D1 and D2 class receptors of the subthalamic projections that innervate the pars reticulata of the subtantia nigra (SNr) were explored in slices of the rat brain using the whole cell patch-clamp technique. Excitatory postsynaptic currents (EPSCs) that could be blocked by 6-cyano-7-nitroquinoxalene-2,3-dione and D-(-)-2-amino-5-phosphonopentanoic acid were evoked onto reticulata GABAergic projection neurons by local field stimulation inside the subthalamic nucleus in the presence of bicuculline. Bath application of (RS)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF-38393), a dopaminergic D1-class receptor agonist, increased evoked EPSCs by approximately 30% whereas the D2-class receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo(3,4-g)quinoline (quinpirole), reduced EPSCs by approximately 25%. These apparently opposing actions were blocked by the specific D1- and D2-class receptor antagonists: R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepinehydrochloride (SCH 23390) and S-(-)-5-amino-sulfonyl-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride), respectively. Both effects were accompanied by changes in the paired-pulse ratio, indicative of a presynaptic site of action. The presynaptic location of dopamine receptors at the subthalamonigral projections was confirmed by mean-variance analysis. The effects of both SKF-38393 and quinpirole could be observed on terminals contacting the same postsynaptic neuron. Sulpiride and SCH 23390 enhanced and reduced the evoked EPSC, respectively, suggesting a constitutive receptor activation probably arising from endogenous dopamine. These data suggest that dopamine presynaptically modulates the subthalamic projection that targets GABAergic neurons of the SNr. Implications of this modulation for basal ganglia function are discussed.

Dopamine D1 receptor-dependent regulation of extracellular citrulline level in the rat nucleus accumbens during conditioned fear response.

PubMed

Saulskaya, Natalia B; Fofonova, Nellia V; Sudorghina, Polina V; Saveliev, Sergey A

2008-08-01

Nucleus accumbens (N.Acc) contains a subclass of nitric oxide (NO)-generating interneurons that are presumably regulated by the dopamine input. Receptor mechanisms underlying dopamine-NO interaction in the N.Acc are poorly understood. In the current study, we used in vivo microdialysis combined with high-performance liquid chromatography to examine participation of dopamine D1 receptors in regulation of extracellular levels of citrulline (an NO co-product) in the medial N.Acc of Sprague-Dawley rats during both pharmacological challenge and a conditioned fear response. The intraaccumbal infusion of the D1 receptor agonist SKF-38393 (100-500 microM) increased dose-dependently the local dialysate citrulline levels. The SKF-38393-induced increase in extracellular citrulline was prevented by intraaccumbal infusions of 500 microM 7-nitroindazole, a neuronal NO synthase inhibitor. In behavioral microdialysis experiment, the accumbal levels of extracellular citrulline markedly increased in rats given a mild footshock paired with tone. The presentation of the tone previously paired with footshock (the conditioned fear response) produced a "conditioned" rise of extracellular citrulline levels in the N.Acc which was attenuated by intraaccumbal infusion of 100 microM SCH-23390, a dopamine D1 receptor antagonist, and prevented by intraaccumbal infusion of 500 microM 7-nitroindazole. The results suggest that in the N.Acc, the dopamine D1 receptors might regulate the neuronal NO synthase activity; this dopamine-dependent mechanism seems to participate in activation of the neuronal NO synthase and probably NO formation in this brain area during the conditioned fear response.

Sexual behavior modulates contextual fear memory through dopamine D1/D5 receptors.

PubMed

Bai, Hua-Yi; Cao, Jun; Liu, Na; Xu, Lin; Luo, Jian-Hong

2009-03-01

Traumatic events always lead to aversive emotional memory, i.e., fear memory. In contrast, positive events in daily life such as sex experiences seem to reduce aversive memory after aversive events. Thus, we hypothesized that post-traumatic pleasurable experiences, especially instinctive behaviors such as sex, might modulate traumatic memory through a memory competition mechanism. Here, we first report that male rats persistently expressed much lower fear responses when exposed to females, but not when exposed to males, for 24 h immediately after contextual fear conditioning. Remarkably, this effect of sexual behavior was blocked by either systemic or intrahippocampal injection of the dopamine D1/D5 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) and was mimicked by systemic but not intrahippocampal injection of the D1/D5 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol hydrochloride (SKF39393). Furthermore, as a candidate mechanism underlying contextual fear memory, the impaired induction of hippocampal long-term potentiation (LTP) elicited by conditioned fear was rescued in male rats immediately exposed to female but not male rats for 24 h. Systemic injection of the dopamine D1/D5 receptor antagonist SCH23390 or agonist SKF38393 prevented or mimicked the effect of sexual behavior on the impaired induction of hippocampal LTP. Thus, our finding suggests that dopaminergic functions may, at least partially, govern competition between contextual fear and enjoyable memories through the modulation of hippocampal LTP.

Treatments for Parkinson disease--past achievements and current clinical needs.

PubMed

Poewe, Werner

2009-02-17

Although idiopathic Parkinson disease (PD) remains the only neurodegenerative disorder for which there are highly effective symptomatic therapies, there are still major unmet needs regarding its long-term management. Although levodopa continues as the gold standard for efficacy, its chronic use is associated with potentially disabling motor complications. Current evidence suggests that these are related to mode of administration, whereby multiple oral doses of levodopa generate pulsatile stimulation of striatal dopamine receptors. Current dopamine agonists, while producing more constant plasma levels, fail to match levodopa's efficacy. Strategies to treat levodopa-related motor complications are only partially effective, rarely abolishing motor fluctuations or dyskinesias. Best results are currently achieved with invasive strategies via subcutaneous (s.c.) or intraduodenal delivery of apomorphine or levodopa, or deep brain stimulation of the subthalamic nucleus. Another area of major unmet medical need is related to nondopaminergic and nonmotor symptoms of PD. Targeting transmitter systems beyond the dopamine system is an interesting approach, both for the motor and nonmotor problems of PD. So far, clinical trial evidence regarding 5-HT agonists, glutamate antagonists, adenosine A(2) antagonists and alpha-adrenergic receptor antagonists, has been inconsistent, but trials with cholinesterase inhibitors and atypical antipsychotics to treat dementia and psychosis, have been successful. However, the ultimate goal of PD medical management is modifying disease progression, thereby delaying the evolution of motor and nonmotor complications of advanced disease. As understanding of preclinical markers for PD develops, there is new hope for neuropreventive strategies to target "at risk" populations before clinical onset of disease.

Virally mediated increased neurotensin 1 receptor in the nucleus accumbens decreases behavioral effects of mesolimbic system activation.

PubMed

Cáceda, Ricardo; Kinkead, Becky; Owens, Michael J; Nemeroff, Charles B

2005-12-14

Dopamine receptor agonist and NMDA receptor antagonist activation of the mesolimbic dopamine system increases locomotion and disrupts prepulse inhibition of the acoustic startle response (PPI), paradigms frequently used to study both the pharmacology of antipsychotic drugs and drugs of abuse. In rats, virally mediated overexpression of the neurotensin 1 (NT1) receptor in the nucleus accumbens antagonized d-amphetamine- and dizocilpine-induced PPI disruption, hyperlocomotion, and D-amphetamine-induced rearing. The NT receptor antagonist SR 142948A [2-[[5-(2,6-dimethoxyphenyl)-1-(4-N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]amino] adamantane-2-carboxylic acid, hydrochloride] blocked inhibition of dizocilpine-induced hyperlocomotion mediated by overexpression of the NT1 receptor. Together, these results suggest that increased nucleus accumbens NT neurotransmission, via the NT1 receptor, can decrease the effects of activation of the mesolimbic dopamine system and disruption of the glutamatergic input from limbic cortices, resembling the action of the atypical antipsychotic drug clozapine. In contrast to clozapine, virally mediated overexpression of the NT1 receptor in the nucleus accumbens had prolonged protective effects (up to 4 weeks after viral injection) without perturbing baseline PPI and locomotor behaviors. These data further confirm the NT1 receptor as the receptor mediating the antistimulant- and antipsychotic-like properties of NT and provide rationale for the development of NT1 receptor agonists as novel antipsychotic drugs. In addition, the NT1 receptor vector might be a valuable tool for understanding the mechanism of action of antipsychotic drugs and drugs of abuse and may have potential therapeutic applications.

Dorsolateral neostriatum contribution to incentive salience: Opioid or dopamine stimulation makes one reward cue more motivationally attractive than another

PubMed Central

DiFeliceantonio, Alexandra G.; Berridge, Kent C.

2016-01-01

Pavlovian cues for rewards can become attractive incentives: approached and ‘wanted’ as the rewards themselves. The motivational attractiveness of a previously learned cue is not fixed, but can be dynamically amplified during re-encounter by simultaneous activation of brain limbic circuitry. Here we report that opioid or dopamine microinjections in the dorsolateral quadrant of the neostriatum (DLS) of rats selectively amplify attraction toward a previously learned Pavlovian cue in an individualized fashion, at the expense of a competing cue. In an autoshaping (sign-tracking vs goal-tracking) paradigm, microinjection of the mu opioid receptor agonist (DAMGO) or dopamine indirect agonist (amphetamine) in DLS of sign-tracker individuals selectively enhanced their sign-tracking attraction toward the reward-predictive lever cue. By contrast, DAMGO or amphetamine in DLS of goal-trackers selectively enhanced prepotent attraction toward the reward-proximal cue of sucrose dish. Amphetamine also enhanced goal-tracking in some sign-tracker individuals (if they ever defected to the dish even once). That DLS enhancement of cue attraction was due to stronger motivation, not stronger habits was suggested by: 1) sign-trackers flexibly followed their cue to a new location when the lever was suddenly moved after DLS DAMGO microinjection, and 2) DAMGO in DLS also made sign-trackers work harder on a new instrumental nose-poke response required to earn presentations of their Pavlovian lever cue (instrumental conditioned reinforcement). Altogether, our results suggest that DLS circuitry can enhance the incentive salience of a Pavlovian reward cue, selectively making that cue a stronger motivational magnet. PMID:26924040

From bench to bedside: An overview of rotigotine for the treatment of restless legs syndrome.

PubMed

Bogan, Richard K

2014-03-01

Restless legs syndrome (RLS) is a common chronic neurologic disorder. Symptoms are most prevalent during the evening and at night, although daytime symptoms may emerge as the disease progresses. Dopamine agonists are currently considered first-line therapy for moderate to severe idiopathic RLS. Most dopamine agonists have short half-lives and are administered in the evening, shortly before the onset of RLS symptoms. Rotigotine is a non-ergot dopamine receptor agonist that has been specifically developed as a transdermal patch to provide continuous drug delivery over a 24-hour period. This review details the development of rotigotine, from the preclinical studies that established its pharmacokinetic profile to large-scale clinical trials in patients with RLS. Placebo-controlled trials that demonstrated the efficacy and tolerability of rotigotine are discussed, in addition to open-label studies that investigated long-term therapy. Studies were identified by a PubMed search using the key word rotigotine in conjunction with restless legs syndrome and by reviewing reference lists of retrieved publications. All clinical trials of rotigotine in RLS published before September 2013 were included. Preclinical studies have established activity of rotigotine as a dopamine receptor agonist, and pharmacokinetic data have shown that transdermal delivery maintains stable plasma levels over 24 hours. Rotigotine has demonstrated efficacy in improving moderate to severe RLS symptoms in randomized, placebo-controlled trials, based on scores on the International RLS Study Group rating scale, the RLS-6 scale, and the Clinical Global Impression-Severity subscale. Results of an open-label extension study suggest that efficacy may be maintained for up to 5 years. A polysomnographic study demonstrated an improvement in periodic limb movement index with rotigotine, and subjective assessments have suggested beneficial effects in terms of amelioration of sleep disturbances. Premature discontinuations from rotigotine treatment have ranged from 8% to 38% in studies of 6 weeks to 12 months in duration; 57% of patients discontinued prematurely during a 5-year study. In each trial, adverse events were typical of dopaminergic stimulation and use of a transdermal patch. The most common adverse events were application-site reactions, with a reported prevalence ranging from 17% (1-month sleep laboratory trial) to 58% (5-year open-label extension study). Clinically significant augmentation was recorded in 39 of 295 patients (13%) receiving rotigotine during the 5-year study, of whom 15 (5%) were receiving a dose within the US Food and Drug Administration-approved range of 1 to 3 mg/24 h. Findings from clinical studies have suggested that rotigotine is efficacious in improving RLS symptoms and is generally well-tolerated. The risk of developing clinically significant augmentation appears to be low. As such, rotigotine represents an important addition for RLS treatment. Copyright © 2014 The Authors. Published by EM Inc USA.. All rights reserved.

Ethanol-induced dopamine elevation in the rat--modulatory effects by subchronic treatment with nicotinic drugs.

PubMed

Löf, Elin; Chau, Pei Pei; Stomberg, Rosita; Söderpalm, Bo

2007-01-26

Chronic nicotine administration is associated with increased ethanol consumption in laboratory animals and in humans. Some smokers report less sedation during acute ethanol intoxication after nicotine administration and the sedative effects from ethanol are mediated by inhibitory GABA(A)-receptors. In a series of in vivo microdialysis experiments we investigated whether subchronic pre-treatment with nicotinic drugs known to enhance ethanol consumption in the rat (nicotine or the peripheral nicotinic antagonist hexamethonium) could modulate the alterations in extracellular dopamine observed in response to administration of ethanol or the sedative GABA(A)-agonist diazepam. In the nucleus accumbens and the dorsal striatum, systemic and/or local ethanol administration resulted in transient increases in extracellular dopamine levels that returned to baseline before the local levels of ethanol started to decline. In hexamethonium pre-treated rats, however, the nucleus accumbens dopamine levels were time-locked to the ethanol levels in the same area after systemic or local ethanol administration. Perfusion of diazepam into the nucleus accumbens produced a significant reduction in nucleus accumbens dopamine in controls. Prior subchronic treatment with nicotine or hexamethonium abolished this effect. The present results suggest that subchronic treatment with the nicotinic acetylcholine receptor antagonist hexamethonium reduces a GABA(A)-R mediated counteraction of the nucleus accumbens dopamine response to ethanol. Additionally, we demonstrate that modulation of nicotinic receptors may reduce the sensitivity of GABA(A) receptors to benzodiazepines. These phenomena may offer a novel explanation to why nicotine and alcohol are often co-abused.

Activation of the dopamine D1 receptor can extend long-term spatial memory persistence via PKA signaling in mice.

PubMed

Zhang, Jiabao; Ko, Sang-Yoon; Liao, Yulan; Kwon, Yubeen; Jeon, Se Jin; Sohn, Aeree; Cheong, Jae Hoon; Kim, Dong Hyun; Ryu, Jong Hoon

2018-05-24

Many works have been performed to understand the mechanisms of the formation and persistence of memory. However, it is not fully understood whether the decay of long-term memory can be modulated by the activation of dopamine D 1 receptor. A Barnes maze task was employed to measure long-term spatial memory. We observed that the spatial memory acquired through 3 trials per session for 4 days had begun to fade out by the 14th day and had completely disappeared by 21 days after the first probe test. The intraperitoneal administration of SKF 38393 (a dopamine D 1 receptor agonist) for 7 days beginning on the 14th day after the first probe test prevented natural memory forgetting, and the intraperitoneal administration of SCH 23390 (a dopamine D 1 receptor antagonist) prevented this memory persistence. In the Western blotting, the administration of SKF 38393 increased the phosphorylation levels of PKA, ERK1/2, CaMKII, and CREB in the hippocampus. In addition, such increased levels were decreased by the corresponding antagonist (SCH 23390). Moreover, the inhibition of PKA could completely reverse the preservation of spatial memory induced by dopamine D 1 receptor activation. These results suggest that the activation of the dopamine D 1 receptor plays a critical role in the persistence of long-term spatial memory through the PKA signaling pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

Dopamine D3 and D2 Receptor Mechanisms in the Abuse-Related Behavioral Effects of Cocaine: Studies with Preferential Antagonists in Squirrel Monkeys

PubMed Central

Grundt, Peter; Cao, Jianjing; Platt, Donna M.; Newman, Amy Hauck; Spealman, Roger D.

2010-01-01

Dopamine (DA) D3 and D2 receptor mechanisms are implicated in cocaine's abuse-related behavioral effects, but the relative contribution of the two receptor subtypes is only partially characterized. This study investigated the role of D3 and D2 subtype mechanisms by determining the degree to which the D3-preferring antagonist PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin- 1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl] and the D2-preferring antagonist L-741626 [3-[4-(4-chlorophenyl)-4- hydroxypiperidin-1-yl]methyl-1H-indole] attenuated several behavioral effects of cocaine in squirrel monkeys. Quantitative observational studies established doses of each antagonist that did not produce untoward effects, which were used in subsequent comparisons. In addition, the ability of the D3-preferring agonist PD128907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] and the D2-preferring agonist sumanirole [(R)-5,6-dihydro-5-(methylamino)-4H- imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate] to reproduce cocaine's discriminative stimulus (DS) and priming effects were compared. In monkeys trained to discriminate cocaine from vehicle, both DA antagonists attenuated and both DA agonists partially reproduced cocaine's DS effects. PG01037 also selectively attenuated the cocaine-like DS effects of PD128907, whereas L-741626 attenuated the cocaine-like DS effects of both agonists. In self-administration studies, L-741626 nonselectively reduced cocaine- and food-maintained responding, whereas PG01037 was ineffective against either reinforcer. In studies involving reinstatement of extinguished cocaine seeking, both antagonists attenuated cocaine-induced reinstatement of responding, and both agonists induced at least partial reinstatement of cocaine seeking. L-741626 also attenuated sumanirole-induced, but not PD128907-induced, reinstatement of responding, whereas PG01037 was ineffective against either DA agonist. The results are consistent with a role for D3 and D2 receptor mechanisms in cocaine's DS effects and cocaine-induced reinstatement of drug seeking, but provide no evidence for a major role of D3 receptors in the direct reinforcing effects of cocaine. PMID:20494958

Functional selectivity of allosteric interactions within G protein-coupled receptor oligomers: the dopamine D1-D3 receptor heterotetramer.

PubMed

Guitart, Xavier; Navarro, Gemma; Moreno, Estefania; Yano, Hideaki; Cai, Ning-Sheng; Sánchez-Soto, Marta; Kumar-Barodia, Sandeep; Naidu, Yamini T; Mallol, Josefa; Cortés, Antoni; Lluís, Carme; Canela, Enric I; Casadó, Vicent; McCormick, Peter J; Ferré, Sergi

2014-10-01

The dopamine D1 receptor-D3 receptor (D1R-D3R) heteromer is being considered as a potential therapeutic target for neuropsychiatric disorders. Previous studies suggested that this heteromer could be involved in the ability of D3R agonists to potentiate locomotor activation induced by D1R agonists. It has also been postulated that its overexpression plays a role in L-dopa-induced dyskinesia and in drug addiction. However, little is known about its biochemical properties. By combining bioluminescence resonance energy transfer, bimolecular complementation techniques, and cell-signaling experiments in transfected cells, evidence was obtained for a tetrameric stoichiometry of the D1R-D3R heteromer, constituted by two interacting D1R and D3R homodimers coupled to Gs and Gi proteins, respectively. Coactivation of both receptors led to the canonical negative interaction at the level of adenylyl cyclase signaling, to a strong recruitment of β-arrestin-1, and to a positive cross talk of D1R and D3R agonists at the level of mitogen-activated protein kinase (MAPK) signaling. Furthermore, D1R or D3R antagonists counteracted β-arrestin-1 recruitment and MAPK activation induced by D3R and D1R agonists, respectively (cross-antagonism). Positive cross talk and cross-antagonism at the MAPK level were counteracted by specific synthetic peptides with amino acid sequences corresponding to D1R transmembrane (TM) domains TM5 and TM6, which also selectively modified the quaternary structure of the D1R-D3R heteromer, as demonstrated by complementation of hemiproteins of yellow fluorescence protein fused to D1R and D3R. These results demonstrate functional selectivity of allosteric modulations within the D1R-D3R heteromer, which can be involved with the reported behavioral synergism of D1R and D3R agonists. U.S. Government work not protected by U.S. copyright.

Disrupted sensory gating in pathological gambling.

PubMed

Stojanov, Wendy; Karayanidis, Frini; Johnston, Patrick; Bailey, Andrew; Carr, Vaughan; Schall, Ulrich

2003-08-15

Some neurochemical evidence as well as recent studies on molecular genetics suggest that pathologic gambling may be related to dysregulated dopamine neurotransmission. The current study examined sensory (motor) gating in pathologic gamblers as a putative measure of endogenous brain dopamine activity with prepulse inhibition of the acoustic startle eye-blink response and the auditory P300 event-related potential. Seventeen pathologic gamblers and 21 age- and gender-matched healthy control subjects were assessed. Both prepulse inhibition measures were recorded under passive listening and two-tone prepulse discrimination conditions. Compared to the control group, pathologic gamblers exhibited disrupted sensory (motor) gating on all measures of prepulse inhibition. Sensory motor gating deficits of eye-blink responses were most profound at 120-millisecond prepulse lead intervals in the passive listening task and at 240-millisecond prepulse lead intervals in the two-tone prepulse discrimination task. Sensory gating of P300 was also impaired in pathologic gamblers, particularly at 500-millisecond lead intervals, when performing the discrimination task on the prepulse. In the context of preclinical studies on the disruptive effects of dopamine agonists on prepulse inhibition, our findings suggest increased endogenous brain dopamine activity in pathologic gambling in line with previous neurobiological findings.

Fisetin inhibits liver cancer growth in a mouse model: Relation to dopamine receptor.

PubMed

Liu, Xiang-Feng; Long, Hai-Jiao; Miao, Xiong-Ying; Liu, Guo-Li; Yao, Hong-Liang

2017-07-01

Fisetin (3,3',4',7-tetrahydroxyflavone), a natural abundant flavonoid, is produced in different vegetables and fruits. Fisetin has been reported to relate to various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. Dopamine receptors (DRs) belonging to G protein‑coupled receptor family, are known as the target of ~50% of all modern medicinal drugs. DRs consist of various proteins, functioning as transduction of intracellular signals for extracellular stimuli. We found that fisetin performed as DR2 agonist to suppress liver cancer cells proliferation, migration and invasion. Caspase-3 signaling was activated to induce apoptosis for fisetin administration. Furthermore, TGF‑β1 was also inhibited in fisetin-treated liver cancer cells, reducing epithelial-mesenchymal transition (EMT). Additionally, fisetin downregulated VEGFR1, p-ERK1/2, p38 and pJNK, ameliorating liver cancer progression. In vivo, the orthotopically implanted tumors from mice were inhibited by fisetin adminisatration accompanied by prolonged survival rate and higher levels of dopamine. Together, the results indicated a novel therapeutic strategy to suppress liver cancer progression associated with DR2 regulation, indicating that dopamine might be of importance in liver cancer progression.

Fisetin inhibits liver cancer growth in a mouse model: Relation to dopamine receptor

PubMed Central

Liu, Xiang-Feng; Long, Hai-Jiao; Miao, Xiong-Ying; Liu, Guo-Li; Yao, Hong-Liang

2017-01-01

Fisetin (3,3′,4′,7-tetrahydroxyflavone), a natural abundant flavonoid, is produced in different vegetables and fruits. Fisetin has been reported to relate to various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. Dopamine receptors (DRs) belonging to G protein-coupled receptor family, are known as the target of ~50% of all modern medicinal drugs. DRs consist of various proteins, functioning as transduction of intracellular signals for extracellular stimuli. We found that fisetin performed as DR2 agonist to suppress liver cancer cells proliferation, migration and invasion. Caspase-3 signaling was activated to induce apoptosis for fisetin administration. Furthermore, TGF-β1 was also inhibited in fisetin-treated liver cancer cells, reducing epithelial-mesenchymal transition (EMT). Additionally, fisetin downregulated VEGFR1, p-ERK1/2, p38 and pJNK, ameliorating liver cancer progression. In vivo, the orthotopically implanted tumors from mice were inhibited by fisetin adminisatration accompanied by prolonged survival rate and higher levels of dopamine. Together, the results indicated a novel therapeutic strategy to suppress liver cancer progression associated with DR2 regulation, indicating that dopamine might be of importance in liver cancer progression. PMID:28560391

The D1 family dopamine receptor, DopR, potentiates hind leg grooming behavior in Drosophila.

PubMed

Pitmon, E; Stephens, G; Parkhurst, S J; Wolf, F W; Kehne, G; Taylor, M; Lebestky, T

2016-03-01

Drosophila groom away debris and pathogens from the body using their legs in a stereotyped sequence of innate motor behaviors. Here, we investigated one aspect of the grooming repertoire by characterizing the D1 family dopamine receptor, DopR. Removal of DopR results in decreased hind leg grooming, as substantiated by quantitation of dye remaining on mutant and RNAi animals vs. controls and direct scoring of behavioral events. These data are also supported by pharmacological results that D1 receptor agonists fail to potentiate grooming behaviors in headless DopR flies. DopR protein is broadly expressed in the neuropil of the thoracic ganglion and overlaps with TH-positive dopaminergic neurons. Broad neuronal expression of dopamine receptor in mutant animals restored normal grooming behaviors. These data provide evidence for the role of DopR in potentiating hind leg grooming behaviors in the thoracic ganglion of adult Drosophila. This is a remarkable juxtaposition to the considerable role of D1 family dopamine receptors in rodent grooming, and future investigations of evolutionary relationships of circuitry may be warranted. © 2016 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

Effects of dopaminergic modulation on electrophysiological brain response to affective stimuli.

PubMed

Franken, Ingmar H A; Nijs, Ilse; Pepplinkhuizen, Lolke

2008-01-01

Several theoretical accounts of the role of dopamine suggest that dopamine has an influence on the processing of affective stimuli. There is some indirect evidence for this from studies showing an association between the treatment with dopaminergic agents and self-reported affect. We addressed this issue directly by examining the electrophysiological correlates of affective picture processing during a single-dose treatment with a dopamine D2 agonist (bromocriptine), a dopamine D2 antagonist (haloperidol), and a placebo. We compared early and late event-related brain potentials (ERPs) that have been associated with affective processing in the three medication treatment conditions in a randomized double-blind crossover design amongst healthy males. In each treatment condition, subjects attentively watched neutral, pleasant, and unpleasant pictures while ERPs were recorded. Results indicate that neither bromocriptine nor haloperidol has a selective effect on electrophysiological indices of affective processing. In concordance with this, no effects of dopaminergic modulation on self-reported positive or negative affect was observed. In contrast, bromocriptine decreased overall processing of all stimulus categories regardless of their affective content. The results indicate that dopaminergic D2 receptors do not seem to play a crucial role in the selective processing of affective visual stimuli.

Dopamine D1 receptor activation leads to object recognition memory in a coral reef fish.

PubMed

Hamilton, Trevor J; Tresguerres, Martin; Kline, David I

2017-07-01

Object recognition memory is the ability to identify previously seen objects and is an adaptive mechanism that increases survival for many species throughout the animal kingdom. Previously believed to be possessed by only the highest order mammals, it is now becoming clear that fish are also capable of this type of memory formation. Similar to the mammalian hippocampus, the dorsolateral pallium regulates distinct memory processes and is modulated by neurotransmitters such as dopamine. Caribbean bicolour damselfish ( Stegastes partitus ) live in complex environments dominated by coral reef structures and thus likely possess many types of complex memory abilities including object recognition. This study used a novel object recognition test in which fish were first presented two identical objects, then after a retention interval of 10 min with no objects, the fish were presented with a novel object and one of the objects they had previously encountered in the first trial. We demonstrate that the dopamine D 1 -receptor agonist (SKF 38393) induces the formation of object recognition memories in these fish. Thus, our results suggest that dopamine-receptor mediated enhancement of spatial memory formation in fish represents an evolutionarily conserved mechanism in vertebrates. © 2017 The Author(s).

Design, Synthesis, and Structure–Activity Relationship Studies of a Series of [4-(4-Carboxamidobutyl)]-1-arylpiperazines: Insights into Structural Features Contributing to Dopamine D3 versus D2 Receptor Subtype Selectivity

PubMed Central

2015-01-01

Antagonist and partial agonist modulators of the dopamine D3 receptor (D3R) have emerged as promising therapeutics for the treatment of substance abuse and neuropsychiatric disorders. However, development of druglike lead compounds with selectivity for the D3 receptor has been challenging because of the high sequence homology between the D3R and the dopamine D2 receptor (D2R). In this effort, we synthesized a series of acylaminobutylpiperazines incorporating aza-aromatic units and evaluated their binding and functional activities at the D3 and D2 receptors. Docking studies and results from evaluations against a set of chimeric and mutant receptors suggest that interactions at the extracellular end of TM7 contribute to the D3R versus D2R selectivity of these ligands. Molecular insights from this study could potentially enable rational design of potent and selective D3R ligands. PMID:25126833

Integration of animal behaviors under stresses with different time courses

PubMed Central

Zheng, Lun; Zheng, Xigeng

2014-01-01

We used animal models of “forced swim stress” and “chronic unpredictable stress”, and tried to reveal whether a passive coping style of high flotation behavior in forced swim stress predicts anhedonia behavior after chronic unpredictable stress, and whether the dopamine system regulates floating and anhedonia behaviors. Our results confirmed that depression-prone rats use “floating behavior” as a coping strategy in forced swim stress and more readily suffer from anhedonia during chronic unpredictable stress. Intraperitoneal injection or nucleus accumbens microinjection of the dopamine 2/3 receptor subtype agonist ropinirole reduced floating behaviors in depression-prone animals, but increased sucrose preference in rats showing anhedonia. These data indicate that floating behavior is a defensive mode that is preferred by susceptible individuals under conditions of acute stress. Simultaneously, these animals more readily experienced anhedonia under long-term stress; that is, they were more readily affected by depression. Our results suggest that dopamine 2/3 receptor subtypes in the nucleus accumbens play an important role in floating behaviors and anhedonia. PMID:25317159

Effects of activation and blockade of dopamine receptors on the extinction of a passive avoidance reaction in mice with a depressive-like state.

PubMed

Dubrovina, N I; Zinov'eva, D V

2010-01-01

Learning and extinction of a conditioned passive avoidance reaction resulting from neuropharmacological actions on dopamine D(1) and D(2) receptors were demonstrated to be specific in intact mice and in mice with a depressive-like state. Learning was degraded only after administration of the D(2) receptor antagonist sulpiride and was independent of the initial functional state of the mice. In intact mice, activation of D(2) receptors with quinpirole led to a deficit of extinction, consisting of a reduction in the ability to acquire new inhibitory learning in conditions associated with the disappearance of the expected punishment. In mice with the "behavioral despair" reaction, characterized by delayed extinction, activation of D(1) receptors with SKF38393 normalized this process, while the D(2) agonist was ineffective. A positive effect consisting of accelerated extinction of the memory of fear of the dark ("dangerous") sector of the experimental chamber was also seen on blockade of both types of dopamine receptor.

Pharmacological therapy of Parkinson's disease: current options and new avenues.

PubMed

Simola, Nicola; Pinna, Annalisa; Fenu, Sandro

2010-11-01

Parkinson's disease is a neurodegenerative pathology which affects the dopaminergic neurons in the mesencephalon, leading to a progressive and relentless motor disability and to non-motor symptoms of different severity. The aim of this review is to summarize the features of drugs currently used in the pharmacotherapy of Parkinson's disease, with a look at their beneficial effects and limitations. Drugs acting on dopamine transmission, as L-DOPA, direct dopaminergic agonists, inhibitors for either the MAO or COMT enzymes and drugs acting on neurotransmitters other than dopamine (e.g. acetylcholine, glutamate) will be covered. Investigational drugs currently under examination for their therapeutic potential in Parkinson's disease and recent patents which may be relevant to the field will be also discussed.

A Role for Sigma Receptors in Stimulant Self-Administration and Addiction.

PubMed

Katz, Jonathan L; Hiranita, Takato; Hong, Weimin C; Job, Martin O; McCurdy, Christopher R

2017-01-01

Sigma receptors (σRs) are structurally unique proteins that function intracellularly as chaperones. Historically, σRs have been implicated as modulators of psychomotor stimulant effects and have at times been proposed as potential avenues for modifying stimulant abuse. However, the influence of ligands for σRs on the effects of stimulants, such as cocaine or methamphetamine, in various preclinical procedures related to drug abuse has been varied. The present paper reviews the effects of σR agonists and antagonists in three particularly relevant procedures: stimulant discrimination, place conditioning, and self-administration. The literature to date suggests limited σR involvement in the discriminative-stimulus effects of psychomotor stimulants, either with σR agonists substituting for the stimulant or with σR antagonists blocking stimulant effects. In contrast, studies of place conditioning suggest that administration of σR antagonists or down-regulation of σR protein can block the place conditioning induced by stimulants. Despite place conditioning results, selective σR antagonists are inactive in blocking the self-administration of stimulants. However, compounds binding to the dopamine transporter and blocking σRs can selectively decrease stimulant self-administration. Further, after self-administration of stimulants, σR agonists are self-administered, an effect not seen in subjects without that specific history. These findings suggest that stimulants induce unique changes in σR activity, and once established, the changes induced create redundant, and dopamine independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and σR proteins produces a selective antagonism of those pathways, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse.

Pramipexole and Compulsive Masturbation

PubMed Central

Ferlan, Mark

2007-01-01

Objective: Exploration of a possible relationship between pramipexole and compulsive masturbation. Methods: We present a case report. Results: Given the temporal overlap between pramipexole prescription and its discontinuation, and the onset and cessation of the patient's hypersexual behavior, there appears to be a strong likelihood of association. Conclusions: Like other dopamine agonists, pramipexole may precipitate compulsive behaviors, including hypersexual behavior in the form of compulsive masturbation. PMID:20532122

AFRRI Reports: January-March 1990

DTIC Science & Technology

1990-04-01

coordinating move- Travel to polar or geostationary orbits or travel to the ment). Oxotremorine , an acetylcholine agonist, was used to mnoon or the planes has...not survive.) tat oxotremorine -enhanced, potassium-stimulated dope- mine release in vitro, an effect that Nisted at least 14 days DISCUSSION (7...shortly after irradiaiio, with 10,000 rads of high-energy electrons 17/). However, oxotremorine enhancement of K -evoked release of dopamine was reduced

Effects of Acute and Chronic Treatments with Dopamine D2 and D3 Receptor Ligands on Cocaine versus Food Choice in Rats.

PubMed

Thomsen, Morgane; Barrett, Andrew C; Butler, Paul; Negus, S Stevens; Caine, S Barak

2017-07-01

Dopamine D 3 receptor ligands are potential medications for psychostimulant addiction. Medication assessment may benefit from preclinical studies that evaluate chronic medication effects on choice between an abused drug and an alternative, nondrug reinforcer. This study compared acute and chronic effects of dopamine D 2 - and D 3 -preferring ligands on choice between intravenous cocaine and palatable food in rats. Under baseline conditions, cocaine maintained dose-dependent increases in cocaine choice and reciprocal decreases in food choice. Acutely, the D 2 agonist R -(-)-norpropylapomorphine (NPA) and antagonist L-741,626 [3-[[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1 H -indole] produced leftward and rightward shifts in cocaine dose-effect curves, respectively, whereas the partial agonist terguride had no effect. All three drugs dose-dependently decreased food-maintained responding. Chronically, the effects of R -(-)-norpropylapomorphine and L-741,626 on cocaine self-administration showed marked tolerance, whereas suppression of food-reinforced behavior persisted. Acute effects of the D 3 ligands were less systematic and most consistent with nonselective decreases in cocaine- and food-maintained responding. Chronically, the D 3 agonist PF-592,379 [5-[(2 R ,5 S )-5-methyl-4-propylmorpholin-2-yl]pyridin-2-amine] increased cocaine choice, whereas an intermediate dose of the D 3 antagonist PG01037 [ N -[( E )-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]but-2-enyl]-4-pyridin-2-ylbenzamide] produced a therapeutically desirable decrease in cocaine choice early in treatment; however, tolerance to this effect developed, and lower and higher doses were ineffective. D 3 ligands failed to significantly modify total cocaine intake but caused persistent decreases in food intake. Thus, D 2 -and D 3 -preferring ligands showed distinct profiles, consistent with different pharmacological actions. In addition, these results highlight the role of acute versus chronic treatment as a determinant of test drug effects. With the possible exception of the D 3 antagonist PG01037, no ligand was promising in terms of cocaine addiction treatment. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Involvement of dopamine receptors within the dorsal hippocampus in suppression of the formalin-induced orofacial pain.

PubMed

Shamsizadeh, Ali; Pahlevani, Pouyan; Haghparast, Amir; Moslehi, Maryam; Zarepour, Leila; Haghparast, Abbas

2013-12-01

It is widely established that the dopaminergic system has profound effects on pain modulation in different regions of the brain including the hippocampus, the salient area for brain functions. The orofacial region is one of the most densely innervated (by the trigeminal nerves) areas of the body susceptible to acute and chronic pains. In this study, we tried to examine the effects of dopamine receptors located in the dorsal hippocampus (CA1) region upon the modulation of orofacial pain induced by the formalin test. To induce orofacial pain in male Wistar rats, 50μl of 1% formalin was subcutaneously injected into the upper lip. In control and experimental groups, two guide cannulae were stereotaxically implanted in the CA1, and SKF-38393 (0.25, 0.5, 1 and 2μg/0.5μl saline) as a D1-like receptor agonist, SCH-23390 (1μg/0.5μl saline) as a D1-like receptor antagonist, Quinpirole (0.5, 1, 2 and 4μg/0.5μl saline) as a D2-like receptor agonist and Sulpiride(3μg/0.5μl DMSO) as a D2-like receptor antagonist or vehicles were microinjected. For induction of orofacial pain, 50μl of 1% formalin was subcutaneously injected into the left side of the upper lip. Results indicated that SKF-38393 at the dose of 1 and 2μg significantly reduced pain during the first and second phases of observed pain while SCH-23390 reversed such analgesic effect. Moreover, there is a significant difference between groups in which animals received 2 and 4μg quinpirole or vehicle in the first phase (early phase) of pain. The three high doses of this compound (1, 2 and 4μg) appeared to have an analgesic effect during the second (late) phase. Furthermore, Sulpiride could potentially reverse the observed analgesic effects already induced by an agonist. Current findings suggest that the dorsal hippocampal dopamine receptors exert an analgesic effect during the orofacial pain test. Copyright © 2013 Elsevier Inc. All rights reserved.

The effect of administering a dopamine agonist (Cabergoline) on follicular and luteal development during pro-estrus and estrus in the female greyhound.

PubMed

De Rensis, F; Spattini, G; Ballabio, R; Scaramuzzi, R J

2006-09-01

To study the effect of the dopamine agonist Cabergoline, on ovarian activity in the female dog during pro-estrus and estrus, 6 greyhounds were treated with 5 microg/kg per os of Cabergoline for 20 days beginning on the first day of pro-estrus; 6 animals were left untreated (controls). Ovarian morphology was determined by ultrasound examination once a day during pro-estrus and twice a day during estrus. Follicles were divided into three classes on the basis of their diameter: F1 (<3mm), F2 (3-6mm) and F3 (>6mm). The presence and diameters of post-ovulatory follicles (F-POST) and corpora lutea (CL) were also recorded. Blood samples were taken once a day during pro-estrus and twice a day during estrus. The plasma was assayed for LH, prolactin and progesterone by radioimmunoassay. There were no differences between Cabergoline-treated and control dogs in the duration of pro-estrus or estrus. There was a progressive increase in follicle diameter from the start of pro-estrus when follicles were mainly class F1 to the day of estrus when follicles were mainly class F3. Three days after the start of estrus, the first F-POST follicles were detected. This pattern of development continued and on day 5 the first CLs were detected. By day 9, only CLs were detected. The peak of pre-ovulatory LH was within 3 days of estrus and ovulation was detected in all animals within 3 days of the LH peak. There were no differences in LH concentrations between groups. Plasma prolactin levels varied between animals and were reduced in treated dogs, however, this was not statistically significant (P=0.12). Plasma progesterone levels were below 1.0 ng/ml before the LH surge and thereafter gradually increased. There were no differences in plasma progesterone concentrations between treated and control dogs. In conclusion these results show that the administration of the dopamine agonist Cabergoline during pro-estrus and estrus did not affect the duration of pro-estrus or estrus or the pattern of follicular and luteal development in female dogs.

Dopamine D1 receptor modulation in nucleus accumbens lowers voluntary wheel running in rats bred to run high distances.

PubMed

Roberts, Michael D; Gilpin, Leigh; Parker, Kyle E; Childs, Thomas E; Will, Matthew J; Booth, Frank W

2012-02-01

Dopamine signaling in the nucleus accumbens (NAc) has been postulated to influence reward development towards drugs of abuse and exercise. Herein, we used generation 4-5 rats that were selectively bred to voluntary run high (HVR) versus low (LVR) distances in order to examine if dopamine-like 1 (D1) receptor modulation in the NAc differentially affects nightly voluntary wheel running between these lines. A subset of generation 5-6 HVR and LVR rats were also used to study the mRNA expression of key genes related to reward and addiction in the NAc (i.e., DRD1, DRD5, DRD2, Nr4a2, FosB, and BDNF). In a crossover fashion, a D1-like agonist SKF 82958 (2 μg per side) or D1-like full antagonist SCH 23390 (4 μg per side) was bilaterally injected into the NAc of HVR and LVR female Wistar rats prior to their high running nights. Notably, during hours 2-4 (between 2000 and 2300) of the dark cycle there was a significant decrement in running distances in the HVR rats treated with the D1 agonist (p=0.025) and antagonist (p=0.017) whereas the running distances in LVR rats were not affected. Interestingly, HVR and LVR rats possessed similar NAc concentrations of the studied mRNAs. These data suggest that: a) animals predisposed to run high distances on a nightly basis may quickly develop a rewarding response to exercise due to an optimal D1-like receptor signaling pathway in the NAc that can be perturbed by either activation or blocking, b) D1-like agonist or antagonist injections do not increase running distances in rats that are bred to run low nightly distances, and c) running differences between HVR and LVR animals are seemingly not due to the expression of the studied mRNAs. Given the societal prevalence of obesity and extraneous physical inactivity, future studies should be performed in order to further determine the culprit for the low running phenotype observed in LVR animals. Copyright © 2011. Published by Elsevier Inc.

Effects of Dopamine D2/D3 Receptor Ligands on Food-Cocaine Choice in Socially Housed Male Cynomolgus Monkeys

PubMed Central

Czoty, Paul W.

2013-01-01

Dopamine D2/D3 receptor partial agonists have been suggested as medications for cocaine dependence. The present experiments examined the effect of acute and repeated administration of drugs with varying intrinsic efficacy at D2/D3 receptors on the relative reinforcing strength of cocaine. Use of socially housed cynomolgus monkeys permitted the assessment of whether social status, known to alter D2/D3 receptor availability, influenced the behavioral effects of D2/D3 receptor compounds. The high-efficacy agonist R(−)−norpropylapomorphine [(−)−NPA], low-efficacy agonist aripiprazole (ARI), and antagonist eticlopride (ETIC) were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine self-administration dose-effect curve was determined daily. The effects of 5-day treatment with ARI and (−)−NPA were characterized under conditions in which monkeys did (ARI) or did not [ARI and (−)−NPA] self-administer cocaine during treatment. When administered acutely, ARI and ETIC increased the choice of low cocaine doses, and only (−)−NPA decreased the choice of higher cocaine doses and cocaine intake; effects were similar across social ranks. When administered repeatedly while self administration occurred only on days 1 and 5 of treatment, ARI, but not (−)−NPA, decreased cocaine choice in dominant monkeys, whereas (−)−NPA, but not ARI, did so in subordinates. When dominant monkeys self-administered cocaine on all five days of ARI treatment, however, these effects were not observed. The results indicate that the behavioral effects of D2/D3 receptor agonists can differ according to intrinsic efficacy and subject characteristics. Moreover, these results suggest that exposure to cocaine during treatment can counteract treatment-induced reductions in the reinforcing effects of cocaine. PMID:23211363

Comodulation of dopamine and serotonin on prefrontal cortical rhythms: a theoretical study

PubMed Central

Wang, Da-Hui; Wong-Lin, KongFatt

2013-01-01

The prefrontal cortex (PFC) is implicated to play an important role in cognitive control. Abnormal PFC activities and rhythms have been observed in some neurological and neuropsychiatric disorders, and evidences suggest influences from the neuromodulators dopamine (DA) and serotonin (5-HT). Despite the high level of interest in these brain systems, the combined effects of DA and 5-HT modulation on PFC dynamics remain unknown. In this work, we build a mathematical model that incorporates available experimental findings to systematically study the comodulation of DA and 5-HT on the network behavior, focusing on beta and gamma band oscillations. Single neuronal model shows pyramidal cells with 5-HT1A and 2A receptors can be non-monotonically modulated by 5-HT. Two-population excitatory-inhibitory type network consisting of pyramidal cells with D1 receptors can provide rich repertoires of oscillatory behavior. In particular, 5-HT and DA can modulate the amplitude and frequency of the oscillations, which can emerge or cease, depending on receptor types. Certain receptor combinations are conducive for the robustness of the oscillatory regime, or the existence of multiple discrete oscillatory regimes. In a multi-population heterogeneous model that takes into account possible combination of receptors, we demonstrate that robust network oscillations require high DA concentration. We also show that selective D1 receptor antagonists (agonists) tend to suppress (enhance) network oscillations, increase the frequency from beta toward gamma band, while selective 5-HT1A antagonists (agonists) act in opposite ways. Selective D2 or 5-HT2A receptor antagonists (agonists) can lead to decrease (increase) in oscillation amplitude, but only 5-HT2A antagonists (agonists) can increase (decrease) the frequency. These results are comparable to some pharmacological effects. Our work illustrates the complex mechanisms of DA and 5-HT when operating simultaneously through multiple receptors. PMID:23935568

Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens.

PubMed

Bardo, M T

1998-01-01

Multiple lines of research have implicated the mesolimbic dopamine system in drug reward measured by either the drug self-administration or conditioned place preference paradigm. The present review summarizes recent work that examines the neuropharmacological mechanisms by which drugs impinge on this dopaminergic neural circuitry, as well as other systems that provide input and output circuits to the mesolimbic dopamine system. Studies examining the effect of selective agonist and antagonist drugs administered systemically have indicated that multiple neurotransmitters are involved, including dopamine, serotonin, acetylcholine, glutamate, GABA, and various peptides. Direct microinjection studies have also provided crucial evidence indicating that, in addition to the mesolimbic dopamine system, other structures play a role in drug reward, including the ventral pallidum, amygdala, hippocampus, hypothalamus, and pedunculopontine tegmental nucleus. GABAergic circuitry descending from the nucleus accumbens to the pedunculopontine tegmental nucleus via the ventral pallidum appears to be especially important in directing the behavioral sequelae associated with reward produced by various drugs of abuse. However, activation of the reward circuitry is achieved differently for various drugs of abuse. With amphetamine and cocaine, initiation of reward is controlled within the nucleus accumbens and prefrontal cortex, respectively. With opiates, initiation of reward involves the ventral tegmental area, nucleus accumbens, hippocampus, and hypothalamus. It is not clear presently if these multiple anatomical structures mediate opiate reward by converging on a single output system or multiple output systems.

The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model­

PubMed Central

VandenBroeke, Marie; Youn, Jiun; Ellenbroek, Arabella K.; Karel, Peter; Shan, Ling; van Boxtel, Ruben; Ooms, Sharon; Balemans, Monique; Langedijk, Jacqueline; Muller, Mareike; Vriend, Gert; Cools, Alexander R.; Cuppen, Edwin; Ellenbroek, Bart A.

2016-01-01

ABSTRACT Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1 receptor (Drd1). Because current Drd1 receptor agonists are not Drd1 selective, pharmacological tools are not sufficient to delineate the role of the Drd1. Here, we describe a novel rat model with a genetic mutation in Drd1 in which we measured basic behavioural phenotypes and social cognition. The I116S mutation was predicted to render the receptor less stable. In line with this computational prediction, this Drd1 mutation led to a decreased transmembrane insertion of Drd1, whereas Drd1 expression, as measured by Drd1 mRNA levels, remained unaffected. Owing to decreased transmembrane Drd1 insertion, the mutant rats displayed normal basic motoric and neurological parameters, as well as locomotor activity and anxiety-like behaviour. However, measures of social cognition like social interaction, scent marking, pup ultrasonic vocalizations and sociability, were strongly reduced in the mutant rats. This profile of the Drd1 mutant rat offers the field of neuroscience a novel genetic rat model to study a series of psychiatric disorders including schizophrenia, autism, depression, bipolar disorder and drug addiction. PMID:27483345

Dopamine, urges to smoke, and the relative salience of drug versus non-drug reward.

PubMed

Freeman, Tom P; Das, Ravi K; Kamboj, Sunjeev K; Curran, H Valerie

2015-01-01

When addicted individuals are exposed to drug-related stimuli, dopamine release is thought to mediate incentive salience attribution, increasing attentional bias, craving and drug seeking. It is unclear whether dopamine acts specifically on drug cues versus other rewards, and if these effects correspond with craving and other forms of cognitive bias. Here, we administered the dopamine D2/D3 agonist pramipexole (0.5 mg) to 16 tobacco smokers in a double-blind placebo-controlled crossover design. Visual fixations on smoking and money images were recorded alongside smoking urges and fluency tasks. Pramipexole attenuated a marked bias in initial orienting towards smoking relative to money but did not alter a maintained attentional bias towards smoking. Pramipexole decreased urges to smoke retrospectively after the task but not on a state scale. Fewer smoking words were generated after pramipexole but phonological and semantic fluency were preserved. Although these treatment effects did not correlate with each other, changes in initial orienting towards smoking and money were inversely related to baseline scores. In conclusion, pramipexole can reduce the salience of an addictive drug compared with other rewards and elicit corresponding changes in smoking urges and cognitive bias. These reward-specific and baseline-dependent effects support an 'inverted-U' shaped profile of dopamine in addiction. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Upregulation of lymphocyte apoptosis as a strategy for preventing and treating autoimmune disorders: a role for whole-food vegan diets, fish oil and dopamine agonists.

PubMed

McCarty, M F

2001-08-01

Induced apoptosis of autoreactive T-lymphocyte precursors in the thymus is crucial for the prevention of autoimmune disorders. IGF-I and prolactin, which are lymphocyte growth factors, may have the potential to suppress apoptosis in thymocytes and thus encourage autoimmunity; conversely, dietary fish oil rich in omega-3 fats appears to upregulate apoptosis in lymphocytes. Since whole-food vegan diets may downregulate systemic IGF-I activity, it is proposed that such a diet, in conjunction with fish oil supplementation and treatment with dopamine agonists capable of suppressing prolactin secretion, may have utility for treating and preventing autoimmune disorders. This prediction is consistent with the extreme rarity of autoimmune disorders among sub-Saharan black Africans as long as they followed their traditional quasi-vegan lifestyles, and with recent ecologic studies correlating risks for IDDM and for multiple sclerosis mortality with animal product and/or saturated fat consumption. Moreover, there is evidence that vegan or quasi-vegan diets are useful in the management of rheumatoid arthritis, multiple sclerosis, and possibly SLE. The dopamine agonist bromocryptine exerts anti-inflammatory effects in rodent models of autoimmunity, and there is preliminary evidence that this drug may be clinically useful in several human autoimmune diseases; better tolerated D2-specific agonists such as cabergoline may prove to be more practical for use in therapy. The moderate clinical utility of supplemental fish oil in rheumatoid arthritis and certain other autoimmune disorders is documented. It is not unlikely that extra-thymic anti-inflammatory effects contribute importantly to the clinical utility of vegan diets, bromocryptine, and fish oil in autoimmunity. The favorable impact of low latitude or high altitude on autoimmune risk may be mediated by superior vitamin D status, which is associated with decreased secretion of parathyroid hormone; there are theoretical grounds for suspecting that parathyroid hormone may inhibit apoptosis in thymocytes. Androgens appear to up-regulate thymocyte apoptosis, may be largely responsible for the relative protection from autoimmunity enjoyed by men, and merit further evaluation for the management of autoimmunity in women. It will probably prove more practical to prevent autoimmune disorders than to reverse them once established; a whole-food vegan diet, coupled with fish oil and vitamin D supplementation, may represent a practical strategy for achieving this prevention, while concurrently lowering risk for many other life-threatening 'Western' diseases. Copyright 2001 Harcourt Publishers Ltd.

Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/-2-amino versions: Impact on functional activity and selectivity for dopamine D2/D3 receptors

PubMed Central

Gopishetty, Bhaskar; Zhang, Suhong; Kharkar, Prashant S.; Antonio, Tamara; Reith, Maarten; Dutta, Aloke K.

2013-01-01

The goal of the present study was to explore, in our previously developed hybrid template, the effect of introduction of additional heterocyclic rings (mimicking catechol hydroxyl groups as bioisosteric replacement) on selectivity and affinity for the D3 versus D2 receptor. In addition, we wanted to explore the effect of derivatization of functional groups of the agonist binding moiety in compounds developed by us earlier from the hybrid template. Binding affinity (Ki) of the new compounds was measured with tritiated spiperone as the radioligand and HEK-293 cells expressing either D2 or D3 receptors. Functional activity of selected compounds was assessed in the GTPγS binding assay. In the imidazole series, compound 10a exhibited the highest D3 affinity whereas the indole derivative 13 exhibited similar high D3 affinity. Functionalization of the amino group in agonist (+)-9d with different sulfonamides derivatives improved the D3 affinity significantly with (+)-14f exhibiting the highest affinity. However, functionalization of the hydroxyl and amino groups of 15 and (+)-9d, known agonist and partial agonist, to sulfonate ester and amide in general modulated the affinity. In both cases loss of agonist potency resulted from such derivatization. PMID:23623679

Differential involvement of dopamine receptors in conditioned suppression induced by cocaine.

PubMed

Grakalic, Ivana; Panlilio, Leigh V; Thorndike, Eric B; Schindler, Charles W

2007-11-14

Cocaine-paired stimuli can suppress food-reinforced operant behavior in rats, providing an animal model of conditioned drug effects. To study the neuropharmacological basis of this phenomenon, we examined the effects of various dopamine receptor antagonists on the acquisition and expression of cocaine-induced conditioned suppression in rats. Superimposed on an ongoing baseline of food-reinforced operant responding, a stimulus was paired with response-independent cocaine (3.0 mg/kg, i.v.) during each of 8 training sessions. To study acquisition, independent groups of rats were given saline, the dopamine D(1)-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) (0.001-0.03 mg/kg, i.p.), or the dopamine D(2)-like receptor antagonist eticlopride (0.001-0.03 mg/kg, i.p.) prior to each training session. To study expression, independent groups of rats were trained first, then given saline, SCH 23390, eticlopride, or N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide (BP 897) (a dopamine D(3) partial receptor agonist; 0.1-1.0 mg/kg, i.p.) before test sessions in which the stimulus was presented without cocaine. Pre-treatment with either SCH 23390 or eticlopride during acquisition reduced the direct suppressant effects of cocaine, but conditioning was blocked only in rats that were treated with SCH 23390 during acquisition training. Expression of conditioning was attenuated only by eticlopride. Thus, dopamine at least partially mediates both the acquisition and expression of cocaine-induced conditioned suppression, with activation of dopamine D(1)- and D(2)-like receptors underlying these respective processes.

Colocalization of Mating-Induced Fos and D2-Like Dopamine Receptors in the Medial Preoptic Area: Influence of Sexual Experience.

PubMed

Nutsch, Victoria L; Will, Ryan G; Robison, Christopher L; Martz, Julia R; Tobiansky, Daniel J; Dominguez, Juan M

2016-01-01

Dopamine in the medial preoptic area (mPOA) stimulates sexual activity in males. This is evidenced by microdialysis and microinjection experiments revealing that dopamine receptor antagonists in the mPOA inhibit sexual activity, whereas agonists facilitate behavior. Microdialysis experiments similarly show a facilitative role for dopamine, as levels of dopamine in the mPOA increase with mating. While the majority of evidence suggests an important role for dopamine receptors in the mPOA in the regulation of male sexual behaviors, whether sexual activity or sexual experience influence dopamine receptor function in the mPOA has not been previously shown. Here we used immunohistochemical assays to determine whether varying levels of sexual activity or experience influence the number of cells containing Fos or D2 receptor immunoreactivity. Results show that sexual experience facilitated subsequent behavior, namely experience decreased latencies. Moreover, the number of cells with immunoreactivity for Fos or D2 correlated with levels of sexual experience and sexual activity. Sexual activity increased Fos immunoreactivity. Sexually experienced animals also had significantly more D2-positive cells. Sexually inexperienced animals copulating for the first time had a larger percentage of D2-positive cells containing Fos, when compared to sexually experienced animals. Finally, regardless of experience, animals that had sex prior to sacrifice had significantly more D2-positive cells that contained Fos, vs. animals that did not copulate. These findings are noteworthy because sexually experienced animals display increased sexual efficiency. The differences in activation of D2 and changes in receptor density may play a role in this efficiency and other behavioral changes across sexual experience.

Histamine H3 Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons.

PubMed

Varaschin, Rafael Koerich; Osterstock, Guillaume; Ducrot, Charles; Leino, Sakari; Bourque, Marie-Josée; Prado, Marco A M; Prado, Vania Ferreira; Salminen, Outi; Rannanpää Née Nuutinen, Saara; Trudeau, Louis-Eric

2018-04-15

Histamine H 3 receptors are widely distributed G i -coupled receptors whose activation reduces neuronal activity and inhibits release of numerous neurotransmitters. Although these receptors are abundantly expressed in the striatum, their modulatory role on activity-dependent dopamine release is not well understood. Here, we observed that histamine H 3 receptor activation indirectly diminishes dopamine overflow in the ventral striatum by reducing cholinergic interneuron activity. Acute brain slices from C57BL/6 or channelrhodopsin-2-transfected DAT-cre mice were obtained, and dopamine transients evoked either electrically or optogenetically were measured by fast-scan cyclic voltammetry. The H 3 agonist α-methylhistamine significantly reduced electrically- evoked dopamine overflow, an effect blocked by the nicotinic acetylcholine receptor antagonist dihydro-β-erythroidine, suggesting involvement of cholinergic interneurons. None of the drug treatments targeting H 3 receptors affected optogenetically evoked dopamine overflow, indicating that direct H 3 -modulation of dopaminergic axons is unlikely. Next, we used qPCR and confirmed the expression of histamine H 3 receptor mRNA in cholinergic interneurons, both in ventral and dorsal striatum. Activation of H 3 receptors by α-methylhistamine reduced spontaneous firing of cholinergic interneurons in the ventral, but not in the dorsal striatum. Resting membrane potential and number of spontaneous action potentials in ventral-striatal cholinergic interneurons were significantly reduced by α-methylhistamine. Acetylcholine release from isolated striatal synaptosomes, however, was not altered by α-methylhistamine. Together, these results indicate that histamine H 3 receptors are important modulators of dopamine release, specifically in the ventral striatum, and that they do so by decreasing the firing rate of cholinergic neurons and, consequently, reducing cholinergic tone on dopaminergic axons. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Dopamine Increases CD14+CD16+ Monocyte Transmigration across the Blood Brain Barrier: Implications for Substance Abuse and HIV Neuropathogenesis.

PubMed

Calderon, Tina M; Williams, Dionna W; Lopez, Lillie; Eugenin, Eliseo A; Cheney, Laura; Gaskill, Peter J; Veenstra, Mike; Anastos, Kathryn; Morgello, Susan; Berman, Joan W

2017-06-01

In human immunodeficiency virus-1 (HIV) infected individuals, substance abuse may accelerate the development and/or increase the severity of HIV associated neurocognitive disorders (HAND). It is proposed that CD14 + CD16 + monocytes mediate HIV entry into the central nervous system (CNS) and that uninfected and infected CD14 + CD16 + monocyte transmigration across the blood brain barrier (BBB) contributes to the establishment and propagation of CNS HIV viral reservoirs and chronic neuroinflammation, important factors in the development of HAND. The effects of substance abuse on the frequency of CD14 + CD16 + monocytes in the peripheral circulation and on the entry of these cells into the CNS during HIV neuropathogenesis are not known. PBMC from HIV infected individuals were analyzed by flow cytometry and we demonstrate that the frequency of peripheral blood CD14 + CD16 + monocytes in HIV infected substance abusers is increased when compared to those without active substance use. Since drug use elevates extracellular dopamine concentrations in the CNS, we examined the effects of dopamine on CD14 + CD16 + monocyte transmigration across our in vitro model of the human BBB. The transmigration of this monocyte subpopulation is increased by dopamine and the dopamine receptor agonist, SKF 38393, implicating D1-like dopamine receptors in the increase in transmigration elicited by this neurotransmitter. Thus, elevated extracellular CNS dopamine may be a novel common mechanism by which active substance use increases uninfected and HIV infected CD14 + CD16 + monocyte transmigration across the BBB. The influx of these cells into the CNS may increase viral seeding and neuroinflammation, contributing to the development of HIV associated neurocognitive impairments.

Trace amines depress D2-autoreceptor-mediated responses on midbrain dopaminergic cells

PubMed Central

Ledonne, Ada; Federici, Mauro; Giustizieri, Michela; Pessia, Mauro; Imbrici, Paola; Millan, Mark J; Bernardi, Giorgio; Mercuri, Nicola B

2010-01-01

Background and purpose: Although trace amines (TAs) are historically considered ‘false neurotransmitters’ on the basis of their ability to induce catecholamine release, there is evidence that they directly affect neuronal activity via TA receptors, ligand-gated receptor channels and/or σ receptors. Here, we have investigated the effects of two TAs, tyramine (TYR) and β-phenylethylamine (β-PEA), on electrophysiological responses of substantia nigra pars compacta (SNpc) dopaminergic cells to the D2 receptor agonist, quinpirole. Experimental approach: Electrophysiological recordings of D2 receptor-activated G-protein-gated inward rectifier K+ channel (GIRK) currents were performed on dopaminergic cells from midbrain slices of mice and on Xenopus oocytes expressing D2 receptors and GIRK channels. Key results: TYR and β-PEA reversibly reduced D2 receptor-activated GIRK currents in a concentration-dependent manner on SNpc neurones. The inhibitory effect of TAs was still present in transgenic mice with genetically deleted TA1 receptors and they could not be reproduced by the selective TA1 agonist, o-phenyl-3-iodotyramine (O-PIT). Pretreatment with antagonists of σ1 and σ2 receptors did not block TA-induced effects. In GTPγS-loaded neurones, the irreversibly-activated GIRK-current was still reversibly reduced by β-PEA. Moreover, β-PEA did not affect basal or dopamine-evoked GIRK-currents in Xenopus oocytes. Conclusions and implications: TAs reduced dopamine-induced responses on SNpc neurones by acting at sites different from TA1, σ-receptors, D2 receptors or GIRK channels. Although their precise mechanism of action remains to be identified, TAs, by antagonizing the inhibitory effects of dopamine, may render dopaminergic neurones less sensitive to autoreceptor feedback inhibition and hence enhance their sensitivity to stimulation. PMID:20590640

"Hyperglutamatergic cortico-striato-thalamo-cortical circuit" breaker drugs alleviate tics in a transgenic circuit model of Tourette׳s syndrome.

PubMed

Nordstrom, Eric J; Bittner, Katie C; McGrath, Michael J; Parks, Clinton R; Burton, Frank H

2015-12-10

The brain circuits underlying tics in Tourette׳s syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive-compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice׳s tics were alleviated by the TS drugs clonidine and dopamine D2 receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice׳s tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c receptor antagonist ritanserin and the NE alpha-1 receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/imidazoline I1 receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons׳ glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

The role of beta-arrestin2 in shaping fMRI BOLD responses to dopaminergic stimulation.

PubMed

Sahlholm, Kristoffer; Ielacqua, Giovanna D; Xu, Jinbin; Jones, Lynne A; Schlegel, Felix; Mach, Robert H; Rudin, Markus; Schroeter, Aileen

2017-07-01

The dopamine D 2 receptor (D 2 R) couples to inhibitory G i/o proteins and is targeted by antipsychotic and antiparkinsonian drugs. Beta-arrestin2 binds to the intracellular regions of the agonist-occupied D 2 R to terminate G protein activation and promote internalization, but also to initiate downstream signaling cascades which have been implicated in psychosis. Functional magnetic resonance imaging (fMRI) has proven valuable for measuring dopamine receptor-mediated changes in neuronal activity, and might enable beta-arrestin2 function to be studied in vivo. The present study examined fMRI blood oxygenation level dependent (BOLD) signal changes elicited by a dopamine agonist in wild-type (WT) and beta-arrestin2 knockout (KO) mice, to investigate whether genetic deletion of beta-arrestin2 prolongs or otherwise modifies D 2 R-dependent responses. fMRI BOLD data were acquired on a 9.4 T system. During scans, animals received 0.2 mg/kg apomorphine, i.v. In a subset of experiments, animals were pretreated with 2 mg/kg of the D 2 R antagonist, eticlopride. Following apomorphine administration, BOLD signal decreases were observed in caudate/putamen of WT and KO animals. The time course of response decay in caudate/putamen was significantly slower in KO vs. WT animals. In cingulate cortex, an initial BOLD signal decrease was followed by a positive response component in WT but not in KO animals. Eticlopride pretreatment significantly reduced apomorphine-induced BOLD signal changes. The prolonged striatal response decay rates in KO animals might reflect impaired D 2 R desensitization, consistent with the known function of beta-arrestin2. Furthermore, the apomorphine-induced positive response component in cingulate cortex may depend on beta-arrestin2 signaling downstream of D 2 R.

The dopamine D2/D3 receptor agonist quinpirole increases checking-like behaviour in an operant observing response task with uncertain reinforcement: A novel possible model of OCD?

PubMed Central

Eagle, Dawn M.; Noschang, Cristie; d’Angelo, Laure-Sophie Camilla; Noble, Christie A.; Day, Jacob O.; Dongelmans, Marie Louise; Theobald, David E.; Mar, Adam C.; Urcelay, Gonzalo P.; Morein-Zamir, Sharon; Robbins, Trevor W.

2014-01-01

Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an ‘observing’ lever for information about the location of an ‘active’ lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5 mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial. PMID:24406720

Contribution of a mesocorticolimbic subcircuit to drug context-induced reinstatement of cocaine-seeking behavior in rats.

PubMed

Lasseter, Heather C; Xie, Xiaohu; Arguello, Amy A; Wells, Audrey M; Hodges, Matthew A; Fuchs, Rita A

2014-02-01

Cocaine-seeking behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)-basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of cocaine-seeking behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose-dependently attenuated cocaine-seeking behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced cocaine-seeking behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra- and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC-BLA functional interactions. Thus, a VTA-OFC-BLA neural circuit promotes drug context-induced motivated behavior.

Effects of pramipexole on the acquisition of responding with opioid-conditioned reinforcement in the rat

PubMed Central

Bertz, Jeremiah W.; Chen, Jianyong; Woods, James H.

2014-01-01

Rationale Dopamine D3 receptor-preferring ligands may be able to modify the conditioned reinforcing effects of drug-associated stimuli. In evaluating the effects of these compounds, it is important to clarify the extent to which responding depends on (1) conditioned reinforcement vs. other behavioral mechanisms and (2) dopamine D3 vs. D2 receptor activity. Objectives Use behaviorally stringent new-response acquisition procedures to characterize the effects of the D3-preferring agonist, pramipexole, on the conditioned reinforcing effects of a stimulus paired with the opioid agonist, remifentanil. Methods First, in Pavlovian conditioning (PAV) sessions, rats received response-independent IV injections of remifentanil and presentations of a light–noise stimulus. In separate groups, injections and stimuli either always co-occurred (“paired PAV”) or occurred with no consistent relationship (“random PAV” control). Next, in instrumental acquisition (ACQ) sessions, all animals could respond in two nose-poke manipulanda: an active nose-poke, which produced the stimulus alone, or an inactive nose-poke. Pramipexole was injected SC prior to ACQ sessions with or without pretreatments of the D3-preferring antagonist, SB-277011A, or the dopamine D2-preferring antagonist, L-741,626. Results After paired PAV, but not random PAV, rats acquired nose-poke responding during ACQ (i.e., active > inactive). Pramipexole dose-dependently increased active responding without changing inactive responding. Pramipexole-induced increases in responding were blocked by pretreatment with L-741,626, but not SB-277011A. Conclusions Pramipexole specifically enhanced remifentanil-conditioned reinforcement: active responding was selectively increased only after the stimulus was paired with remifentanil. Although pramipexole is D3-preferring, the antagonist effects obtained presently suggest an important role for the D2 receptor in opiod-conditioned reinforcement. PMID:24985891

Putative dopamine agonist (KB220Z) attenuates lucid nightmares in PTSD patients: role of enhanced brain reward functional connectivity and homeostasis redeeming joy.

PubMed

McLaughlin, Thomas; Blum, Kenneth; Oscar-Berman, Marlene; Febo, Marcelo; Agan, Gozde; Fratantonio, James L; Simpatico, Thomas; Gold, Mark S

2015-06-01

Lucid dreams are frequently pleasant and training techniques have been developed to teach dreamers to induce them. In addition, the induction of lucid dreams has also been used as a way to ameliorate nightmares. On the other hand, lucid dreams may be associated with psychiatric conditions, including Post-Traumatic Stress Disorder (PTSD) and Reward Deficiency Syndrome-associated diagnoses. In the latter conditions, lucid dreams can assume an unpleasant and frequently terrifying character. We present two cases of dramatic alleviation of terrifying lucid dreams in patients with PTSD. In the first case study, a 51-year-old, obese woman, diagnosed with PTSD and depression, had attempted suicide and experienced terrifying lucid nightmares linked to sexual/physical abuse from early childhood by family members including her alcoholic father. Her vivid "bad dreams" remained refractory in spite of 6 months of treatment with Dialectical Behavioral Therapy (DBT) and standard pharmaceutical agents which included prazosin, clonidie and Adderall. The second 39-year-old PTSD woman patient had also suffered from lucid nightmares. The medication visit notes reveal changes in the frequency, intensity and nature of these dreams after the complex putative dopamine agonist KB220Z was added to the first patient's regimen. The patient reported her first experience of an extended period of happy dreams. The second PTSD patient, who had suffered from lucid nightmares, was administered KB220Z to attenuate methadone withdrawal symptoms and incidentally reported dreams full of happiness and laughter. These cases are discussed with reference to the known effects of KB220Z including enhanced dopamine homeostasis and functional connectivity of brain reward circuitry in rodents and humans. Their understanding awaits intensive investigation involving large-population, double-blinded studies.

Dorsolateral neostriatum contribution to incentive salience: opioid or dopamine stimulation makes one reward cue more motivationally attractive than another.

PubMed

DiFeliceantonio, Alexandra G; Berridge, Kent C

2016-05-01

Pavlovian cues for rewards can become attractive incentives: approached and 'wanted' as the rewards themselves. The motivational attractiveness of a previously learned cue is not fixed, but can be dynamically amplified during re-encounter by simultaneous activation of brain limbic circuitry. Here it was reported that opioid or dopamine microinjections in the dorsolateral quadrant of the neostriatum (DLS) of rats selectively amplify attraction toward a previously learned Pavlovian cue in an individualized fashion, at the expense of a competing cue. In an autoshaping (sign-tracking vs. goal-tracking) paradigm, microinjection of the mu opioid receptor agonist (DAMGO) or dopamine indirect agonist (amphetamine) in the DLS of sign-tracker individuals selectively enhanced their sign-tracking attraction toward the reward-predictive lever cue. By contrast, DAMGO or amphetamine in the DLS of goal-trackers selectively enhanced prepotent attraction toward the reward-proximal cue of sucrose dish. Amphetamine also enhanced goal-tracking in some sign-tracker individuals (if they ever defected to the dish even once). That DLS enhancement of cue attraction was due to stronger motivation, not stronger habits, was suggested by: (i) sign-trackers flexibly followed their cue to a new location when the lever was suddenly moved after DLS DAMGO microinjection; and (ii) DAMGO in the DLS also made sign-trackers work harder on a new instrumental nose-poke response required to earn presentations of their Pavlovian lever cue (instrumental conditioned reinforcement). Altogether, the current results suggest that DLS circuitry can enhance the incentive salience of a Pavlovian reward cue, selectively making that cue a stronger motivational magnet. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Activation of D1 dopamine receptors induces emergence from isoflurane general anesthesia

PubMed Central

Taylor, Norman E.; Chemali, Jessica J.; Brown, Emery N.; Solt, Ken

2012-01-01

BACKGROUND A recent study showed that methylphenidate induces emergence from isoflurane anesthesia. Methylphenidate inhibits dopamine and norepinephrine reuptake transporters. The objective of this study was to test the hypothesis that selective dopamine receptor activation induces emergence from isoflurane anesthesia. METHODS In adult rats, we tested the effects of chloro-APB (D1 agonist) and quinpirole (D2 agonist) on time to emergence from isoflurane general anesthesia. We then performed a dose–response study to test for chloro-APB-induced restoration of righting during continuous isoflurane anesthesia. SCH-23390 (D1 antagonist) was used to confirm that the effects induced by chloro-APB are specifically mediated by D1 receptors. In a separate group of animals, spectral analysis was performed on surface electroencephalogram recordings to assess neurophysiological changes induced by chloro-APB and quinpirole during isoflurane general anesthesia. RESULTS Chloro-APB decreased median time to emergence from 330s to 50s. The median difference in time to emergence between the saline control group (n=6) and the chloro-APB group (n = 6) was 222s (95% CI: 77–534s, Mann-Whitney test). This difference was statistically significant (p = 0.0082). During continuous isoflurane anesthesia, chloro-APB dose-dependently restored righting (n = 6) and decreased electroencephalogram delta power (n = 4). These effects were inhibited by pretreatment with SCH-23390. Quinpirole did not restore righting (n = 6) and had no significant effect on the electroencephalogram (n = 4) during continuous isoflurane anesthesia. CONCLUSIONS Activation of D1 receptors by chloro-APB decreases time to emergence from isoflurane anesthesia, and produces behavioral and neurophysiological evidence of arousal during continuous isoflurane anesthesia. These findings suggest that selective activation of a D1 receptor-mediated arousal mechanism is sufficient to induce emergence from isoflurane general anesthesia. PMID:23221866

Ethanol and Mesolimbic Serotonin/Dopamine Interactions Via 5-HT1B Receptors

DTIC Science & Technology

2006-03-01

baclofen , a GABAB receptor agonist, into the VTA probe and the response of extracellular DA in the ipsilateral NACC was determined. A significant...decrease (50% deduction) in extracellular DA in the ipsilateral NACC after perfusion with baclofen was considered an appropriate implantation of the...the VTA with baclofen were included in data analyses. Approximately 70% of the animals that had undergone surgery had both probes correctly implanted

Central and Peripheral Mechanisms of Antipsychotic Medication-Induced Metabolic Dysregulation

DTIC Science & Technology

2016-10-01

generation APD haloperidol or second-generation APD olanzapine (via i.p. administration). We will also measure serum fasting glucose and insulin levels...food consumption in beta cell-specific D2R (and wildtype littermate controls) treated with either with first- generation APD haloperidol or second...effects of D2R agonists (dopamine, quinpirole) versus APD antagonists ( haloperidol and olanzapine). § We will treat pancreatic islets from wildtype

PCBs Alter Dopamine Mediated Function in Aging Workers

DTIC Science & Technology

2011-01-01

inhibitors, COX-2 inhibi- tors, other non - steroidal anti - inflammatory agents, opiate agonists, miscellaneous analgesics and antipyretics, thyroid...DA) similar to changes previously seen in PCB exposed adult non -human primates. To test that hypothesis we used [123I]β-CIT SPECT imaging to...adult non -human primates (Seegal et al., 1994a), also occur in occupationally exposed humans. In this study, we used in vivo molecular imaging of the

Concomitant development of hypersexuality and delusional jealousy in patients with Parkinson's disease: a case series.

PubMed

Poletti, Michele; Lucetti, Claudio; Baldacci, Filippo; Del Dotto, Paolo; Bonuccelli, Ubaldo

2014-11-01

Both impulse-control disorders and delusional jealousy (DJ) may be considered non-motor side-effects of dopamine agonist therapy in Parkinson's disease (PD). We aimed to investigate the possible concomitant development of these features in PD and their clinical correlates. We performed a cross-sectional investigation in 1063 consecutive PD patients with the Questionnaire for Impulsive Compulsive Disorders in Parkinson's disease and the Parkinson's Psychosis Questionnaire. 81 patients presented ICDs (prevalence 7.61%) and 23 patients presented DJ (17 males, 6 females; prevalence 2.16%). 9 male PD patients presented both DJ and ICDs (39.13% of patients with DJ, 11.11% of patients with ICDs; prevalence of 0.84% in the whole PD sample), with a concomitant onset of delusional jealousy and hypersexuality in 8 cases and a concomitant onset of delusional jealousy and pathological gambling in 2 cases. Hypersexuality and delusional jealousy may occur independently in PD patients "on" dopamine agonist therapy, but may develop together probably reflecting a common alteration of sexuality (sexual arousal and jealousy) The presence of both of these clinical features and sexuality more in general should be investigated when features of either one of them appear. Further confirmation is needed in larger samples of patients. Copyright © 2014. Published by Elsevier Ltd.

Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans

PubMed Central

Newton, Thomas F.; Haile, Colin N.; Mahoney, James J.; Shah, Ravi; Verrico, Christopher D.; De La Garza, Richard; Kosten, Thomas R.

2015-01-01

Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine’s reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0 mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40 mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine. PMID:26239766

Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans.

PubMed

Newton, Thomas F; Haile, Colin N; Mahoney, James J; Shah, Ravi; Verrico, Christopher D; De La Garza, Richard; Kosten, Thomas R

2015-11-30

Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine's reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine. Published by Elsevier Ireland Ltd.

Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo

PubMed Central

Kaushal, Nidhi; Seminerio, Michael J.; Robson, Matthew J.; McCurdy, Christopher R.; Matsumoto, Rae R.

2013-01-01

Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it acts in part as an agonist. SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity. PMID:22921523

Brexpiprazole: A Partial Dopamine Agonist for the Treatment of Schizophrenia.

PubMed

Ekinci, Asli; Ekinci, Okan

2018-01-31

Schizophrenia is a chronic and debilitating mental disorder that affects the patient's and their family's life. The disease remains a complicated disorder that is challenging to treat, despite there being a large antipsychotic armamentarium. Brexpiprazole acts both as a partial agonist at the serotonin 5-HT1A and dopamine D2 receptors and as an antagonist at the serotonin 5- HT2A and noradrenaline alpha1B and alpha2C receptors, all with similar potency. This balanced receptor profile may produce promising antipsychotic effects on positive, negative and cognitive symptoms in schizophrenia with minimal adverse effects. This review summarizes the pharmacodynamics and pharmacokinetic profile of brexpiprazole and the clinical trial information pertaining to its effectiveness and safety and tolerability, discusses its best clinical use, and compares its clinical profile to those of other widely used antipsychotic agents. Brexpiprazole demonstrated significant clinical efficacy and had good safety and tolerability in well-designed trials with patients with schizophrenia. This agent may be a useful treatment alternative. However, it will be valuable to consider a long-term observational study that includes an active comparator, especially other second-generation antipsychotics (SGAs), to further evaluate the efficacy and safety of brexpiprazole in the treatment of schizophrenia. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo.

PubMed

Kaushal, Nidhi; Seminerio, Michael J; Robson, Matthew J; McCurdy, Christopher R; Matsumoto, Rae R

2013-08-01

Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it "acts in part as an agonist." SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

Relationship between inhibition of cyclic AMP production in Chinese hamster ovary cells expressing the rat D2(444) receptor and antagonist/agonist binding ratios.

PubMed Central

Harley, E. A.; Middlemiss, D. N.; Ragan, C. I.

1995-01-01

1. Radioligand binding assays using [3H]-(-)-sulpiride, in the presence of 1 mM ethylenediaminetetraacetic acid (EDTA) and 100 microM guanylylimidodiphosphate (GppNHp) and [3H]-N0437 were developed to label the low and high agonist affinity states of the rD2(444) receptor (long form of the rat D2 receptor) respectively. The ratios of the affinities of compounds in these two assays (Kapp [3H]-(-)-supiride/Kapp [3H]-N-0437) were then calculated. 2. The prediction that the binding ratio reflected the functional efficacy of a compound was supported by measurement of the ability of a number of compounds acting at dopamine receptors to inhibit rD2(444)-mediated inhibition of cyclic AMP production. When the rank order of the ratios of a number of these compounds was compared to their ability to inhibit the production of cyclic AMP, a significant correlation was seen (Spearman rank correlation coefficient = 0.943, P = 0.01). 3. In conclusion, the sulpiride/N-0437 binding ratio reliably predicted the efficacy of compounds acting at dopamine receptors to inhibit cyclic AMP production mediated by the rD2(444) receptor. PMID:7582561

Clinical pharmacology and efficacy of rotigotine (Neupro® patch) in the treatment of restless leg syndrome.

PubMed

Ferini-Strambi, Luigi; Marelli, Sara; Galbiati, Andrea

2016-08-01

Restless legs syndrome/Willis Ekbom disease (RLS/WED) is a sensorimotor disorder characterized by unpleasant sensations in the legs accompanied by an urge to move them, that typically occurs and tend to worsen in the evening/night or during period of inactivity. Standard medications for RLS/WED are dopamine agonists and calcium channel α-2-δ ligands. The clinical spectrum of RLS/WED is very broad, ranging from individuals suffering from the disease during limited periods up to those severely affected, with daily symptoms. In such cases a long-acting drug like rotigotine should be considered. The clinical pharmacology and efficacy of rotigotine was examined to evaluate the evidence supporting its use in RLS/WED. The rotigotine transdermal patch provides constant delivery of the drug, maintaining a stable plasma concentration over 24 hours by means of a single daily application. Several randomized, double-blind, placebo-controlled trials have demonstrated the efficacy of rotigotine in improving moderate-to-severe RLS/WED symptoms. Rotigotine is generally well tolerated. The most common adverse effects were application-site reactions, dose-dependent, more frequently reported in the first period of treatment. Incidence of augmentation in RLS/WED patients treated with oral dopamine agonists is higher when compared with the use of transdermal rotigotine.

Effects of cabergoline and rotigotine on tacrine-induced tremulous jaw movements in rats.

PubMed

Koganemaru, Go; Abe, Hiroshi; Kuramashi, Aki; Ebihara, Kosuke; Matsuo, Hisae; Funahashi, Hideki; Yasuda, Kazuya; Ikeda, Tetsuya; Nishimori, Toshikazu; Ishida, Yasushi

2014-11-01

We examined the effects of two dopamine agonists, cabergoline and rotigotine, on tacrine-induced tremor and c-Fos expression in rats. Rats received intraperitoneal injection of cabergoline (0.5, 1.0, or 5.0mg/kg), rotigotine (1.0, 2.5, or 10.0mg/kg), or vehicle 30min before intraperitoneal injection of tacrine (5.0mg/kg). The number of tremulous jaw movements (TJMs) after tacrine administration was counted for 5min. Animals were sacrificed 2h later under deep anesthesia, and the brain sections were immunostained in order to evaluate the c-Fos expression. Induction of TJMs by tacrine was dose-dependently reduced by pretreatment with cabergoline and rotigotine. The number of c-Fos-positive cells was significantly enhanced in the medial striatum, nucleus accumbens core, and nucleus accumbens shell after tacrine administration, and the enhanced expression of c-Fos in these three regions was significantly attenuated by cabergoline, while rotigotine suppressed c-Fos expression in two regions except the nucleus accumbens core. These results suggest that tacrine-induced TJMs would be relieved by either cabergoline or rotigotine and that anticholinesterase-induced TJMs and the ameliorating effects of dopamine agonists would relate to neuronal activation in the striatum and nucleus accumbens. Copyright © 2014 Elsevier Inc. All rights reserved.

Pharmacotherapeutics for substance-use disorders: a focus on dopaminergic medications

PubMed Central

Verrico, Christopher D; Haile, Colin N; Newton, Thomas F; Kosten, Thomas R; De La Garza, Richard

2015-01-01

Introduction Illicit substance-use is a substantial public health concern, contributing over $150 billion in costs annually to Americans. A complex disease, a substance-use disorder affects neural circuits involved in reinforcement, motivation, learning and memory, and inhibitory control. Areas covered The modulatory influence of dopamine in mesocorticolimbic circuits contributes to encoding the primary reinforcing effects of substances and numerous studies suggest that aberrant signaling within these circuits contributes to the development of a substance-use disorder in some individuals. Decades of research focused on the clinical development of medications that directly target dopamine receptors has led to recent studies of agonist-like dopaminergic treatments for stimulant-use disorders and, more recently, cannabis-use disorder. Human studies evaluating the efficacy of dopaminergic agonist-like medications to reduce reinforcing effects and substance-use provide some insight into the design of future pharmacotherapy trials. A search of PubMed using specific brain regions, medications, and/or the terms ‘dopamine’, ‘cognition’, ‘reinforcement’, ‘cocaine’, ‘methamphetamine’, ‘amphetamine’, ‘cannabis’, ‘treatment/pharmacotherapy’, ‘addiction/abuse/dependence’ identified articles relevant to this review. Expert opinion Conceptualization of substance-use disorders and their treatment continues to evolve. Current efforts increasingly focus on a strategy fostering combination pharmacotherapies that target multiple neurotransmitter systems. PMID:24033127

Dynorphin/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction.

PubMed

Karkhanis, Anushree; Holleran, Katherine M; Jones, Sara R

2017-01-01

The dynorphin/kappa opioid receptor (KOR) system is implicated in the "dark side" of addiction, in which stress exacerbates maladaptive responses to drug and alcohol exposure. For example, acute stress and acute ethanol exposure result in an elevation in dynorphin, the KOR endogenous ligand. Activation of KORs results in modulation of several neurotransmitters; however, this chapter will focus on its regulatory effects on dopamine in mesolimbic areas. Specifically, KOR activation has an inhibitory effect on dopamine release, thereby influencing reward processing. Repeated stimulation of KORs, for example, via chronic drug and/or stress exposure, results in increased function of the dynorphin/KOR system. This augmentation in KOR function shifts the homeostatic balance in favor of an overall reduction in dopamine signaling via either by reducing dopamine release or by increasing dopamine transporter function. This chapter examines the effects of chronic ethanol exposure on KOR function and the downstream effects on dopamine transmission. Additionally, the impact of chronic cocaine exposure and its effects on KOR function will be explored. Further, KORs may also be involved in driving excessive consumption of food, contributing to the risk of developing obesity. While some studies have shown that KOR agonists reduce drug intake, other studies have shown that antagonists reduce addiction-like behaviors, demonstrating therapeutic potential. For example, KOR inhibition reduces ethanol intake in dependent animals, motivation to self-administer cocaine in chronic stress-exposed animals, and food consumption in obese animals. This chapter will delve into the mechanisms by which modulation of the dynorphin/KOR system may be therapeutic. © 2017 Elsevier Inc. All rights reserved.

Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim test.

PubMed

Li, Yan; Zhu, Zhuo R; Ou, Bao C; Wang, Ya Q; Tan, Zhou B; Deng, Chang M; Gao, Yi Y; Tang, Ming; So, Ji H; Mu, Yang L; Zhang, Lan Q

2015-02-15

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses. The traditional antidepressants often take several weeks, even months, to obtain clinical effects. However, recent clinical studies have shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects within 2h and are long-lasting. The aim of the present study was to investigate whether dopaminergic system was involved in the rapid antidepressant effects of ketamine. The acute administration of ketamine (20 mg/kg) significantly reduced the immobility time in the forced swim test. MK-801 (0.1 mg/kg), the more selective NMDA antagonist, also exerted rapid antidepressant-like effects. In contrast, fluoxetine (10 mg/kg) did not significantly reduced the immobility time in the forced swim test after 30 min administration. Notably, pretreatment with haloperidol (0.15 mg/kg, a nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1 mg/kg, a selective dopamine D1 receptor antagonist), significantly prevented the effects of ketamine or MK-801. Moreover, the administration of sub-effective dose of ketamine (10 mg/kg) in combination with pramipexole (0.3 mg/kg, a dopamine D2/D3 receptor agonist) exerted antidepressant-like effects compared with each drug alone. In conclusion, our results indicated that the dopamine D2/D3 receptors, but not D1 receptors, are involved in the rapid antidepressant-like effects of ketamine. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of exposure to 56Fe particles on the acquisition of a conditioned place preference in rats

NASA Technical Reports Server (NTRS)

Rabin, B. M.; Shukitt-Hale, B.; Joseph, J. A.; Denissova, N.

2001-01-01

Exposure to low doses of 56Fe particles produces changes in neural function and behavior. The present experiments were designed to examine the effects of irradiation on the acquisition of a dopamine-mediated conditioned place preference (CPP). In the CPP procedure, rats are given an injection of the dopamine agonist amphetamine in one distinctive compartment and a saline injection in a different compartment of a three-compartment apparatus. Control rats develop a preference for the amphetamine-paired compartment. In contrast, rats exposed to 1 Gy of 56Fe particles fail to develop a similar preference. The results of the experiment indicate that exposure to low doses of heavy particles can disrupt the neural mechanisms that mediate the reinforcement of behavior.

Sensitivity to apomorphine-induced yawning and hypothermia in rats eating standard or high-fat chow.

PubMed

Baladi, Michelle G; Thomas, Yvonne M; France, Charles P

2012-07-01

Feeding conditions modify sensitivity to indirect- and direct-acting dopamine receptor agonists as well as the development of sensitization to these drugs. This study examined whether feeding condition affects acute sensitivity to apomorphine-induced yawning or changes in sensitivity that occur over repeated drug administration. Quinpirole-induced yawning was also evaluated to see whether sensitization to apomorphine confers cross-sensitization to quinpirole. Drug-induced yawning was measured in different groups of male Sprague Dawley rats (n = 6/group) eating high (34.3%) fat or standard (5.7% fat) chow. Five weeks of eating high-fat chow rendered otherwise drug-naïve rats more sensitive to apomorphine- (0.01-1.0 mg/kg, i.p.) and quinpirole- (0.0032-0.32 mg/kg, i.p.) induced yawning, compared with rats eating standard chow. In other rats, tested weekly with apomorphine, sensitivity to apomorphine-induced yawning increased (sensitization) similarly in rats with free access to standard or high-fat chow; conditioning to the testing environment appeared to contribute to increased yawning in both groups of rats. Food restriction decreased sensitivity to apomorphine-induced yawning across five weekly tests. Rats with free access to standard or high-fat chow and sensitized to apomorphine were cross-sensitized to quinpirole-induced yawning. The hypothermic effects of apomorphine and quinpirole were not different regardless of drug history or feeding condition. Eating high-fat chow or restricting access to food alters sensitivity to direct-acting dopamine receptor agonists (apomorphine, quinpirole), although the relative contribution of drug history and dietary conditions to sensitivity changes appears to vary among agonists.

Agonist-induced glycogenolysis in rabbit retinal slices and cultures.

PubMed Central

Ghazi, H.; Osborne, N. N.

1989-01-01

1. The effects of different putative retinal transmitters and/or modulators on glycogenolysis in rabbit retinal slices and in retinal Müller cell cultures were examined. 2. Incubation of rabbit retinal slices or primary retinal cultures (either 3-5 day-old or 25-30 day-old) in a buffer solution containing [3H]-glucose resulted in the accumulation of newly synthesized [3H]-glycogen. 3. Noradrenaline (NA), isoprenaline, vasoactive intestinal peptide (VIP), 5-hydroxytryptamine (5-HT) and 8-hydroxy-dipropylaminetetralin (8-OH-DPAT) stimulated the hydrolysis of this newly formed 3H-polymer. The potency order of maximal stimulations was: VIP greater than NA greater than isoprenaline greater than 5-HT greater than 8-OH-DPAT. 4. The putative retinal transmitters, dopamine, gamma-aminobutyric acid (GABA), glycine and taurine and the muscarinic agonist carbachol (CCh) had no effect on [3H]-glycogen content. 5. The glycogenolytic effects of NA/isoprenaline and 5-HT/8-OH-DPAT appear to be mediated by beta-adrenoceptors and 5-HT1 receptors (possibly 5-HT1A), respectively while the VIP-induced response involved another receptor subtype. 6. Agonists which mediated [3H]-glycogen hydrolysis also stimulated an increase in adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation. Both responses are blocked to a similar extent by the same antagonists and so are probably mediated via the same receptor subtypes. Moreover, dibutyryl cyclic AMP (db cyclic AMP) promoted tritiated glycogen breakdown in the three retinal preparations. 7. Not all receptors linked to cyclic AMP production however promote glycogenolysis. Dopamine and apomorphine stimulated cyclic AMP formation via D1-receptors without influencing glycogenolysis. These receptors are exclusively associated with neurones. PMID:2568145

Differential Modulation of Beta-Adrenergic Receptor Signaling by Trace Amine-Associated Receptor 1 Agonists

PubMed Central

Nürnberg, Daniela; Grüters, Annette; Führer-Sakel, Dagmar; Krude, Heiko; Köhrle, Josef; Schöneberg, Torsten; Biebermann, Heike

2011-01-01

Trace amine-associated receptors (TAAR) are rhodopsin-like G-protein-coupled receptors (GPCR). TAAR are involved in modulation of neuronal, cardiac and vascular functions and they are potentially linked with neurological disorders like schizophrenia and Parkinson's disease. Subtype TAAR1, the best characterized TAAR so far, is promiscuous for a wide set of ligands and is activated by trace amines tyramine (TYR), phenylethylamine (PEA), octopamine (OA), but also by thyronamines, dopamine, and psycho-active drugs. Unfortunately, effects of trace amines on signaling of the two homologous β-adrenergic receptors 1 (ADRB1) and 2 (ADRB2) have not been clarified yet in detail. We, therefore, tested TAAR1 agonists TYR, PEA and OA regarding their effects on ADRB1/2 signaling by co-stimulation studies. Surprisingly, trace amines TYR and PEA are partial allosteric antagonists at ADRB1/2, whereas OA is a partial orthosteric ADRB2-antagonist and ADRB1-agonist. To specify molecular reasons for TAAR1 ligand promiscuity and for observed differences in signaling effects on particular aminergic receptors we compared TAAR, tyramine (TAR) octopamine (OAR), ADRB1/2 and dopamine receptors at the structural level. We found especially for TAAR1 that the remarkable ligand promiscuity is likely based on high amino acid similarity in the ligand-binding region compared with further aminergic receptors. On the other hand few TAAR specific properties in the ligand-binding site might determine differences in ligand-induced effects compared to ADRB1/2. Taken together, this study points to molecular details of TAAR1-ligand promiscuity and identified specific trace amines as allosteric or orthosteric ligands of particular β-adrenergic receptor subtypes. PMID:22073124

Role of ventral pallidal D2 dopamine receptors in the consolidation of spatial memory.

PubMed

Péczely, László; Ollmann, Tamás; László, Kristóf; Kovács, Anita; Gálosi, Rita; Kertes, Erika; Zagorácz, Olga; Kállai, Veronika; Karádi, Zoltán; Lénárd, László

2016-10-15

The role of dopamine (DA) receptors in spatial memory consolidation has been demonstrated in numerous brain regions, among others in the nucleus accumbens which innervates the ventral pallidum (VP). The VP contains both D1 and D2 DA receptors. We have recently shown that the VP D1 DA receptor activation facilitates consolidation of spatial memory in Morris water maze test. In the present study, the role of VP D2 DA receptors was investigated in the same paradigm. In the first experiment, the D2 DA receptor agonist quinpirole was administered into the VP of male Wistar rats in three doses (0.1, 1.0 or 5.0μg, respectively in 0.4μl physiological saline). In the second experiment, the D2 DA receptor antagonist sulpiride was applied to elucidate whether it can antagonise the effects of quinpirole. The antagonist (4.0μg, dissolved in 0.4μl physiological saline) was microinjected into the VP either by itself or prior to 1.0μg agonist treatment. Control animals received saline in both experiments. The two higher doses (1.0 and 5.0μg) of the agonist accelerated memory consolidation relative to controls and increased the stability of the consolidated memory against extinction. Sulpiride pretreatment antagonised the effects of quinpirole. In addition, the antagonist microinjected into the VP immediately after the second conditioning trial impaired learning functions. The present data provide evidences for the important role of VP D2 DA receptors in the consolidation and stabilization of spatial memory. Copyright © 2016 Elsevier B.V. All rights reserved.

A fighter's comeback: dopamine is necessary for recovery of aggression after social defeat in crickets.

PubMed

Rillich, Jan; Stevenson, Paul A

2014-09-01

Social defeat, i.e. losing an agonistic dispute with a conspecific, is followed by a period of suppressed aggressiveness in many animal species, and is generally regarded as a major stressor, which may play a role in psychiatric disorders such as depression and post-traumatic stress disorder. Despite numerous animal models, the mechanisms underlying loser depression and subsequent recovery are largely unknown. This study on crickets is the first to show that a neuromodulator, dopamine (DA), is necessary for recovery of aggression after social defeat. Crickets avoid any conspecific male just after defeat, but regain their aggressiveness over 3 h. This recovery was prohibited after depleting nervous stores of DA and octopamine (OA, the invertebrate analogue of noradrenaline) with α-methyl-tyrosine (AMT). Loser recovery was also prohibited by the insect DA-receptor (DAR) antagonist fluphenazine, but not the OA-receptor (OAR) blocker epinastine, or yohimbine, which blocks receptors for OA's precursor tyramine. Conversely, aggression was restored prematurely in both untreated and amine depleted losers given either chlordimeform (CDM), a tissue permeable OAR-agonist, or the DA-metabolite homovanillyl alcohol (HVA), a component of the honeybee queen mandibular pheromone. As in honeybees, HVA acts in crickets as a DAR-agonist since its aggression promoting effect on losers was selectively blocked by the DAR-antagonist, but not by the OAR-antagonist. Conversely, CDM's aggression promoting effect was selectively blocked by the OAR-antagonist, but not the DAR-antagonist. Hence, only DA is necessary for recovery of aggressiveness after social defeat, although OA can promote loser aggression independently to enable experience dependent adaptive responses. Copyright © 2014 Elsevier Inc. All rights reserved.

Dopamine D1 receptor agonist treatment attenuates extinction of morphine conditioned place preference while increasing dendritic complexity in the nucleus accumbens core.

PubMed

Kobrin, Kendra L; Arena, Danielle T; Heinrichs, Stephen C; Nguyen, Olivia H; Kaplan, Gary B

2017-03-30

The dopamine D1 receptor (D1R) has a role in opioid reward and conditioned place preference (CPP), but its role in CPP extinction is undetermined. We examined the effect of D1R agonist SKF81297 on the extinction of opioid CPP and associated dendritic morphology in the nucleus accumbens (NAc), a region involved with reward integration and its extinction. During the acquisition of morphine CPP, mice received morphine and saline on alternate days; injections were given immediately before each of eight daily conditioning sessions. Mice subsequently underwent six days of extinction training designed to diminish the previously learned association. Mice were treated with either 0.5mg/kg SKF81297, 0.8mg/kg SKF81297, or saline immediately after each extinction session. There was a dose-dependent effect, with the highest dose of SKF81297 attenuating extinction, as mice treated with this dose had significantly higher CPP scores than controls. Analysis of medium spiny neuron morphology revealed that in the NAc core, but not in the shell, dendritic arbors were significantly more complex in the morphine conditioned, SKF81297-treated mice compared to controls. In separate experiments using mice conditioned with only saline, SKF81297 administration after extinction sessions had no effect on CPP and produced differing effects on dendritic morphology. At the doses used in our experiments, SKF81297 appears to maintain previously learned opioid conditioned behavior, even in the face of new information. The D1R agonist's differential, rather than unidirectional, effects on dendritic morphology in the NAc core suggests that it may be involved in encoding reward information depending on previously learned behavior. Published by Elsevier B.V.

Drinking sucrose enhances quinpirole-induced yawning in rats

PubMed Central

Baladi, Michelle G; Newman, Amy H; Thomas, Yvonne M; France, Charles P

2011-01-01

Food and drugs can activate brain dopamine systems and sensitivity to the effects of drugs acting on those systems is influenced by amount and content of food consumed. This study examined the effects of drinking sucrose on behavioral effects of the directly-acting dopamine receptor agonist quinpirole. Male Sprague-Dawley rats (n=6/group) had free access to water or 10% sucrose and quinpirole dose-response curves (yawning and hypothermia) were generated weekly for 8 weeks. Subsequently, all rats drank water for 8 weeks with quinpirole dose-response curves determined on weeks 9, 10, and 16. In rats drinking sucrose, the ascending (D3 receptor-mediated), but not descending (D2 receptor-mediated), limb of the yawning dose-response curve shifted leftward. The D3 receptor-selective antagonist PG01037 shifted the ascending limb of the dose-response curve to the right in all rats. When rats that previously drank sucrose drank water, their sensitivity to quinpirole did not return to normal. Quinpirole-induced hypothermia was not different between groups. These data show that drinking sucrose increases sensitivity to a dopamine D3, but not D2, receptor-mediated effect and that this change is long lasting. Dopamine receptors mediate the effects of many drugs and the actions of those drugs are likely impacted by dietary factors. PMID:21979833

Drinking sucrose enhances quinpirole-induced yawning in rats.

PubMed

Baladi, Michelle G; Newman, Amy H; Thomas, Yvonne M; France, Charles P

2011-12-01

Food and drugs can activate brain dopamine systems and sensitivity to the effects of drugs acting on those systems is influenced by amount and content of food consumed. This study examined the effects of drinking sucrose on behavioral effects of the direct-acting dopamine receptor agonist quinpirole. Male Sprague-Dawley rats (n=6/group) had free access to water or 10% sucrose and quinpirole dose-response curves (yawning and hypothermia) were generated weekly for 8 weeks. Subsequently, all rats drank water for 8 weeks with quinpirole dose-response curves determined on weeks 9, 10, and 16. In rats drinking sucrose, the ascending (D3 receptor-mediated), but not descending (D2 receptor-mediated), limb of the yawning dose-response curve shifted leftward. The D3 receptor-selective antagonist PG01037 shifted the ascending limb of the dose-response curve to the right in all rats. When rats that previously drank sucrose drank water, their sensitivity to quinpirole did not return to normal. Quinpirole-induced hypothermia was not different between groups. These data show that drinking sucrose increases sensitivity to a dopamine D3, but not D2, receptor-mediated effect and that this change is long lasting. Dopamine receptors mediate the effects of many drugs and the actions of those drugs are likely impacted by dietary factors.

Dopamine D1 receptor stimulation modulates the formation and retrieval of novel object recognition memory: Role of the prelimbic cortex

PubMed Central

Pezze, Marie A.; Marshall, Hayley J.; Fone, Kevin C.F.; Cassaday, Helen J.

2015-01-01

Previous studies have shown that dopamine D1 receptor antagonists impair novel object recognition memory but the effects of dopamine D1 receptor stimulation remain to be determined. This study investigated the effects of the selective dopamine D1 receptor agonist SKF81297 on acquisition and retrieval in the novel object recognition task in male Wistar rats. SKF81297 (0.4 and 0.8 mg/kg s.c.) given 15 min before the sampling phase impaired novel object recognition evaluated 10 min or 24 h later. The same treatments also reduced novel object recognition memory tested 24 h after the sampling phase and when given 15 min before the choice session. These data indicate that D1 receptor stimulation modulates both the encoding and retrieval of object recognition memory. Microinfusion of SKF81297 (0.025 or 0.05 μg/side) into the prelimbic sub-region of the medial prefrontal cortex (mPFC) in this case 10 min before the sampling phase also impaired novel object recognition memory, suggesting that the mPFC is one important site mediating the effects of D1 receptor stimulation on visual recognition memory. PMID:26277743

Dopaminergic modulation of semantic priming in healthy volunteers.

PubMed

Roesch-Ely, Daniela; Weiland, Stephan; Scheffel, Hans; Schwaninger, Markus; Hundemer, Hans-Peter; Kolter, Thomas; Weisbrod, Matthias

2006-09-15

Semantic priming is a function related to prefrontal cortical (PFC) networks and is lateralized. There is evidence that semantic priming underlies dopaminergic modulation. It is known that the D1-receptor is more abundant in prefrontal networks; however, until now there have been no studies investigating the selective modulation of semantic priming with dopamine agonists. Furthermore, D1 receptor dysfunction has been described in schizophrenia, and patients with formal thought disorder seem to have disturbed focusing of associations and increased indirect priming. With a subtraction design, we compared the influence of pergolide (D1/D2 agonist) with bromocriptine (D2 agonist) and placebo, in a randomized, double-blind, crossover design in 40 healthy male volunteers. Subjects performed a lateralized lexical decision task including direct and indirect related prime-target pairs (stimulus onset asynchrony = 750 msec). Only on pergolide a decrease of the indirect priming in the left hemisphere presentations was found. These findings point to a potential selective modulation of agonists with a D1 component on the focusing of semantic associations. The clinical relevance of this study is that it might help the development of therapeutic strategies for treating cognitive deficits in schizophrenia and Parkinson's disease, which are highly relevant to the functional outcome.

Amphetamine-enhanced accumulation of ( sup 3 H)-spiperone in mouse corpus striatum in vivo: Modification by other drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dorris, R.L.

1989-01-01

Other investigators have reported that amphetamine administered to rodents results in an increase in the in vivo accumulation of either the tritiated dopamine receptor ligand, spiperone or pimozide in the dopaminergic corpus striatum, (specific binding) while not altering that in the sparsely dopaminergically innervated cerebellum (non-specific binding). Experiments were undertaken to determine if the results could be replicated and if some other drugs would modify the effect. Male mice were injected with ({sup 3}H)-spiperone (20 {mu}Ci/Kg, 0.0003 mg/kg) s.c. and killed 2 hrs later for determination of radioactivity in corpus striatum and cerebellum. Amphetamine (20 mg/kg, i.p.) given 15 minmore » before ({sup 3}H)-spiperone, increased accumulation in striatum but not cerebellum. The increase was inhibited by {alpha} - methyltyrosine ({alpha}-MT), haloperidol, reserpine or amantadine. It is suggested that the amphetamine-induced increase in accumulation of ({sup 3}H)-spiperone in corpus striatum (specific binding) depends on release of large amounts of dopamine, which then must be able to interact with the dopamine receptor. The antagonism of the effect by {alpha}-MT or reserpine can be explained by dopamine depletion, that of haloperidol by antagonism for binding at the receptor site. It is suggested that amantadine acts by a dual mechanism: (1) as a low efficacy agonist, it competes for binding to the receptor and (2) it has some ability to block dopamine release.« less

The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model.

PubMed

Homberg, Judith R; Olivier, Jocelien D A; VandenBroeke, Marie; Youn, Jiun; Ellenbroek, Arabella K; Karel, Peter; Shan, Ling; van Boxtel, Ruben; Ooms, Sharon; Balemans, Monique; Langedijk, Jacqueline; Muller, Mareike; Vriend, Gert; Cools, Alexander R; Cuppen, Edwin; Ellenbroek, Bart A

2016-10-01

Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1 receptor (Drd1). Because current Drd1 receptor agonists are not Drd1 selective, pharmacological tools are not sufficient to delineate the role of the Drd1. Here, we describe a novel rat model with a genetic mutation in Drd1 in which we measured basic behavioural phenotypes and social cognition. The I116S mutation was predicted to render the receptor less stable. In line with this computational prediction, this Drd1 mutation led to a decreased transmembrane insertion of Drd1, whereas Drd1 expression, as measured by Drd1 mRNA levels, remained unaffected. Owing to decreased transmembrane Drd1 insertion, the mutant rats displayed normal basic motoric and neurological parameters, as well as locomotor activity and anxiety-like behaviour. However, measures of social cognition like social interaction, scent marking, pup ultrasonic vocalizations and sociability, were strongly reduced in the mutant rats. This profile of the Drd1 mutant rat offers the field of neuroscience a novel genetic rat model to study a series of psychiatric disorders including schizophrenia, autism, depression, bipolar disorder and drug addiction. © 2016. Published by The Company of Biologists Ltd.

Reduced dopaminergic tone in hypothalamic neural circuits: expression of a "thrifty" genotype underlying the metabolic syndrome?

PubMed

Pijl, Hanno

2003-11-07

The thrifty genotype hypothesis postulates that the genetically determined ability to grow obese and insulin resistant in times of food abundance confers a survival advantage in times of famine. Obviously, this ability poses a major health threat in modern times, where food is always available in large quantities. In the last 10-15 years, many genes encoding pathways that orchestrate energy balance and fuel flux have been discovered. This paper summarizes the evidence that diminished dopaminergic tone in hypothalamic nuclei contributes to the "thrifty" genotype/phenotype. Reduced dopaminergic neurotransmission in the suprachiasmatic nucleus of seasonally obese animals appears to drive noradrenalin and NPY mediated transmissions in other nuclei to induce the obesity syndrome at the appropriate time of year. Treatment with dopamine D(2) receptor agonists can fully reverse the metabolic syndrome in these animals. Similar mechanisms are operative in non-seasonal obese animal models. In man, treatment with dopamine D(2) receptor antagonists induces obesity and type 2 diabetes mellitus, whereas dopamine D(2) receptor activation ameliorates the metabolic profile in obese nondiabetic and diabetic humans. Various loss of function mutations of the dopamine D(2) receptor gene are associated with overweight in humans. In concert, the data support the notion that diminution of dopaminergic (dopamine D(2) receptor mediated) transmission in relevant hypothalamic nuclei sets the stage for efficient partitioning of ingested nutrients to contribute to a phenotype that is not so thrifty anymore.

Understanding the Role of Serotonin in Female Hypoactive Sexual Desire Disorder and Treatment Options.

PubMed

Croft, Harry A

2017-12-01

The neurobiology of sexual response is driven in part by dopamine and serotonin-the former modulating excitatory pathways and the latter regulating inhibitory pathways. Neurobiological underpinnings of hypoactive sexual desire disorder (HSDD) are seemingly related to overactive serotonin activity that results in underactive dopamine activity. As such, pharmacologic agents that decrease serotonin, increase dopamine, or some combination thereof, have therapeutic potential for HSDD. To review the role of serotonin in female sexual function and the effects of pharmacologic interventions that target the serotonin system in the treatment of HSDD. Searches of the Medline database for articles on serotonin and female sexual function. Relevant articles from the peer-reviewed literature were included. Female sexual response is regulated not only by the sex hormones but also by several neurotransmitters. It is postulated that dopamine, norepinephrine, oxytocin, and melanocortins serve as key neuromodulators for the excitatory pathways, whereas serotonin, opioids, and endocannabinoids serve as key neuromodulators for the inhibitory pathways. Serotonin appears to be a key inhibitory modulator of sexual desire, because it decreases the ability of excitatory systems to be activated by sexual cues. Centrally acting drugs that modulate the excitatory and inhibitory pathways involved in sexual desire (eg, bremelanotide, bupropion, buspirone, flibanserin) have been investigated as treatment options for HSDD. However, only flibanserin, a multifunctional serotonin agonist and antagonist (5-hydroxytryptamine [5-HT] 1A receptor agonist and 5-HT 2A receptor antagonist), is currently approved for the treatment of HSDD. The central serotonin system is 1 biochemical target for medications intended to treat HSDD. This narrative review integrates findings from preclinical studies and clinical trials to elucidate neurobiological underpinnings of HSDD but is limited to 1 neurotransmitter system (serotonin). Serotonin overactivity is a putative cause of sexual dysfunction in patients with HSDD. The unique pharmacologic profile of flibanserin tones down inhibitory serotonergic function and restores dopaminergic and noradrenergic function. Croft HA. Understanding the Role of Serotonin in Female Hypoactive Sexual Desire Disorder and Treatment Options. J Sex Med 2017;14:1575-1584. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Duodenal bicarbonate secretion and mucosal protection. Neurohumoral influence and transport mechanisms.

PubMed

Säfsten, B

1993-01-01

Duodenal mucosal bicarbonate secretion (DMBS) plays an important role in the defence against acid discharged from the stomach. The secretion by duodenum immediately distal to the Brunner's glands area and devoid of pancreatic and biliary secretions, was investigated in vivo in anaesthetized Sprague-Dawley rats and in vitro in mucosae isolated from the American bullfrog. Transport mechanisms were studied in isolated rat duodenal enterocytes and identified by use of digitized microfluorometry and the fluoroprobe BCECF. Cyclic AMP production in enterocytes of villus vs. crypt origin was measured with radioimmunoassay. The benzodiazepines diazepam and Ro 15-1788 stimulated DMBS in the rat when administered intravenously or intracerebroventricularly; however, their stimulatory effect was abolished by bilateral proximal vagotomy, and they had no effect on the secretion by isolated bullfrog mucosa. It is concluded that these benzodiazepines stimulate secretion by acting upon the central nervous system and that their effects are vagally mediated. Dopamine, the catechol-O-methyl-transferase-inhibitor nitecapone, and the dopamine D1 agonist SKF-38393 all stimulated DMBS. The peripherally acting antagonist domperidone while having no influence on basal DMBS did prevent the influences of SKF-38393 and nitecapone. The alpha 1-antagonist prazosin had no such effects and the combined results suggest that DMBS is stimulated via peripheral dopamine D1 receptors. Intravenous, but not central nervous, administration of the muscarinic M1 receptor antagonists pirenzepine and telenzepine effectively stimulated DMBS; however their effectiveness was dependent on intact vagal nerves. Phentolamine, an unselective alpha-adrenergic antagonist, prevented the stimulation by pirenzepine and telenzepine and stimulation by carbachol was abolished by hexamethonium. It is concluded that peripheral nicotinergic and muscarinergic M1 receptors mediate stimulation of DMBS, in part by acting upon peripheral sympathetic ganglia. Whereas dopamine and SKF-38393 caused a time-dependent increase in the accumulation of cyclic AMP in duodenal enterocytes of crypt and villous origin, the D2 agonist quinpirole had an inhibitive influence. Crypt and villus cells differed in their respective time-courses in response to vasoactive intestinal polypeptide. Finally, Cl-/HCO3- exchange, Na+/H+ exchange and NaHCO3 cotransport were identified as membrane acid/base transport mechanisms in isolated duodenal enterocytes.

AFRRI Reports, Second Quarter 1992.

DTIC Science & Technology

1992-07-01

onvotoxbhavor The pension task), and oxotremorine -enhanced K+-evoked release and late effects of these particles on motor behavior. The of dopamine from...agonists, such as oxotremorine , can activate the het- tissue chopper, and the slices from each animal were placed into a small mreceptors. which potentiate...as well as the MATERIALS AND METHODS other components described above (pH 7.4). One chamber of the pair for each animal received 500 p0! oxotremorine

Symptom relief in Parkinson disease by safinamide: Biochemical and clinical evidence of efficacy beyond MAO-B inhibition.

PubMed

Stocchi, F; Vacca, L; Grassini, P; De Pandis, M F; Battaglia, G; Cattaneo, C; Fariello, R G

2006-10-10

In an open pilot study, doses of safinamide (100, 150, and 200 mg once a day, higher than previously tested) were administered to 13 parkinsonian patients along with a stable dose of dopamine (DA) agonist, causing a significant progressive improvement in motor performance as evaluated by the Unified Parkinson Disease Rating Scale (UPDRS) part III over an 8-week period (4.2 points; P < 0.001). In association with levodopa, the same doses of safinamide in another group of patients (N = 11) induced a significant decrease in motor fluctuations (UPDRS part IV, 2.1 points; P < 0.001), accompanied by a dose-proportional increase of the levodopa AUC, up to 77% from baseline. Because MAO-B was fully inhibited (95%) at all doses tested, we suggest that these biochemical and symptomatic dose-dependent effects must be related to additional mechanisms of action, such as inhibition of glutamate release, increased dopamine release, or inhibition of dopamine re-uptake. These hypotheses are under investigation and will pursue confirmation in controlled clinical trials.

In vivo evidence of D3 dopamine receptor sensitization in parkinsonian primates and rodents with L-DOPA-induced dyskinesias

PubMed Central

Sánchez-Pernaute, Rosario; Jenkins, Bruce G.; Choi, Ji-Kyung; Chen, Yin-Ching Iris; Isacson, Ole

2008-01-01

A growing body of evidence indicates a role for D3 receptors in L-DOPA-induced dyskinesias. This involvement could be amenable to non-invasive in vivo analysis using functional neuroimaging. With this goal, we examined the hemodynamic response to the dopamine D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2 aminotetralin (7-OHDPAT) in naïve, parkinsonian and L-DOPA-treated, dyskinetic rodents and primates using pharmacological MRI (phMRI) and relative cerebral blood volume (rCBV) mapping. Administration of 7-OHDPAT induced minor negative changes of rCBV in the basal ganglia in naïve and parkinsonian animals. Remarkably, the hemodynamic response was reversed (increased rCBV) in the striatum of parkinsonian animals rendered dyskinetic by repeated L-DOPA treatment. Such increase in rCBV is consistent with D1 receptor-like signaling occurring in response to D3 stimulation, demonstrates a dysregulation of dopamine receptor function in dyskinesia and provides a potentially novel means for the characterization and treatment of L-DOPA-induced dyskinesia in patients. PMID:17588764

A well-refined in vitro model derived from human embryonic stem cell for screening phytochemicals with midbrain dopaminergic differentiation-boosting potential for improving Parkinson's disease.

PubMed

Hsieh, Wen-Ting; Chiang, Been-Huang

2014-07-09

Stimulation of endogenous neurogenesis is a potential approach to compensate for loss of dopaminergic neurons of substantia nigra compacta nigra (SNpc) in patients with Parkinson's disease (PD). This objective was to establish an in vitro model by differentiating pluripotent human embryonic stem cells (hESCs) into midbrain dopaminergic (mDA) neurons for screening phytochemicals with mDA neurogenesis-boosting potentials. Consequently, a five-stage differentiation process was developed. The derived cells expressed many mDA markers including tyrosine hydroxylase (TH), β-III tubulin, and dopamine transporter (DAT). The voltage-gated ion channels and dopamine release were also examined for verifying neuron function, and the dopamine receptor agonists bromocriptine and 7-hydroxy-2-(dipropylamino)tetralin (7-OH-DPAT) were used to validate our model. Then, several potential phytochemicals including green tea catechins and ginsenosides were tested using the model. Finally, ginsenoside Rb1 was identified as the most potent phytochemical which is capable of upregulating neurotrophin expression and inducing mDA differentiation.

SEXUAL BEHAVIOR IN MALE RODENTS

PubMed Central

Hull, Elaine M.; Dominguez, Juan M.

2007-01-01

The hormonal factors and neural circuitry that control copulation are similar across rodent species, although there are differences in specific behavior patterns. Both estradiol (E) and dihydrotestosterone (DHT) contribute to the activation of mating, although E is more important for copulation and DHT, for genital reflexes. Hormonal activation of the medial preoptic area (MPOA) is most effective, although implants in the medial amygdala (MeA) can also stimulate mounting in castrates. Chemosensory inputs from the main and accessory olfactory systems are the most important stimuli for mating in rodents, especially in hamsters, although genitosensory input also contributes. Dopamine agonists facilitate sexual behavior, and serotonin (5-HT) is generally inhibitory, though certain 5-HT receptor subtypes facilitate erection or ejaculation. Norepinephrine agonists and opiates have dose-dependent effects, with low doses facilitating and high doses inhibiting behavior. PMID:17499249

High Fat Diet Augments Amphetamine Sensitization in Mice: Role of Feeding Pattern, Obesity, and Dopamine Terminal Changes

PubMed Central

Fordahl, Steve C.; Locke, Jason L.; Jones, Sara R.

2016-01-01

High fat (HF) diet-induced obesity has been shown to augment behavioral responses to psychostimulants that target the dopamine system. The purpose of this study was to characterize dopamine terminal changes induced by a HF diet that correspond with enhanced locomotor sensitization to amphetamine. C57BL/6J mice had limited (2hr 3d/week) or extended (24h 7d/week) access to a HF diet or standard chow for six weeks. Mice were then repeatedly exposed to amphetamine (AMPH), and their locomotor responses to an amphetamine challenge were measured. Fast scan cyclic voltammetry was used to identify changes in dopamine terminal function after AMPH exposure. Exposure to a HF diet reduced dopamine uptake and increased locomotor responses to acute, high-dose AMPH administration compared to chow fed mice. Microdialysis showed elevated extracellular dopamine in the nucleus accumbens (NAc) coincided with enhanced locomotion after acute AMPH in HF-fed mice. All mice exhibited locomotor sensitization to amphetamine, but both extended and limited access to a HF diet augmented this response. Neither HF-fed group showed the robust amphetamine sensitization-induced increases in dopamine release, reuptake, and amphetamine potency observed in chow fed animals. However, the potency of amphetamine as an uptake inhibitor was significantly elevated after sensitization in mice with extended (but not limited) access to HF. Conversely, after amphetamine sensitization, mice with limited (but not extended) access to HF displayed reduced autoreceptor sensitivity to the D2/D3 agonist quinpirole. Additionally, we observed reduced membrane dopamine transporter (DAT) levels after HF, and a shift in DAT localization to the cytosol was detected with limited access to HF. This study showed that different patterns of HF exposure produced distinct dopamine terminal adaptations to repeated AMPH, which differed from chow fed mice, and enhanced sensitization to AMPH. Locomotor sensitization in chow fed mice coincided with elevated DAT function and increased AMPH potency; however, the enhanced behavioral response to AMPH after HF exposure was unique in that it coincided with reduced DAT function and diet pattern-specific adaptations. PMID:27267686

The atypical antipsychotic blonanserin reverses (+)-PD-128907- and ketamine-induced deficit in executive function in common marmosets.

PubMed

Kotani, Manato; Enomoto, Takeshi; Murai, Takeshi; Nakako, Tomokazu; Iwamura, Yoshihiro; Kiyoshi, Akihiko; Matsumoto, Kenji; Matsumoto, Atsushi; Ikejiri, Masaru; Nakayama, Tatsuo; Ogi, Yuji; Ikeda, Kazuhito

2016-05-15

Antagonism of the dopamine D3 receptor is considered a promising strategy for the treatment of cognitive impairment associated with schizophrenia. We have previously reported that the atypical antipsychotic blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptor antagonist, highly occupies dopamine D3 receptors at its antipsychotic dose range in rats. In the present study, we evaluated the effects of blonanserin on executive function in common marmosets using the object retrieval with detour (ORD) task. The dopamine D3 receptor-preferring agonist (+)-PD-128907 at 1mg/kg decreased success rate in the difficult trial, but not in the easy trial. Since the difference between the two trials is only cognitive demand, our findings indicate that excess activation of dopamine D3 receptors impairs executive function in common marmosets. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by (+)-PD-128907 in the difficult trial. This finding indicates that blonanserin has beneficial effect on executive function deficit induced by activation of the dopamine D3 receptor in common marmosets. Next, and based on the glutamatergic hypothesis of schizophrenia, the common marmosets were treated with the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. Ketamine at sub-anesthetic doses decreased success rate in the difficult trial, but not in the easy trial. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by ketamine in the difficult trial. The findings of this study suggest that blonanserin might have beneficial effect on executive dysfunction in patients with schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

Late Reduction of Cocaine Cravings in a Randomized, Double-Blind Trial of Aripiprazole vs Perphenazine in Schizophrenia and Comorbid Cocaine Dependence.

PubMed

Beresford, Thomas; Buchanan, Jennifer; Thumm, Elizabeth Brie; Emrick, Chad; Weitzenkamp, David; Ronan, Patrick J

2017-12-01

Co-occurring schizophrenia spectrum disorder and International Statistical Classification of Diseases, 10th Revision cocaine dependence present a particularly destructive constellation that is often difficult to treat. Both conditions raise dopamine transmission effects in the brain. Traditional neuroleptics block dopamine receptors, whereas aripiprazole modulates dopamine activity as an agonist/antagonist. We tested whether dopamine modulation is superior to dopamine blocking in dual-diagnosis patients. In a randomized, double-blind, comparison design, cocaine-dependent schizophrenic subjects actively using cocaine received either aripiprazole or perphenazine in an 8-week trial. Primary outcome targeted cocaine-free urine sample proportions, whereas cocaine craving scores were a secondary variable. Subjects (N = 44) randomized (n = 22 per group) did not differ at baseline. The proportion of cocaine-free urine samples did not differ by medication group. Contrasting weeks 3 to 5 vs 6 to 8 revealed significant late reductions in craving with aripiprazole. On the respective 5-point subscales, craving intensity decreased by 1.53 ± 0.43 (P < 0.0005) points, craving frequency by 1.4 ± 0.40 (P > 0.0004) points, and craving duration by 1.76 ± 0.44 (P > 0.0001) points. A drug effect of aripiprazole on craving items appeared at week 6 of treatment, on average, and was not seen before that length of drug exposure. The data suggest that dopamine modulation reduces cocaine cravings but requires an acclimation period. To understand the mechanism of action better, a trial of depot aripiprazole may be useful. Clinically, a reduction in craving potentially offers a clearer focus for ongoing behavioral treatment. It may also offer a longer-term treatment effect with respect to the severity of relapse.

Pro-dopamine regulator, KB220Z, attenuates hoarding and shopping behavior in a female, diagnosed with SUD and ADHD.

PubMed

McLaughlin, Thomas; Blum, Kenneth; Steinberg, Bruce; Modestino, Edward J; Fried, Lyle; Baron, David; Siwicki, David; Braverman, Eric R; Badgaiyan, Rajendra D

2018-03-01

Background Addictive-like behaviors (e.g., hoarding and shopping) may be the result of the cumulative effects of dopaminergic and other neurotransmitter genetic variants as well as elevated stress levels. We, therefore, propose that dopamine homeostasis may be the preferred goal in combating such challenging and unwanted behaviors, when simple dopaminergic activation through potent agonists may not provide any resolution. Case presentation C.J. is a 38-year-old, single, female, living with her mother. She has a history of substance use disorder as well as attention deficit hyperactivity disorder, inattentive type. She had been stable on buprenorphine/naloxone combination and amphetamine, dextroamphetamine mixed salts for many years when unexpectedly she lost her job for oversleeping and not calling into work. KB200z (a pro-dopamine compound) was added to her regimen for complaints of low drive and motivation. After taking this nutraceutical for 4 weeks, she noticed a marked improvement in her mental status and many behaviors. She noted that her shopping and hoarding addictions had appreciably decreased. Furthermore, her lifelong history of terrifying lucid dreams was eliminated. Finally, she felt more in control; her locus of control shifted from external to more internal. Discussion The hypothesis is that C.J.'s reported, behavioral, and psychological benefits resulted from the pro-dopamine-regulating effect of KB220Z across the brain reward system. Conclusions This effect, we surmise, could be the result of a new dopamine balance, across C.J.'s brain reward system. Dopamine homeostasis is an effect of KB220Z seen in both animal and human placebo-controlled fMRI experiments.

The effects of benzofury (5-APB) on the dopamine transporter and 5-HT2-dependent vasoconstriction in the rat.

PubMed

Dawson, Patrick; Opacka-Juffry, Jolanta; Moffatt, James D; Daniju, Yusuf; Dutta, Neelakshi; Ramsey, John; Davidson, Colin

2014-01-03

5-APB, commonly marketed as 'benzofury' is a new psychoactive substance and erstwhile 'legal high' which has been implicated in 10 recent drug-related deaths in the UK. This drug was available on the internet and in 'head shops' and was one of the most commonly sold legal highs up until its recent UK temporary ban (UK Home Office). Despite its prominence, very little is known about its pharmacology. This study was undertaken to examine the pharmacology of 5-APB in vitro. We hypothesised that 5-APB would activate the dopamine and 5-HT systems which may underlie its putative stimulant and hallucinogenic effects. Autoradiographic studies showed that 5-APB displaced both [(125)I] RTI-121 and [(3)H] ketanserin from rat brain tissue suggesting affinity at the dopamine transporter and 5-HT2 receptor sites respectively. Voltammetric studies in rat accumbens brain slices revealed that 5-APB slowed dopamine reuptake, and at high concentrations caused reverse transport of dopamine. 5-APB also caused vasoconstriction of rat aorta, an effect antagonised by the 5-HT2A receptor antagonist ketanserin, and caused contraction of rat stomach fundus, which was reversed by the 5-HT2B receptor antagonist RS-127445. These data show that 5-APB interacts with the dopamine transporter and is an agonist at the 5-HT2A and 5-HT2B receptors in the rat. Thus 5-APB's pharmacology is consistent with it having both stimulant and hallucinogenic properties. In addition, 5-APB's activity at the 5-HT2B receptor may cause cardiotoxicity. © 2013.

Glycyrrhetinic acid and E.resveratroloside act as potential plant derived compounds against dopamine receptor D3 for Parkinson’s disease: a pharmacoinformatics study

PubMed Central

Mirza, Muhammad Usman; Mirza, A Hammad; Ghori, Noor-Ul-Huda; Ferdous, Saba

2015-01-01

Parkinson’s disease (PD) is caused by loss in nigrostriatal dopaminergic neurons and is ranked as the second most common neurodegenerative disorder. Dopamine receptor D3 is considered as a potential target in drug development against PD because of its lesser side effects and higher degree of neuro-protection. One of the prominent therapies currently available for PD is the use of dopamine agonists which mimic the natural action of dopamine in the brain and stimulate dopamine receptors directly. Unfortunately, use of these pharmacological therapies such as bromocriptine, apomorphine, and ropinirole provides only temporary relief of the disease symptoms and is frequently linked with insomnia, anxiety, depression, and agitation. Thus, there is a need for an alternative treatment that not only hinders neurodegeneration, but also has few or no side effects. Since the past decade, much attention has been given to exploitation of phytochemicals and their use in alternative medicine research. This is because plants are a cheap, indispensable, and never ending resource of active compounds that are beneficial against various diseases. In the current study, 40 active phytochemicals against PD were selected through literature survey. These ligands were docked with dopamine receptor D3 using AutoDock and AutoDockVina. Binding energies were compared to docking results of drugs approved by the US Food and Drug Administration against PD. The compounds were further analyzed for their absorption, distribution, metabolism, and excretion-toxicity profile. From the study it is concluded that glycyrrhetinic acid and E.resveratroloside are potent compounds having high binding energies which should be considered as potential lead compounds for drug development against PD. PMID:25565772

Glycyrrhetinic acid and E.resveratroloside act as potential plant derived compounds against dopamine receptor D3 for Parkinson's disease: a pharmacoinformatics study.

PubMed

Mirza, Muhammad Usman; Mirza, A Hammad; Ghori, Noor-Ul-Huda; Ferdous, Saba

2015-01-01

Parkinson's disease (PD) is caused by loss in nigrostriatal dopaminergic neurons and is ranked as the second most common neurodegenerative disorder. Dopamine receptor D3 is considered as a potential target in drug development against PD because of its lesser side effects and higher degree of neuro-protection. One of the prominent therapies currently available for PD is the use of dopamine agonists which mimic the natural action of dopamine in the brain and stimulate dopamine receptors directly. Unfortunately, use of these pharmacological therapies such as bromocriptine, apomorphine, and ropinirole provides only temporary relief of the disease symptoms and is frequently linked with insomnia, anxiety, depression, and agitation. Thus, there is a need for an alternative treatment that not only hinders neurodegeneration, but also has few or no side effects. Since the past decade, much attention has been given to exploitation of phytochemicals and their use in alternative medicine research. This is because plants are a cheap, indispensable, and never ending resource of active compounds that are beneficial against various diseases. In the current study, 40 active phytochemicals against PD were selected through literature survey. These ligands were docked with dopamine receptor D3 using AutoDock and AutoDockVina. Binding energies were compared to docking results of drugs approved by the US Food and Drug Administration against PD. The compounds were further analyzed for their absorption, distribution, metabolism, and excretion-toxicity profile. From the study it is concluded that glycyrrhetinic acid and E.resveratroloside are potent compounds having high binding energies which should be considered as potential lead compounds for drug development against PD.

Characterization of the discriminative stimulus produced by the dopamine antagonist tiapride.

PubMed

Cohen, C; Sanger, D J; Perrault, G

1997-11-01

The ability of tiapride, a selective D2/D3 dopamine receptor antagonist, to exert discriminative stimulus control of responding was investigated by training rats to discriminate this drug (30 mg/kg) from saline in a two-lever, food-reinforcement procedure. Acquisition of tiapride discrimination required a relatively lengthy training period (mean of 76 sessions) but stable performance was maintained throughout the 18- month study. The dose of tiapride eliciting 50% tiapride-lever choice (ED50) was 2.2 mg/kg. After determination of the dose-effect curve with tiapride, substitution tests with several dopamine antagonists and other reference compounds were performed. All dopamine antagonists, including amisulpride (ED50 4 mg/kg), sulpiride (18 mg/kg), sultopride (1.5 mg/kg), clebopride (0.13 mg/kg), raclopride (0.16 mg/kg), metoclopramide (1.4 mg/kg), remoxipride (4.8 mg/kg), pimozide (2.7 mg/kg), thioridazine (3.4 mg/kg), olanzapine (0.97 mg/kg), chlorpromazine (1.9 mg/kg), risperidone (0.22 mg/kg) and haloperidol (0.14 mg/kg), except clozapine (>10 mg/kg), produced dose-dependent substitution for tiapride. Tiapride-like stimulus effects were observed at doses that decreased response rates. However, ED50 values for substitution by tiapride, amisulpride, sulpiride, sultopride, pimozide, clebopride and thioridazine were lower than ED50 values for decreasing responding. Additional studies were conducted to evaluate the ability of direct and indirect dopamine agonists to attenuate the tiapride discriminative stimulus. Pretreatment with d-amphetamine and nomifensine antagonized the discriminative stimulus effects of tiapride. Quinpirole, 7-OH-DPAT, bromocriptine and apomorphine partially blocked the stimulus effects of tiapride whereas SKF 38393 did not affect the discrimination. These results from substitution and antagonism tests indicated that the discriminative effects of tiapride are mediated by activity at D2/D3 dopamine receptors.

A daily single dose of a novel modafinil analogue CE-123 improves memory acquisition and memory retrieval.

PubMed

Kristofova, Martina; Aher, Yogesh D; Ilic, Marija; Radoman, Bojana; Kalaba, Predrag; Dragacevic, Vladimir; Aher, Nilima Y; Leban, Johann; Korz, Volker; Zanon, Lisa; Neuhaus, Winfried; Wieder, Marcus; Langer, Thierry; Urban, Ernst; Sitte, Harald H; Hoeger, Harald; Lubec, Gert; Aradska, Jana

2018-05-02

Dopamine reuptake inhibitors have been shown to improve cognitive parameters in various tasks and animal models. We recently reported a series of modafinil analogues, of which the most promising, 5-((benzhydrylsulfinyl)methyl) thiazole (CE-123), was selected for further development. The present study aims to characterize pharmacological properties of CE-123 and to investigate the potential to enhance memory performance in a rat model. In vitro transporter assays were performed in cells expressing human transporters. CE-123 blocked uptake of [3H] dopamine (IC50 = 4.606 μM) while effects on serotonin (SERT) and the norepinephrine transporter (NET) were negligible. Blood-brain barrier and pharmacokinetic studies showed that the compound reached the brain and lower elimination than R-modafinil. The Pro-cognitive effect was evaluated in a spatial hole-board task in male Sprague-Dawley rats and CE-123 enhances memory acquisition and memory retrieval, represented by significantly increased reference memory indices and shortened latency. Since DAT blockers can be considered as indirect dopamine receptor agonists, western blotting was used to quantify protein levels of dopamine receptors D1R, D2R and D5R and DAT in the synaptosomal fraction of hippocampal subregions CA1, CA3 and dentate gyrus (DG). CE-123 administration in rats increased total DAT levels and D1R protein levels were significantly increased in CA1 and CA3 in treated/trained groups. The increase of D5R was observed in DG only. Dopamine receptors, particularly D1R, seem to play a role in mediating CE-123-induced memory enhancement. Dopamine reuptake inhibition by CE-123 may represent a novel and improved stimulant therapeutic for impairments of cognitive functions. Copyright © 2018 Elsevier B.V. All rights reserved.

Dopamine Modulates Option Generation for Behavior.

PubMed

Ang, Yuen-Siang; Manohar, Sanjay; Plant, Olivia; Kienast, Annika; Le Heron, Campbell; Muhammed, Kinan; Hu, Michele; Husain, Masud

2018-05-21

Animals make innumerable decisions every day, each of which involves evaluating potential options for action. But how are options generated? Although much is now known about decision making when a fixed set of potential options is provided, surprisingly little progress has been made on self-generated options. Some researchers have proposed that such abilities might be modulated by dopamine. Here, we used a new measure of option generation that is quantitative, objective, and culture fair to investigate how humans generate different behavioral options. Participants were asked to draw as many different paths (options) as they could between two points within a fixed time. Healthy individuals (n = 96) exhibited a trade-off between uniqueness (how individually different their options were) and fluency (number of options), generating either many similar or few unique options. To assess influence of dopamine, we first examined patients with Parkinson's disease (n = 35) ON and OFF their dopaminergic medication and compared them to elderly healthy controls (n = 34). Then we conducted a double-blind, placebo-controlled crossover study of the D2 agonist cabergoline in healthy older people (n = 29). Across both studies, dopamine increased fluency but diminished overall uniqueness of options generated, due to the effect of fluency trading off with uniqueness. Crucially, however, when this trade-off was corrected for, dopamine was found to increase uniqueness for any given fluency. Three carefully designed control studies showed that performance on our option-generation task was not related to executing movements, planning actions, or selecting between generated options. These findings show that dopamine plays an important role in modulating option generation. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation.

PubMed

Thomas, David M; Walker, Paul D; Benjamins, Joyce A; Geddes, Timothy J; Kuhn, Donald M

2004-10-01

Methamphetamine intoxication causes long-lasting damage to dopamine nerve endings in the striatum. The mechanisms underlying this neurotoxicity are not known but oxidative stress has been implicated. Microglia are the major antigen-presenting cells in brain and when activated, they secrete an array of factors that cause neuronal damage. Surprisingly, very little work has been directed at the study of microglial activation as part of the methamphetamine neurotoxic cascade. We report here that methamphetamine activates microglia in a dose-related manner and along a time course that is coincident with dopamine nerve ending damage. Prevention of methamphetamine toxicity by maintaining treated mice at low ambient temperature prevents drug-induced microglial activation. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which damages dopamine nerve endings and cell bodies, causes extensive microglial activation in striatum as well as in the substantia nigra. In contrast, methamphetamine causes neither microglial activation in the substantia nigra nor dopamine cell body damage. Dopamine transporter antagonists (cocaine, WIN 35,428 [(-)-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate], and nomifensine), selective D1 (SKF 82958 [(+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide]), D2 (quinpirole), or mixed D1/D2 receptor agonists (apomorphine) do not mimic the effect of methamphetamine on microglia. Hyperthermia, a prominent and dangerous clinical response to methamphetamine intoxication, was also ruled out as the cause of microglial activation. Together, these data suggest that microglial activation represents an early step in methamphetamine-induced neurotoxicity. Other neurochemical effects resulting from methamphetamine-induced overflow of DA into the synapse, but which are not neurotoxic, do not play a role in this response.

Selective activation of mesolimbic and mesocortical dopamine metabolism in rat brain by infusion of a stable substance P analogue into the ventral tegmental area.

PubMed

Elliott, P J; Alpert, J E; Bannon, M J; Iversen, S D

1986-01-15

Microinfusion of the metabolically stable substance P (SP) agonist, [pGlu5,MePhe8,Sar9]-SP5-11 (DiMe-C7), into the ventral tegmental area (VTA) of rat brain increased levels of the dopamine (DA) metabolite dihydroxyphenylacetic acid in the prefrontal cortex (+ 120%) and nucleus accumbens (+30%) but not in other regions of forebrain. In contrast, infusions of DiMe-C7 or SP into the lateral ventricles or microinfusions of SP into VTA failed to elicit increases in DOPAC levels in forebrain. DA levels were unaffected by SP or DiMe-C7 regardless of the route of administration. These data and previous studies suggest a role for endogenous SP in the modulation of mesocortical and mesolimbic DA neurones.

Different contributions of dopamine D1 and D2 receptor activity to alcohol potentiation of brain stimulation reward in C57BL/6J and DBA/2J mice.

PubMed

Fish, Eric W; DiBerto, Jeffrey F; Krouse, Michael C; Robinson, J Elliott; Malanga, C J

2014-08-01

C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, including alcohol. The current study compared effects of D1 and D2 receptor agonists and antagonists, and the interaction between D1/D2 antagonists and alcohol, on intracranial self-stimulation in male C57 and DBA mice to determine the role of dopamine receptors in the effects of alcohol on brain stimulation reward (BSR). In the initial strain comparison, dose effects on BSR thresholds and maximum operant response rates were determined for the D1 receptor agonist SKF-82958 (±-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.1-0.56 mg/kg) and antagonist SCH 23390 (+-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride; 0.003-0.056 mg/kg), and the D2 receptor agonist quinpirole (0.1-3.0 mg/kg) and antagonist raclopride (0.01-0.56 mg/kg). For the alcohol interaction, SCH 23390 (0.003 mg/kg) or raclopride (0.03 mg/kg) was given before alcohol (0.6-2.4 g/kg p.o.). D1 antagonism dose-dependently elevated and SKF-82958 dose-dependently lowered BSR threshold in both strains; DBA mice were more sensitive to SKF-82958 effects. D2 antagonism dose-dependently elevated BSR threshold only in C57 mice. Low doses of quinpirole elevated BSR threshold equally in both strains, whereas higher doses of quinpirole lowered BSR threshold only in C57 mice. SCH 23390, but not raclopride, prevented lowering of BSR threshold by alcohol in DBA mice. Conversely, raclopride, but not SCH 23390, prevented alcohol potentiation of BSR in C57 mice. These results extend C57 and DBA strain differences to D1/D2 sensitivity of BSR, and suggest differential involvement of D1 and D2 receptors in the acute rewarding effects of alcohol in these two mouse strains. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

The role of the dopaminergic system in mood, motivation and cognition in Parkinson's disease: a double blind randomized placebo-controlled experimental challenge with pramipexole and methylphenidate.

PubMed

Drijgers, Rosa L; Verhey, Frans R J; Tissingh, Gerrit; van Domburg, Peter H M F; Aalten, Pauline; Leentjens, Albert F G

2012-09-15

In Parkinson's disease (PD) reduced dopaminergic activity in the mesocorticolimbic pathway is implied in the pathophysiology of several non-motor symptoms related to mood, motivation and cognition. Insight in the pathophysiology of these syndromes may pave the way for more rational treatments. In a double-blind, randomized, placebo controlled, crossover design with three arms, we studied the effects of a direct dopaminergic challenge with the dopamine 2 receptor agonist pramipexole, an indirect challenge with the dopamine reuptake inhibitor methylphenidate, and placebo on measures of mood, motivation and cognition in 23 agonist-naïve PD patients and 23 healthy controls. Acute challenge with pramipexole had a negative effect on mood and fatigue in both patients and controls. In addition, challenge with pramipexole led to increased anger, fatigue, vigor and tension in healthy control subjects, but not in PD patients. Challenge with methylphenidate had a positive effect on anhedonia and vigor in PD patients. Due to its side effects after a single administration, pramipexole is probably less suitable for acute challenge studies. The acute effects of a methylphenidate challenge on anhedonia and vigor in PD patients make this drug an interesting choice for further studies of the treatment of mood and motivational disorders in this population. Copyright © 2012 Elsevier B.V. All rights reserved.

Mutation of Three Residues in the Third Intracellular Loop of the Dopamine D2 Receptor Creates an Internalization-defective Receptor*

PubMed Central

Clayton, Cecilea C.; Donthamsetti, Prashant; Lambert, Nevin A.; Javitch, Jonathan A.; Neve, Kim A.

2014-01-01

Arrestins mediate desensitization and internalization of G protein-coupled receptors and also direct receptor signaling toward heterotrimeric G protein-independent signaling pathways. We previously identified a four-residue segment (residues 212–215) of the dopamine D2 receptor that is necessary for arrestin binding in an in vitro heterologous expression system but that also impairs receptor expression. We now describe the characterization of additional mutations at that arrestin binding site in the third intracellular loop. Mutating two (residues 214 and 215) or three (residues 213–215) of the four residues to alanine partially decreased agonist-induced recruitment of arrestin3 without altering activation of a G protein. Arrestin-dependent receptor internalization, which requires arrestin binding to β2-adaptin (the β2 subunit of the clathrin-associated adaptor protein AP2) and clathrin, was disproportionately affected by the three-residue mutation, with no agonist-induced internalization observed even in the presence of overexpressed arrestin or G protein-coupled receptor kinase 2. The disjunction between arrestin recruitment and internalization could not be explained by alterations in the time course of the receptor-arrestin interaction, the recruitment of G protein-coupled receptor kinase 2, or the receptor-induced interaction between arrestin and β2-adaptin, suggesting that the mutation impairs a property of the internalization complex that has not yet been identified. PMID:25336643

Evidence for a dopamine intrinsic direct role in the regulation of the ovary reproductive function: in vitro study on rabbit corpora lutea.

PubMed

Parillo, Francesco; Maranesi, Margherita; Mignini, Fiorenzo; Marinelli, Lisa; Di Stefano, Antonio; Boiti, Cristiano; Zerani, Massimo

2014-01-01

Dopamine (DA) receptor (DR) type 1 (D1R) has been found to be expressed in luteal cells of various species, but the intrinsic role of the DA/DRs system on corpora lutea (CL) function is still unclear. Experiments were devised to characterize the expression of DR types and the presence of DA, as well as the in vitro effects of DA on hormone productions by CL in pseudopregnant rabbits. Immunoreactivity and gene expression for D1R decreased while that for D3R increased in luteal and blood vessel cells from early to late pseudopregnant stages. DA immunopositivity was evidenced only in luteal cells. The DA and D1R agonist increased in vitro release of progesterone and prostaglandin E2 (PGE2) by early CL, whereas the DA and D3R agonist decreased progesterone and increased PGF2α in vitro release by mid- and late CL. These results provide evidence that the DA/DR system exerts a dual modulatory function in the lifespan of CL: the DA/D1R is luteotropic while the DA/D3R is luteolytic. The present data shed new light on the physiological mechanisms regulating luteal activity that might improve our ability to optimize reproductive efficiency in mammal species, including humans.

Dopamine D4 Receptor Counteracts Morphine-Induced Changes in μ Opioid Receptor Signaling in the Striosomes of the Rat Caudate Putamen

PubMed Central

Suárez-Boomgaard, Diana; Gago, Belén; Valderrama-Carvajal, Alejandra; Roales-Buján, Ruth; Van Craenenbroeck, Kathleen; Duchou, Jolien; Borroto-Escuela, Dasiel O.; Medina-Luque, José; de la Calle, Adelaida; Fuxe, Kjell; Rivera, Alicia

2014-01-01

The mu opioid receptor (MOR) is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine induces changes in MOR protein levels, its pharmacological profile, and MOR-mediated G-protein activation in the striosomal compartment of the rat CPu, by using immunohistochemistry and receptor and DAMGO-stimulated [35S]GTPγS autoradiography. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment in the absence of changes in enkephalin and dynorphin mRNA levels. In addition, co-treatment of morphine with the dopamine D4 receptor (D4R) agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [3H]DAMGO Bmax values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to Gi/0 protein, the present results give support for the existence of antagonistic functional D4R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine. PMID:24451133

The dopamine D1 receptor agonist SKF81297 has dose-related effects on locomotor activity but is without effect in a CER trace conditioning procedure conducted with two versus four trials.

PubMed

Pezze, M A; Marshall, H J; Cassaday, H J

2016-08-01

In an appetitively motivated procedure, we have previously reported that systemic treatment with the dopamine (DA) D1 receptor agonist SKF81297 (0.4 and 0.8 mg/kg) depressed acquisition at a 2 s inter-stimulus-interval (ISI), suitable to detect trace conditioning impairment. However since DA is involved in reinforcement processes, the generality of effects across appetitively- and aversively-motivated trace conditioning procedures cannot be assumed. The present study tested the effects of SKF81297 (0.4 and 0.8 mg/kg) in an established conditioned emotional response (CER) procedure. Trace-dependent conditioning was clearly shown in two experiments: while conditioning was relatively strong at a 3-s ISI, it was attenuated at a 30-s ISI. This was shown after two (Experiment 1) or four (Experiment 2) conditioning trials conducted in - as far as possible - the same CER procedure. Contrary to prediction, in neither experiment was there any indication that trace conditioning was attenuated by treatment with 0.4 or 0.8 mg/kg SKF81297. In the same rats, locomotor activity was significantly enhanced at the 0.8 mg/kg dose of SKF81297. These results suggest that procedural details of the trace conditioning variant in use are an important determinant of the profile of dopaminergic modulation.

Sorting Nexin 1 Loss Results in D5 Dopamine Receptor Dysfunction in Human Renal Proximal Tubule Cells and Hypertension in Mice*

PubMed Central

Villar, Van Anthony M.; Jones, John Edward; Armando, Ines; Asico, Laureano D.; Escano, Crisanto S.; Lee, Hewang; Wang, Xiaoyan; Yang, Yu; Pascua-Crusan, Annabelle M.; Palmes-Saloma, Cynthia P.; Felder, Robin A.; Jose, Pedro A.

2013-01-01

The peripheral dopaminergic system plays a crucial role in blood pressure regulation through its actions on renal hemodynamics and epithelial ion transport. The dopamine D5 receptor (D5R) interacts with sorting nexin 1 (SNX1), a protein involved in receptor retrieval from the trans-Golgi network. In this report, we elucidated the spatial, temporal, and functional significance of this interaction in human renal proximal tubule cells and HEK293 cells stably expressing human D5R and in mice. Silencing of SNX1 expression via RNAi resulted in the failure of D5R to internalize and bind GTP, blunting of the agonist-induced increase in cAMP production and decrease in sodium transport, and up-regulation of angiotensin II receptor expression, of which expression was previously shown to be negatively regulated by D5R. Moreover, siRNA-mediated depletion of renal SNX1 in C57BL/6J and BALB/cJ mice resulted in increased blood pressure and blunted natriuretic response to agonist in salt-loaded BALB/cJ mice. These data demonstrate a crucial role for SNX1 in D5R trafficking and that SNX1 depletion results in D5R dysfunction and thus may represent a novel mechanism for the pathogenesis of essential hypertension. PMID:23152498