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Sample records for dopamine concentration induced

  1. Oxygen concentration control of dopamine-induced high uniformity surface coating chemistry.

    PubMed

    Kim, Hyo Won; McCloskey, Bryan D; Choi, Tae Hwan; Lee, Changho; Kim, Min-Joung; Freeman, Benny D; Park, Ho Bum

    2013-01-23

    Material surface engineering has attracted great interest in important applications, including electronics, biomedicine, and membranes. More recently, dopamine has been widely exploited in solution-based chemistry to direct facile surface modification. However, unsolved questions remain about the chemical identity of the final products, their deposition kinetics and their binding mechanism. In particular, the dopamine oxidation reaction kinetics is a key to improving surface modification efficiency. Here, we demonstrate that high O(2) concentrations in the dopamine solution lead to highly homogeneous, thin layer deposition on any material surfaces via accelerated reaction kinetics, elucidated by Le Chatelier's principle toward dopamine oxidation steps in a Michael-addition reaction. As a result, highly uniform, ultra-smooth modified surfaces are achieved in much shorter deposition times. This finding provides new insights into the effect of reaction kinetics and molecular geometry on the uniformity of modifications for surface engineering techniques.

  2. D2 dopamine receptors enable Δ9-tetrahydrocannabinol induced memory impairment and reduction of hippocampal extracellular acetylcholine concentration

    PubMed Central

    Nava, F; Carta, G; Battasi, A M; Gessa, G L

    2000-01-01

    The systemic administration of Δ9-tetrahydrocannabinol (2.5–7.5 mg kg−1) reduced hippocampal extracellular acetylcholine concentration and impaired working memory in rats.Both effects were antagonized not only by the CB1 cannabinoid receptor antagonist SR141716A (0.5 mg kg−1, i.p.) but also unexpectedly by the D2 dopamine receptor antagonist S(−)-sulpiride (5, 10 and 25 mg kg−1, i.p.). Conversely, Δ9-tetrahydrocannabinol-induced memory impairment and inhibition of hippocampal extracellular acetylcholine concentration were potentiated by the subcutaneous administration of the D2 dopamine receptor agonist (−)-quinpirole (25 and 500 μg kg−1). The inhibition of hippocampal extracellular acetylcholine concentration and working memory produced by the combination of (−)-quinpirole and Δ9-tetrahydrocannabinol was suppressed by either SR141716A or S(−)-sulpiride.Our findings suggest that impairment of working memory and inhibition of hippocampal extracellular acetylcholine concentration are mediated by the concomitant activation of D2 dopamine and CB1 cannabinoid receptors, and that D2 dopamine receptor antagonists may be useful in the treatment of the cognitive deficits induced by marijuana. PMID:10903956

  3. Temporal Profiles Dissociate Regional Extracellular Ethanol versus Dopamine Concentrations

    PubMed Central

    2015-01-01

    In vivo monitoring of dopamine via microdialysis has demonstrated that acute, systemic ethanol increases extracellular dopamine in regions innervated by dopaminergic neurons originating in the ventral tegmental area and substantia nigra. Simultaneous measurement of dialysate dopamine and ethanol allows comparison of the time courses of their extracellular concentrations. Early studies demonstrated dissociations between the time courses of brain ethanol concentrations and dopaminergic responses in the nucleus accumbens (NAc) elicited by acute ethanol administration. Both brain ethanol and extracellular dopamine levels peak during the first 5 min following systemic ethanol administration, but the dopamine response returns to baseline while brain ethanol concentrations remain elevated. Post hoc analyses examined ratios of the dopamine response (represented as a percent above baseline) to tissue concentrations of ethanol at different time points within the first 25–30 min in the prefrontal cortex, NAc core and shell, and dorsomedial striatum following a single intravenous infusion of ethanol (1 g/kg). The temporal patterns of these “response ratios” differed across brain regions, possibly due to regional differences in the mechanisms underlying the decline of the dopamine signal associated with acute intravenous ethanol administration and/or to the differential effects of acute ethanol on the properties of subpopulations of midbrain dopamine neurons. This Review draws on neurochemical, physiological, and molecular studies to summarize the effects of acute ethanol administration on dopamine activity in the prefrontal cortex and striatal regions, to explore the potential reasons for the regional differences observed in the decline of ethanol-induced dopamine signals, and to suggest directions for future research. PMID:25537116

  4. Sources Contributing to the Average Extracellular Concentration of Dopamine in the Nucleus Accumbens

    PubMed Central

    Owesson-White, CA; Roitman, MF; Sombers, LA; Belle, AM; Keithley, RB; Peele, JL; Carelli, RM; Wightman, RM

    2012-01-01

    Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens (NAc). In the past, different techniques have targeted dopamine levels in the NAc to establish a basal concentration. In this study we used in vivo fast scan cyclic voltammetry (FSCV) in the NAc of awake, freely moving rats. The experiments were primarily designed to capture changes in dopamine due to phasic firing – that is, the measurement of dopamine ‘transients’. These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc. A series of experiments were designed to probe regulation of extracellular dopamine. Lidocaine was infused into the ventral tegmental area, the site of dopamine cell bodies, to arrest neuronal firing. While there was virtually no instantaneous change in dopamine concentration, longer sampling revealed a decrease in dopamine transients and a time-averaged decrease in the extracellular level. Dopamine transporter (DAT) inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc. To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter (VMAT2) inhibitor, tetrabenazine, to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals. Tetrabenazine almost abolished phasic dopamine release but increased extracellular dopamine to ~500 nM, presumably by inducing reverse transport by DAT. Taken together, data presented here show that average extracellular dopamine in the NAc is low (20–30 nM) and largely arises from phasic dopamine transients. PMID:22296263

  5. Exchange diffusion of dopamine induced in planar lipid bilayer membranes by the ionophore X537A

    PubMed Central

    Holz, RW

    1977-01-01

    The ionophore X537A causes a large increase in the [(14)C]dopamine (a catecholamine) permeability of planar bilayer membranes. Dopamine transport increases linearly with the ionophore concentration. At relatively high concentrations in the presence of dopamine, the ionophore omdices a conductance which is nearly ideally selective for the dopamine cation. However, the total dopamine flux as determined in tracer experiments is not affected by an electric field and is over 10(5) times larger than predicted from the estimated dopamine conductance. Increasing the dopamine concentration on the side containing radioactive dopamine (the cis side) saturates the dopamine transport. This saturation is relieved by trans addition of nonradioactive dopamine, tyramine, H(+), or K(+). With unequal concentrations of dopamine cis and trans (49 and 12.5 mM), the unidirectional dopamine fluxes are equal. Increasing H(+) cis and trans decreases dopamine transport. It is concluded that at physiological pH, the X537A-induced transport of dopamine occurs via an electrically silent exchange diffusion of dopamine cation with another cation (e.g., dopamine(+), H(+), or K(+)). X537A induces a Ca(++)-independent release of catecholamines from sympathetic nerves by interfering with intracellular storage within storage vesicles (R.W. Holz. 1975. Biochim. Biophys. Acta. 375:138-152). It is suggested that X537A causes an exchange of intravesicular catecholamine with a cytoplasmic cation (perhaps K(+) or H(+)) across the storage vesicle membrane. PMID:16982

  6. Corticosterone regulates both naturally occurring and cocaine-induced dopamine signaling by selectively decreasing dopamine uptake.

    PubMed

    Wheeler, Daniel S; Ebben, Amanda L; Kurtoglu, Beliz; Lovell, Marissa E; Bohn, Austin T; Jasek, Isabella A; Baker, David A; Mantsch, John R; Gasser, Paul J; Wheeler, Robert A

    2017-10-01

    Stressful and aversive events promote maladaptive reward-seeking behaviors such as drug addiction by acting, in part, on the mesolimbic dopamine system. Using animal models, data from our lab and others show that stress and cocaine can interact to produce a synergistic effect on reward circuitry. This effect is also observed when the stress hormone corticosterone is administered directly into the nucleus accumbens (NAc), indicating that glucocorticoids act locally in dopamine terminal regions to enhance cocaine's effects on dopamine signaling. However, prior studies in behaving animals have not provided mechanistic insight. Using fast-scan cyclic voltammetry, we examined the effect of systemic corticosterone on spontaneous dopamine release events (transients) in the NAc core and shell in behaving rats. A physiologically relevant systemic injection of corticosterone (2 mg/kg i.p.) induced an increase in dopamine transient amplitude and duration (both voltammetric measures sensitive to decreases in dopamine clearance), but had no effect on the frequency of transient release events. This effect was compounded by cocaine (2.5 mg/kg i.p.). However, a second experiment indicated that the same injection of corticosterone had no detectable effect on the dopaminergic encoding of a palatable natural reward (saccharin). Taken together, these results suggest that corticosterone interferes with naturally-occurring dopamine uptake locally, and this effect is a critical determinant of dopamine concentration specifically in situations in which the dopamine transporter is pharmacologically blocked by cocaine. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  7. Chlorpromazine, haloperidol, metoclopramide and domperidone release prolactin through dopamine antagonism at low concentrations but paradoxically inhibit prolactin release at high concentrations.

    PubMed Central

    Besser, G. M.; Delitala, G.; Grossman, A.; Stubbs, W. A.; Yeo, T.

    1980-01-01

    1. The effects of chlorpromazine, haloperidol, metoclopramide and domperidone on the release of prolactin from perfused columns of dispersed rat anterior pituitary cells were studied. 2. Chlorpromazine, haloperidol, metoclopramide and domperidone antagonized the dopamine-mediated inhibition of prolactin release at low concentrations. 3. Each dopamine antagonist displaced the dose-response curve for dopamine-induced suppression of prolactin release to the right in a parallel manner. 4. At higher concentrations, the four drugs became less effective as dopamine antagonists. 5. At high concentrations in the absence of dopamine, chlorpromazine, haloperidol, metoclopramide and domperidone paradoxically suppressed prolactin secretion by an unknown mechanism. PMID:6110459

  8. Rising taurine and ethanol concentrations in nucleus accumbens interact to produce dopamine release after ethanol administration.

    PubMed

    Ericson, Mia; Chau, PeiPei; Clarke, Rhona B; Adermark, Louise; Söderpalm, Bo

    2011-07-01

    We have previously demonstrated that glycine receptors in the nucleus accumbens (nAc) are involved in modulating both basal and ethanol-induced dopamine output in the same brain region. Ethanol is known to induce a release of both taurine and dopamine in the nAc, but the relationship between these two neuromodulators has not been investigated thoroughly. In vivo microdialysis was used to measure the effects of systemic ethanol diluted in isotonic (0.9% NaCl) or hypertonic (3.6% NaCl) saline on accumbal taurine and dopamine levels. We found that ethanol given in a hypertonic solution, contrary to an isotonic solution, failed to increase concentrations both of taurine and dopamine in the nAc. However, a modest, non-dopamine elevating concentration of taurine in the nAc disclosed a dopamine-elevating effect of systemic ethanol also when given in a hypertonic solution. In a second experiment, we investigated the effects of ethanol on taurine and dopamine in normal rats and rats with decreased levels of endogenous taurine. Lowering the level of taurine, approximately 40% by adding 5% β-alanine in the drinking water, did not influence taurine or dopamine output over time. We conclude that the elevations of taurine and dopamine in the nAc are closely related, and that in order for ethanol to induce dopamine release, a simultaneous increase of extracellular taurine levels in the nAc is required. These data also provide support for the notion that the nAc is the primary target for ethanol in its dopamine-activating effect after systemic administration.

  9. Estimation from PET data of transient changes in dopamine concentration induced by alcohol: support for a non-parametric signal estimation method

    NASA Astrophysics Data System (ADS)

    Constantinescu, C. C.; Yoder, K. K.; Kareken, D. A.; Bouman, C. A.; O'Connor, S. J.; Normandin, M. D.; Morris, E. D.

    2008-03-01

    We previously developed a model-independent technique (non-parametric ntPET) for extracting the transient changes in neurotransmitter concentration from paired (rest & activation) PET studies with a receptor ligand. To provide support for our method, we introduced three hypotheses of validation based on work by Endres and Carson (1998 J. Cereb. Blood Flow Metab. 18 1196-210) and Yoder et al (2004 J. Nucl. Med. 45 903-11), and tested them on experimental data. All three hypotheses describe relationships between the estimated free (synaptic) dopamine curves (FDA(t)) and the change in binding potential (ΔBP). The veracity of the FDA(t) curves recovered by nonparametric ntPET is supported when the data adhere to the following hypothesized behaviors: (1) ΔBP should decline with increasing DA peak time, (2) ΔBP should increase as the strength of the temporal correlation between FDA(t) and the free raclopride (FRAC(t)) curve increases, (3) ΔBP should decline linearly with the effective weighted availability of the receptor sites. We analyzed regional brain data from 8 healthy subjects who received two [11C]raclopride scans: one at rest, and one during which unanticipated IV alcohol was administered to stimulate dopamine release. For several striatal regions, nonparametric ntPET was applied to recover FDA(t), and binding potential values were determined. Kendall rank-correlation analysis confirmed that the FDA(t) data followed the expected trends for all three validation hypotheses. Our findings lend credence to our model-independent estimates of FDA(t). Application of nonparametric ntPET may yield important insights into how alterations in timing of dopaminergic neurotransmission are involved in the pathologies of addiction and other psychiatric disorders.

  10. Methamphetamine produces bidirectional, concentration-dependent effects on dopamine neuron excitability and dopamine-mediated synaptic currents

    PubMed Central

    Branch, Sarah Y.

    2012-01-01

    Amphetamine-like compounds are commonly used to enhance cognition and to treat attention deficit/hyperactivity disorder, but they also function as positive reinforcers and are self-administered at doses far exceeding clinical relevance. Many of these compounds (including methamphetamine) are substrates for dopamine reuptake transporters, elevating extracellular dopamine by inhibiting uptake and promoting reverse transport. This produces an increase in extracellular dopamine that inhibits dopamine neuron firing through autoreceptor activation and consequently blunts phasic dopamine neurotransmission, an important learning signal. However, these mechanisms do not explain the beneficial behavioral effects observed at clinically useful concentrations. In the present study, we have used patch-clamp electrophysiology in slices of mouse midbrain to show that, surprisingly, low concentrations of methamphetamine actually enhance dopamine neurotransmission and increase dopamine neuron firing through a dopamine transporter-mediated excitatory conductance. Both of these effects are reversed by higher concentrations of methamphetamine, which inhibit firing through dopamine D2 autoreceptor activation and decrease the peak amplitude of dopamine-mediated synaptic currents. These competing, concentration-dependent effects of methamphetamine suggest a mechanistic interplay by which lower concentrations of methamphetamine can overcome autoreceptor-mediated inhibition at the soma to increase phasic dopamine transmission. PMID:22592307

  11. Diet-induced obesity: dopamine transporter function, impulsivity and motivation

    PubMed Central

    Narayanaswami, V; Thompson, AC; Cassis, LA; Bardo, MT; Dwoskin, LP

    2013-01-01

    OBJECTIVE A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. DESIGN To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. METHODS Striatal D2-receptor density was determined by in vitro kinetic analysis of [3H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [3H]dopamine uptake, methamphetamine-evoked [3H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. RESULTS Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [3H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. CONCLUSION Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The

  12. Diet-induced obesity: dopamine transporter function, impulsivity and motivation.

    PubMed

    Narayanaswami, V; Thompson, A C; Cassis, L A; Bardo, M T; Dwoskin, L P

    2013-08-01

    A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. Striatal D2-receptor density was determined by in vitro kinetic analysis of [(3)H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [(3)H]dopamine uptake, methamphetamine-evoked [(3)H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [(3)H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The current animal model shows that

  13. Deep brain light stimulation effects on glutamate and dopamine concentration.

    PubMed

    Kuo, Jinn-Rung; Lin, Shih-Shian; Liu, Janelle; Chen, Shih-How; Chio, Chung-Chin; Wang, Jhi-Joung; Liu, Jia-Ming

    2015-01-01

    Compared to deep brain electrical stimulation, which has been applied to treating pathological brain diseases, little work has been done on the effect of deep brain light stimulation. A fiber-coupled laser stimulator at 840 nm wavelength and 130 Hz pulse repetition rate is developed in this work for deep brain light stimulation in a rat model. Concentration changes in glutamate and dopamine in the striatum are observed using a microdialysis probe when the subthalamic nucleus (STN) is stimulated at various optical power levels. Experimental results show that light stimulation causes the concentration of glutamate to decrease while that of dopamine is increased. This suggests that deep brain light stimulation of the STN is a promising therapeutic strategy for dopamine-related diseases such as Parkinson's disease. The stimulator developed for this work is useful for deep brain light stimulation in biomedical research.

  14. Dopamine elevates intracellular zinc concentration in cultured rat embryonic cortical neurons through the cAMP-nitric oxide signaling cascade.

    PubMed

    Hung, Hui-Hsing; Kao, Lung-Sen; Liu, Pei-Shan; Huang, Chien-Chang; Yang, De-Ming; Pan, Chien-Yuan

    2017-07-01

    Zinc ion (Zn(2+)), the second most abundant transition metal after iron in the body, is essential for neuronal activity and also induces toxicity if the concentration is abnormally high. Our previous results show that exposure of cultured cortical neurons to dopamine elevates intracellular Zn(2+) concentrations ([Zn(2+)]i) and induces autophagosome formation but the mechanism is not clear. In this study, we characterized the signaling pathway responsible for the dopamine-induced elevation of [Zn(2+)]i and the effect of [Zn(2+)]i in modulating the autophagy in cultured rat embryonic cortical neurons. N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a membrane-permeable Zn(2+) chelator, could rescue the cell death and suppress the autophagosome puncta number induced by dopamine. Dopamine treatment increased the lipidation level of the endogenous microtubule-associated protein 1A/1B-light chain 3 (LC3 II), an autophagosome marker. TPEN added 1h before, but not after, dopamine treatment suppressed the dopamine-induced elevation of LC3 II level. Inhibitors of the dopamine D1-like receptor, protein kinase A (PKA), and NOS suppressed the dopamine-induced elevation of [Zn(2+)]i. PKA activators and NO generators directly increased [Zn(2+)]i in cultured neurons. Through cell fractionation, proteins with m.w. values between 5 and 10kD were found to release Zn(2+) following NO stimulation. In addition, TPEN pretreatment and an inhibitor against PKA could suppress the LC3 II level increased by NO and dopamine, respectively. Therefore, our results demonstrate that dopamine-induced elevation of [Zn(2+)]i is mediated by the D1-like receptor-PKA-NO pathway and is important in modulating the cell death and autophagy. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Brain dopamine and amino acid concentrations in Lurcher mutant mice.

    PubMed

    Reader, T A; Strazielle, C; Botez, M I; Lalonde, R

    1998-03-15

    Lurcher mutant mice are characterized by massive degeneration of the cerebellum, including Purkinje cells and granule cells, as well as for the loss of neurons from the inferior olive. Concentrations of dopamine and two of its metabolites and of several amino acid neurotransmitters were determined in the cerebellum and in other brain regions of these mutants. By comparison to wild-type mice of the same background strain, glutamate and taurine concentrations were reduced in the Lurcher cerebellum. No decrease was found for aspartate, gamma-aminobutyric acid (GABA), glycine, as well as dopamine and its metabolites. Moreover, no neurochemical alterations occurred in the brain stem, thalamus, or neostriatum of Lurcher mutants. A selective reduction of glutamate concentration was found in the hippocampus, while all amino acids measured were decreased in the entorhinal-piriform areas. These results indicate region-selective reductions of neurotransmitter concentrations in a mouse mutant with a defined cerebellar cortical pathology.

  16. Hypothyroidism leads to increased dopamine receptor sensitivity and concentration

    SciTech Connect

    Crocker, A.D.; Overstreet, D.H.; Crocker, J.M.

    1986-06-01

    Rats treated with iodine-131 were confirmed to be hypothyroid by their reduced baseline core body temperatures, reduced serum thyroxine concentrations and elevated serum thyroid stimulating hormone concentrations. When hypothyroid rats were compared to euthyroid controls they were more sensitive to the effects of apomorphine (1.0 mumol/kg) on stereotypy, operant responding and body temperature and showed a smaller reduction in locomotor activity after injection of haloperidol (0.25 mumol/kg). Receptor binding studies on striatal homogenates indicated that hypothyroid rats had increased concentrations of D2 dopamine receptors but there was no change in the affinity. It is concluded that hypothyroidism increases dopamine receptor sensitivity by increasing receptor concentration.

  17. PET imaging of dopamine receptors in MPTP-induced parkinsonism

    SciTech Connect

    Larson, S.M.; DiChiro, G.; Burns, R.S.; Dannals, R.F.; Kopin, I.J.; Brooks, R.A.; Kessler, R.M.; Wagner, R.F.; Eckelman, W.C.; Margolin, R.A.

    1984-01-01

    MPTP(N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces parkinsonism in animals and man by selectively destroying dopaminergic neurons in the pars compacta of the substantia nigra. The postsynaptic neurons (and presumably the dopamine receptors) are intact. The authors have imaged dopamine receptors in a patient with MPTP induced parkinsonism, using /sup 11/CMS (3-N(/sup 11/C) methylspiperone. Seven and 9 mCi's, respectively, were injected at one week intervals while the patient was first off, and then on, L-dopa. As measured by NeuroPET (NIH), putamen to cerebellum concentration ratios rose progressively to 5.5:1, by 90 min. after injection. At this time the concentration of /sup 11/CMS was 10 picomole/cc (off L-dopa), and 14 picomole/cc (on L-dopa). The Duvoisin scale was used to assess the severity of the patient's parkinsonism immediately prior and at the end of PET imaging. On both occasions, despite the small mass amount of /sup 11/CMS injected, (1.1 g/kg), a transient worsening of symptoms was seen. The effect of L-Dopa was almost completely reversed by the /sup 11/CMS. In contrast, off L-Dopa the patients severe basal state was worsened only slightly. The PET scans suggested that dopamine receptors are not reduced in MPTP-induced parkinsonism. The findings were consistent with the hypotheses that PET may identify patients who will benefit from L-Dopa, and that expression of parkinsonian symptoms reflects desaturation of dopamine receptors in striatum.

  18. Pharmacokinetic and pharmacodynamic studies of chlorpromazine in rats: effect of chlorpromazine on dopamine and dopamine metabolite concentration in rat striatum.

    PubMed

    Sato, S; Koitabashi, T; Koshiro, A

    1995-07-01

    The concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum were increased after the i.v. administration of chlorpromazine (CPZ). Assuming that the enhancement of dopamine concentration in the striatum after CPZ administration is caused by the release of dopamine from the dopamine neuronal terminals, the relationship between the enhancement of dopamine concentration in the striatum and CPZ concentration in the cerebrospinal fluid (CSF) and the striatum were analyzed using the sigmoid Emax model. The enhancement of dopamine concentration in the striatum could be described quantitatively by this model. The time courses of DOPAC and HVA concentration in the striatum after CPZ administration were analyzed using the dopamine metabolism model, which has an apparent first-order clearance from dopamine to DOPAC and HVA, and also using the Michaelis-Menten type elimination kinetics of DOPAC and HVA. The values of the metabolism parameters for DOPAC and HVA were fixed to the estimated values of the L-dopa study. The calculated values of DOPAC and HVA concentrations in the striatum were greater than those of the observed data. The elimination parameters for DOPAC and HVA were reestimated by the nonlinear least squares method. The time courses of DOPAC and HVA concentration in the striatum could be described using these reestimated elimination parameters. These results indicated that the turnover rate of dopamine and dopamine metabolites, DOPAC and HVA in the striatum after CPZ administration is different from that after L-dopa administration.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Platelet activating factor induces dopamine release in PC-12 cell line

    SciTech Connect

    Bussolino, F.; Tessari, F.; Turrini, F.; Braquet, P.; Camussi, G.; Prosdocimi, M.; Bosia, A. Institut Henri Beaufour, Le Plessis Robinson )

    1988-10-01

    The ability of platelet activating factor (PAF) to stimulate dopamine release and modify calcium homeostasis in PC-12 cell line was studied. PAF-induced dopamine release is related to its molecular form, with only the R-form steric configuration ((R)PAF), but not its S-form or its 2-lyso derivative, effective at being active. In addition, PAF acts at very low concentrations in a dose-dependent manner (0.1-30 nM). Preincubation with PAF receptor antagonists (CV-3988 and BN52021) as well as the specific desensitization of PC-12 cells to (R)PAF abolish the (R)PAF-induced dopamine release. Several lines of evidence suggest that dopamine release is dependent on a (R)PAF-induced calcium influx and efflux modulation. Dopamine release by PC-12 cells challenged with (R)PAF is associated with a rapid {sup 45}Ca influx and efflux and a rise in cytoplasmic calcium concentrations ((Ca{sup 2+}){sub i}) evaluated by using the calcium indicators fura-2 and quin2. At 30 nM (R)PAF, the absence of extracellular calcium inhibits the dopamine release but not the rise of (Ca{sup 2+}){sub i} from the internal stores, suggesting the importance of calcium influx in (R)PAF-induced dopamine release. PAF, which has been reported to be synthesized by stimulated neuronal cells may thus have a physiological modulatory role on cells with neurosecretory properties.

  20. Relationship between cocaine-induced subjective effects and dopamine transporter occupancy

    SciTech Connect

    Volkow, N.D.; Fischman, M.; Wang, G.J.

    1997-05-01

    The ability of cocaine to occupy the dopamine transporter has been linked to its reinforcing properties. However, such a relationship has not been demonstrated in humans. Methods: Positron Emission Tomography and [C-11]cocaine were used to estimate dopamine transporter occupancies after different doses of cocaine in 18 active cocaine abusers. The ratio of the distribution volume of [C-11]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1 and is insensitive to changes in cerebral blood flow, was our measure of dopamine transporter availability. In parallel subjective effects were measured to assess the relationship between dopamine transporter occupancy and cocaines behavioral effects. Intravenous cocaine produced a significant dose,-dependent blockade of dopamine transporters: 73 % for 0.6 mg/kg; 601/6 for 0.3 mg/kg; 48 % for 0.1 mg/kg iv and 40 % for 0.05 mg/kg. In addition, dopamine transporter occupancies were significantly correlated with cocaine plasma concentration (r = 0.55 p < 0.001). Cocaine also produced dose-dependent increases in self-reported ratings of {open_quotes}high{close_quotes} which were significantly correlated with the levels of dopamine transporter blockade. Discussion: These results provide the first documentation in humans that dopamine transporter occupancy is associated with cocaine induced subjective effects. They also suggest that dopamine transporter occupancies equal to or greater than 60% are required to produce significant effects on ratings of {open_quotes}high{close_quotes}.

  1. Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition.

    PubMed

    de La Fuente-Fernández, R; Lim, A S; Sossi, V; Holden, J E; Calne, D B; Ruth, T J; Stoessl, A J

    2001-10-01

    The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors.

  2. Prenatal L-DOPA exposure produces lasting changes in brain dopamine content, cocaine-induced dopamine release and cocaine conditioned place preference.

    PubMed

    Ren, Jia-Qian; Jiang, Yan; Wang, Zhihui; McCarthy, Deirdre; Rajadhyaksha, Anjali M; Tropea, Thomas F; Kosofsky, Barry E; Bhide, Pradeep G

    2011-01-01

    Dopamine, its receptors and transporter are present in the brain beginning from early in the embryonic period. Dopamine receptor activation can influence developmental events including neurogenesis, neuronal migration and differentiation raising the possibility that dopamine imbalance in the fetal brain can alter development of the brain and behavior. We examined whether elevated dopamine levels during gestation can produce persisting changes in brain dopamine content and dopamine-mediated behaviors. We administered L-3,4-dihydroxyphenylalanine (L-DOPA) in drinking water to timed-pregnant CD1 mice from the 11th day of gestation until the day of parturition. The prenatal L-DOPA exposure led to significantly lower cocaine conditioned place preference, a behavioral test of reward, at postnatal day 60 (P60). However, in vivo microdialysis measurements showed significant increases in cocaine-induced dopamine release in the caudate putamen of P26 and P60 mice exposed to L-DOPA prenatally, ruling out attenuated dopamine release in the caudate putamen as a contributor to decreased conditioned place preference. Although dopamine release was induced in the nucleus accumbens of prenatally L-DOPA exposed mice at P60 by cocaine, the dopamine release in the nucleus accumbens was not significantly different between the L-DOPA and control groups. However, basal dopamine release was significantly higher in the prenatally L-DOPA exposed mice at P60 suggesting that the L-DOPA exposed mice may require a higher dose of cocaine for induction of cocaine place preference than the controls. The prenatal L-DOPA exposure did not alter cocaine-induced locomotor response, suggesting dissociation between the effects of prenatal L-DOPA exposure on conditioned place preference and locomotor activity. Tissue concentration of dopamine and its metabolites in the striatum and ventral midbrain were significantly affected by the L-DOPA exposure as well as by developmental changes over the P14-P60

  3. Trans-synaptic (GABA-dopamine) modulation of cocaine induced dopamine release: A potential therapeutic strategy for cocaine abuse

    SciTech Connect

    Dewey, S.L.; Straughter-Moore, R.; Chen, R.

    1995-05-01

    We recently developed a new experimental strategy for measuring interactions between functionally-linked neurotransmitter systems in the primate and human brain with PET. As part of this research, we demonstrated that increases in endogenous GABA concentrations significantly reduced striatal dopamine concentrations in the primate brain. We report here the application of the neurotransmitter interaction paradigm with PET and with microdialysis to the investigation of a novel therapeutic strategy for treating cocaine abuse based on the ability of GABA to inhibit cocaine induced increases in striatal dopamine. Using gamma-vinyl GABA (GVG, a suicide inhibitor of GABA transaminase), we performed a series of PET studies where animals received a baseline PET scan with labeled raclopride injection, animals received cocaine (2.0 mg/kg). Normally, a cocaine challenge significantly reduces the striatal binding of {sup 11}C-raclopride. However, in animals pretreated with GVG, {sup 11}C-raclopride binding was less affected by a cocaine challenge compared to control studies. Furthermore, microdialysis studies in freely moving rats demonstrate that GVG (300 mg/kg) significantly inhibited cocaine-induced increases in extracellular dopamine release. GVG also attenuated cocaine-induced increases in locomotor activity. However, at a dose of 100 mg/kg, GVG had no effect. Similar findings were obtained with alcohol. Alcohol pretreatment dose dependantly (1-4 g/kg) inhibited cocaine-induced increases in extracellular dopamine concentrations in freely moving rats. Taken together, these studies suggest that therapeutic strategies targeted at increasing central GABA concentrations may be beneficial for the treatment of cocaine abuse.

  4. Dopamine D3 receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: Role of hyperthermia

    PubMed Central

    Baladi, Michelle G.; Newman, Amy H.; Nielsen, Shannon M.; Hanson, Glen R.; Fleckenstein, Annette E.

    2014-01-01

    Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. PMID:24685638

  5. Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia.

    PubMed

    Baladi, Michelle G; Newman, Amy H; Nielsen, Shannon M; Hanson, Glen R; Fleckenstein, Annette E

    2014-06-05

    Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia.

  6. Rising taurine and ethanol concentrations in nucleus accumbens interact to produce the dopamine-activating effects of alcohol.

    PubMed

    Ericson, Mia; Chau, Peipei; Adermark, Louise; Söderpalm, Bo

    2013-01-01

    Alcohol misuse and addiction is a worldwide problem causing enormous individual suffering as well as financial costs for the society. To develop pharmacological means to reduce suffering, we need to understand the mechanisms underlying the effects of ethanol in the brain. Ethanol is known to increase extracellular levels of both dopamine and taurine in the nucleus accumbens (nAc), a part of the brain reward system, but the two events have not been connected. In previous studies we have demonstrated that glycine receptors in the nAc are involved in modulating both basal- and ethanol-induced dopamine output in the same brain region. By means of in vivo microdialysis in freely moving rats we here demonstrate that the endogenous glycine receptor ligand taurine mimics ethanol in activating the brain reward system. Furthermore, administration of systemic ethanol diluted in an isotonic (0.9% NaCl) or hypertonic (3.6% NaCl) saline solution was investigated with respect to extracellular levels of taurine and dopamine in the nAc. We found that ethanol given in a hypertonic solution, contrary to an isotonic solution, failed to increase concentrations of both taurine and dopamine in the nAc. However, a modest, non-dopamine elevating concentration of taurine in the nAc disclosed a dopamine elevating effect of systemic ethanol also when given in a hypertonic solution. We conclude that the elevations of taurine and dopamine in the nAc are closely related and that in order for ethanol to induce dopamine release, a simultaneous increase of extracellular taurine levels in the nAc is required. These data also -provide support for the notion that the nAc is the primary target for ethanol in its dopamine-activating effect after systemic administration and that taurine is a prominent participant in activating the brain reward system.

  7. Systemic inflammation enhances stimulant-induced striatal dopamine elevation.

    PubMed

    Petrulli, J R; Kalish, B; Nabulsi, N B; Huang, Y; Hannestad, J; Morris, E D

    2017-03-28

    Changes in the mesolimbic dopamine (DA) system are implicated in a range of neuropsychiatric conditions including addiction, depression and schizophrenia. Dysfunction of the neuroimmune system is often comorbid with such conditions and affects similar areas of the brain. The goal of this study was to use positron emission tomography with the dopamine D2 antagonist tracer, (11)C-raclopride, to explore the effect of acute immune activation on striatal DA levels. DA transmission was modulated by an oral methylphenidate (MP) challenge in order to reliably elicit DA elevation. Elevation in DA concentration due to MP was estimated via change in (11)C-raclopride binding potential from the baseline scan. Prior to the post-MP scan, subjects were pre-treated with either the immune activator lipopolysaccharide (LPS) or placebo (PBO) in a cross-over design. Immune activation was confirmed by measuring tumor necrosis factor alpha (TNFα), interleukin (IL)-6 and IL-8 concentration in plasma. Eight healthy subjects were scanned four times each to determine the MP-induced DA elevation under both LPS and PBO pre-treatment conditions. MP-induced DA elevation in the striatum was significantly greater (P<0.01) after LPS pre-treatment compared to PBO pre-treatment. Seven of eight subjects responded similarly. This effect was observed in the caudate and putamen (P<0.02), but was not present in ventral striatum. DA elevation induced by MP was significantly greater when subjects were pre-treated with LPS compared to PBO. The amplification of stimulant-induced DA signaling in the presence of systemic inflammation may have important implications for our understanding of addiction and other diseases of DA dysfunction.

  8. Dopamine-sensitive signaling mediators modulate psychostimulant-induced ultrasonic vocalization behavior in rats.

    PubMed

    Williams, Stacey N; Undieh, Ashiwel S

    2016-01-01

    The mesolimbic dopamine system plays a major role in psychostimulant-induced ultrasonic vocalization (USV) behavior in rodents. Within this system, psychostimulants elevate synaptic concentrations of dopamine thereby leading to exaggerated activation of postsynaptic dopamine receptors within the D1-like and D2-like subfamilies. Dopamine receptor stimulation activate several transmembrane signaling systems and cognate intracellular mediators; downstream activation of transcription factors then conveys the information from receptor activation to appropriate modulation of cellular and physiologic functions. We previously showed that cocaine-induced USV behavior was associated with enhanced expression of the neurotrophin BDNF. Like cocaine, amphetamine also increases synaptic dopamine levels, albeit primarily through facilitating dopamine release. Therefore, in the present study we investigated whether amphetamine and cocaine similarly activate dopamine-linked signaling cascades to regulate intracellular mediators leading to induction of USV behavior. The results show that amphetamine increased the emission of 50 kHz USVs and this effect was blocked by SCH23390, a D1 receptor antagonist. Similar to cocaine, amphetamine increased BDNF protein expression in discrete brain regions, while pretreatment with K252a, a trkB neurotrophin receptor inhibitor, significantly reduced amphetamine-induced USV behavior. Inhibition of cyclic-AMP/PKA signaling with H89 or inhibition of PLC signaling with U73122 significantly blocked both the acute and subchronic amphetamine-induced USV behavior. In contrast, pharmacologic inhibition of either pathway enhanced cocaine-induced USV behavior. Although cocaine and amphetamine similarly modulate neurotrophin expression and USV, the molecular mechanisms by which these psychostimulants differentially activate dopamine receptor subtypes or other monoaminergic systems may be responsible for the distinct aspects of behavioral responses.

  9. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration.

    PubMed

    Mor, Danielle E; Tsika, Elpida; Mazzulli, Joseph R; Gould, Neal S; Kim, Hanna; Daniels, Malcolm J; Doshi, Shachee; Gupta, Preetika; Grossman, Jennifer L; Tan, Victor X; Kalb, Robert G; Caldwell, Kim A; Caldwell, Guy A; Wolfe, John H; Ischiropoulos, Harry

    2017-09-18

    Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

  10. Dopamine receptor agonists mediate neuroprotection in malonate-induced striatal lesion in the rat.

    PubMed

    Armentero, Marie-Thérèse; Fancellu, Roberto; Nappi, Giuseppe; Blandini, Fabio

    2002-12-01

    Mitochondrial bioenergetic defects are involved in neurological disorders associated with neuronal damage in the striatum, such as Huntington's disease and cerebral ischemia. The striatal release of neurotransmitters, in particular dopamine, may contribute to the development of the neuronal damage. Recent studies have shown that dopamine agonists may exert neuroprotective effects via multiple mechanisms, including modulation of dopamine release from nigrostriatal dopaminergic terminals. In rats, intrastriatal injection of malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces a lesion similar to that observed following focal ischemia or in Huntington's disease. In this study, we used the malonate model to explore the neuroprotective potential of dopamine agonists. Sprague-Dawley rats were injected systemically with increasing concentrations of D(1), D(2), or mixed D(1)/D(2) dopamine agonists prior to malonate intrastriatal insult. Administration of increasing doses of the D(2)-specific agonist quinpirole resulted in increased protection against malonate toxicity. Conversely, the D(1)-specific agonist SKF-38393, as well as the mixed D(1)/D(2) agonist apomorphine, conferred higher neuroprotection at lower than at higher concentrations. Our data suggest that malonate-induced striatal toxicity can be attenuated by systemic administration of dopamine agonists, with D(1) and D(2) agonists showing different profiles of efficacy.

  11. Propentophylline increases striatal dopamine release but dampens methamphetamine-induced dopamine dynamics: A microdialysis study.

    PubMed

    Gough, B; Pereira, F C; Fontes Ribeiro, C A; Ali, S F; Binienda, Z K

    2014-10-01

    While there are currently no medications approved for methamphetamine (METH) addiction, it has been shown that propentofylline (PPF), an atypical methylxanthine, can suppress the rewarding effects of methamphetamine (METH) in mice. This experiment studied the interactions of PPF with METH in striatal dopaminergic transmission. Herein, the impact of PPF (10-40mM, intrastriatally perfused (80min) on the effect of METH (5mg/kg, i.p.) on striatal dopamine (DA) release was evaluated using brain microdialysis in Sprague-Dawley adult rats. METH was injected at the 60min time point of the 80min PPF perfusion. The extracellular levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined using high performance liquid chromatography with electrochemical detection (HPLC-ED). PPF induced a concentration-dependent increase in DA release beginning 30min after the onset of PPF perfusion. DA peak levels evoked by 40mM PPF were similar to those induced by 5mg/kg METH i.p. Only the highest concentration of PPF decreased the METH-induced DA peak (circa 70%). The significant decreases in extracellular levels of DOPAC and HVA evoked by METH were partially blocked by 10 and 20mM PPF. Although 40mM of PPF also partially blocked the METH-induced DOPAC decrease, it completely blocked HVA depletion after a transient increase in HVA levels in METH-treated rats. Data indicates for the first time that while PPF increases presynaptic striatal DA dynamics it attenuates METH-induced striatal DA release and metabolism. Published by Elsevier Ltd.

  12. Inhaled dopamine induces bronchodilatation in patients with bronchial asthma.

    PubMed

    Cabezas, G A; Lezama, Y; Vidal, A; Velasco, M

    1999-10-01

    To determine the probable bronchodilating effect of dopamine administered by inhalation route in patients with crisis of bronchial asthma and the effect of dopamine on bronchial motor tone. We have studied eighteen (18) patients with crisis of bronchial asthma, ten (10) subjects with bronchial hyperreactivity and ten (10) healthy subjects. Patients with other pulmonary or cardiac disease were excluded. All received by inhalation placebo (0.9% saline solution), dopamine at 0.5 microg/kg/min (controlled by heart rate and arterial pressure with a dynamap), and placebo. Respiratory parameters: forced vital capacity (FVC), forced expiratory volume at the first second (FEV1), forced maximal expiratory flow (FEFmax) and forced expiratory flow at the 50% of vital capacity (FEF50) were measured in each protocol period. Student's paired t test, Wilcoxon and Mann Whitney analysis were performed. After dopamine inhalation, there was an increase of FVC by 23% (p<0.001); an increase of FEV1 by 39% (p<0.0001); an increase of FEF50 by 33% (p<0.001) and an increase of FEFmax by 31% (p<0.001). There were no respiratory parameter changes in both, subjects with bronchial hyperreactivity and normal after dopamine inhalation. Inhaled dopamine induces bronchodilatation in patients with crisis of bronchial asthma. Inhaled dopamine neither alters basal bronchial tone in healthy subjects nor in subjects with bronchial hyperreactivity.

  13. Dopamine alleviates salt-induced stress in Malus hupehensis.

    PubMed

    Li, Chao; Sun, Xiangkai; Chang, Cong; Jia, Dongfeng; Wei, Zhiwei; Li, Cuiying; Ma, Fengwang

    2015-04-01

    Dopamine mediates many physiological processes in plants. We investigated its role in regulating growth, ion homeostasis and the response to salinity in Malus hupehensis Rehd. Both hydroponics and field-pot experiments were conducted under saline conditions. Salt-stressed plants had reduced growth and a marked decline in their net photosynthetic rates, values for Fv /Fm and chlorophyll contents. However, pretreatment with 100 or 200 μM dopamine significantly alleviated this inhibition and enabled plants to maintain their photosynthetic capacity. In addition to changing stomatal behavior, supplementation with dopamine positively influenced the uptake of K, N, P, S, Cu and Mn ions but had an inhibitory effect on Na and Cl uptake, the balance of which is responsible for managing the response to salinity by Malus plants. Dopamine pretreatment also controlled the burst of hydrogen peroxide, possibly through direct scavenging and by enhancing the activities of antioxidative enzymes and the capacity of the ascorbate-glutathione cycle. We also investigated whether dopamine might regulate salt overly sensitive pathway genes under salinity. Here, MdHKT1, MdNHX1 and MdSOS1 were greatly upregulated in roots and leaves, which possibly contributed to the maintenance of ion homeostasis and, thus, improved salinity resistance in plants exposed earlier to exogenous dopamine. These results support our conclusion that dopamine alleviates salt-induced stress not only at the level of antioxidant defense but also by regulating other mechanisms of ion homeostasis.

  14. Endogenous dopamine increases extracellular concentrations of glutamate and GABA in striatum of the freely moving rat: involvement of D1 and D2 dopamine receptors.

    PubMed

    Expósito, I; Del Arco, A; Segovia, G; Mora, F

    1999-07-01

    Interactions between endogenous dopamine, glutamate, GABA, and taurine were investigated in striatum of the freely moving rat by using microdialysis. Intrastriatal infusions of the selective dopamine uptake inhibitor nomifensine (NMF) were used to increase the endogenous extracellular dopamine. NMF produced a dose-related increase in extracellular dopamine and also increased extracellular concentrations of glutamate, GABA, and taurine. Extracellular increases of dopamine were significantly correlated with extracellular increases of glutamate and GABA, but not taurine. To investigate whether the increased extracellular dopamine produced by NMF was responsible for the concomitant increase of glutamate and GABA, D1, and D2 receptor antagonists were used. Dopamine receptor antagonists D1 (SCH23390) and D2 (sulpiride) significantly attenuated the increases of glutamate and GABA produced by NMF. These data suggest that endogenous dopamine, through both D1 and D2 dopamine receptors, plays a role in releasing glutamate and GABA in striatum of the freely moving rat.

  15. Neuroprotective effects mediated by dopamine receptor agonists against malonate-induced lesion in the rat striatum.

    PubMed

    Fancellu, R; Armentero, M-T; Nappi, G; Blandini, F

    2003-10-01

    In rats, intrastriatal injection of malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces a lesion similar to that observed following focal ischemia or in Huntington's disease. In this study we used the malonate model to explore the neuroprotective potential of dopamine agonists. Rats were injected intraperitoneally with increasing concentrations of D1, D2, or mixed D1/D2 dopamine agonists prior to intrastriatal injection of malonate. Administration of increasing doses of the D2-specific agonist quinpirole resulted in increased protection against malonate toxicity. Conversely, the D1-specific agonist SKF-38393, as well as the mixed D1/D2 agonist apomorphine, conferred higher neuroprotection at lower than at higher drug concentrations. Our data suggest that malonate- induced striatal toxicity can be attenuated by systemic administration of dopamine agonists, with D1 and D2 agonists showing different profiles of efficacy.

  16. Monitoring Dopamine Quinone-Induced Dopaminergic Neurotoxicity Using Dopamine Functionalized Quantum Dots.

    PubMed

    Ma, Wei; Liu, Hui-Ting; Long, Yi-Tao

    2015-07-08

    Dopamine (DA) quinone-induced dopaminergic neurotoxicity is known to occur due to the interaction between DA quinone and cysteine (Cys) residue, and it may play an important a role in pathological processes associated with neurodegeneration. In this study, we monitored the interaction process of DA to form DA quinone and the subsequent Cys residue using dopamine functionalized quantum dots (QDs). The fluorescence (FL) of the QD bioconjugates changes as a function of the structure transformation during the interaction process, providing a potential FL tool for monitoring dopaminergic neurotoxicity.

  17. Dopamine-Induced Conformational Changes in Alpha-Synuclein

    PubMed Central

    Outeiro, Tiago F.; Klucken, Jochen; Bercury, Kathryn; Tetzlaff, Julie; Putcha, Preeti; Oliveira, Luis M. A.; Quintas, Alexandre; McLean, Pamela J.; Hyman, Bradley T.

    2009-01-01

    Background Oligomerization and aggregation of α-synuclein molecules play a major role in neuronal dysfunction and loss in Parkinson's disease [1]. However, α-synuclein oligomerization and aggregation have mostly been detected indirectly in cells using detergent extraction methods [2], [3], [4]. A number of in vitro studies showed that dopamine can modulate the aggregation of α-synuclein by inhibiting the formation of or by disaggregating amyloid fibrils [5], [6], [7]. Methodology/Principal Findings Here, we show that α-synuclein adopts a variety of conformations in primary neuronal cultures using fluorescence lifetime imaging microscopy (FLIM). Importantly, we found that dopamine, but not dopamine agonists, induced conformational changes in α-synuclein which could be prevented by blocking dopamine transport into the cell. Dopamine also induced conformational changes in α-synuclein expressed in neuronal cell lines, and these changes were also associated with alterations in oligomeric/aggregated species. Conclusion/Significance Our results show, for the first time, a direct effect of dopamine on the conformation of α-synuclein in neurons, which may help explain the increased vulnerability of dopaminergic neurons in Parkinson's disease. PMID:19730729

  18. Signaling Mechanisms in the Nitric Oxide Donor- and Amphetamine-Induced Dopamine Release in Mesencephalic Primary Cultured Neurons.

    PubMed

    Salum, Cristiane; Schmidt, Fanny; Michel, Patrick P; Del-Bel, Elaine; Raisman-Vozari, Rita

    2016-01-01

    Previous research has shown that nitric oxide (NO) synthase inhibitors prevent rodents' sensorimotor gating impairments induced by dopamine releasing drugs, such as amphetamine (Amph) and methylphenidate. The mechanisms of this effect have not been entirely understood. In the present work, we investigated some possible mechanisms by which the NO donor, NOC-12 (3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene), influence spontaneous and Amph-induced dopamine release, using rat mesencephalic primary cultured neurons preparations. Our results showed that NOC-12 increased dopamine release in a concentration-dependent manner and potentiated the Amph-induced one. Dopamine release induced by NOC-12 was disrupted by N-acetyl-L-cystein (NAC-a free radical scavenger) and MK-801, a NMDA (N-methyl-D-aspartate) non-competitive antagonist, and was concentration dependently affected by oxadiazolo[4,3]quinoxalin-1-one, an inhibitor of the soluble guanylate cyclase (sGC). In contrast, dopamine released by Amph was facilitated by NAC and by MK-801 and not affected by nifedipine (a L-type-Ca(+2) channel blocker), which enhanced NOC-12-induced dopamine release. The present work demonstrates that DA release induced by NOC-12 is partially dependent on sGC and on NMDA activation, and is modulated by L-type Ca(+2) channel and the antioxidant NAC. This mechanism differs from the Amph-induced one, which appears not to depend on L-type Ca(+2) channel and seems to be facilitated by NMDA channel blocking and by NAC. These results suggest that Amph and NOC-12 induce dopamine release through complementary pathways, which may explain the potentiation of Amph-induced dopamine release by NOC-12. These findings contribute to understand the involvement of NO in dopamine-related neuropsychiatric and neurodegenerative diseases.

  19. Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human α-synuclein.

    PubMed

    Lam, Hoa A; Wu, Nanping; Cely, Ingrid; Kelly, Rachel L; Hean, Sindalana; Richter, Franziska; Magen, Iddo; Cepeda, Carlos; Ackerson, Larry C; Walwyn, Wendy; Masliah, Eliezer; Chesselet, Marie-Françoise; Levine, Michael S; Maidment, Nigel T

    2011-07-01

    Overexpression or mutation of α-synuclein (α-Syn), a protein associated with presynaptic vesicles, causes familial forms of Parkinson's disease in humans and is also associated with sporadic forms of the disease. We used in vivo microdialysis, tissue content analysis, behavioral assessment, and whole-cell patch clamp recordings from striatal medium-sized spiny neurons (MSSNs) in slices to examine dopamine transmission and dopaminergic modulation of corticostriatal synaptic function in mice overexpressing human wild-type α-Syn under the Thy1 promoter (α-Syn mice). Tonic striatal extracellular dopamine and 3-methoxytyramine levels were elevated in α-Syn mice at 6 months of age, prior to any reduction in total striatal tissue content, and were accompanied by an increase in open-field activity. Dopamine clearance and amphetamine-induced dopamine efflux were unchanged. The frequency of MSSN spontaneous excitatory postsynaptic currents (sEPSCs) was lower in α-Syn mice. Amphetamine reduced sEPSC frequency in wild types (WTs) but produced no effect in α-Syn mice. Furthermore, whereas quinpirole reduced and sulpiride increased sEPSC frequency in WT mice, they produced the opposite effects in α-Syn mice. These observations indicate that overexpression of α-Syn alters dopamine efflux and D2 receptor modulation of corticostriatal glutamate release at a young age. At 14 months of age, the α-Syn mice presented with significantly lower striatal tissue dopamine and tyrosine hydroxylase content relative to WT littermates, accompanied by an L-DOPA-reversible sensory motor deficit. Together, these data further validate this transgenic mouse line as a slowly progressing model of Parkinson's disease and provide evidence for early dopamine synaptic dysfunction prior to loss of striatal dopamine. Copyright © 2011 Wiley-Liss, Inc.

  20. Delta 9-tetrahydrocannabinol induces dopamine release in the human striatum.

    PubMed

    Bossong, Matthijs G; van Berckel, Bart N M; Boellaard, Ronald; Zuurman, Lineke; Schuit, Robert C; Windhorst, Albert D; van Gerven, Joop M A; Ramsey, Nick F; Lammertsma, Adriaan A; Kahn, René S

    2009-02-01

    The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that Delta 9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D(2)/D(3) receptor tracer [(11)C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [(11)C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia.

  1. Dual regulating effects of gastrodin on extracellular dopamine concentration in rats models of Tourette's syndrome.

    PubMed

    Zhang, Feng; Li, Anyuan

    2015-01-01

    Evaluate the dual regulating effects of gastrodin on striatal extracellular dopamine (DA) concentration in Tourette's syndrome (TS) rat models, and explore the underlying pharmacological mechanisms. Seventy Wistar rats were randomly divided into control group and TS model group. The former was intraperitoneally injected with saline (0.9%), while in the later, the rats were injected with Apomorphine (Apo) and 3,3'-iminodipropionitrile (IDPN) respectively to manipulate two kinds of TS rat models. Both Apo and IDPN induced rats were further assigned to three conditions, and the related rats were treated respectively by oral gavage with saline, gastrodin and Haloperidol (Hal). Data of stereotypy of the rats were collected. After 8 weeks, the extracellular content of DA and HVA in striatum were examined by intracerebral microdialysis and follow-up high-performance liquid chromatography (HPLC), and the expression of dopamine transporter (DAT) was probed by Western blot. Gastrodin improved the stereotyped behaviors in TS rats. Furthermore, it down-regulated the elevated striatal extracellular DA concentration in Apo-induced rats and up-regulated the decreased DA content in the rats exposed to IDPN. Meanwhile, a dramatic down-regulation was detected in DAT protein expression in Apo + GAS group, while an opposite profile was showed in the IDPN + GAS group. The dual regulating effects of gastrodin on extracellular DA level have been established, and the related mechanisms would be the dual regulating effects of gastrodin on the expression of DAT, a glycoprotein in the regulation of the extracellular DA concentration.

  2. Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.

    PubMed

    Gross, Noah B; Duncker, Patrick C; Marshall, John F

    2011-11-01

    Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex. Copyright © 2011 Wiley-Liss, Inc.

  3. [Study of extracellular concentration of dopamine and its metabolites in mice striatum by a microdialysis technique at intraperitoneal administration of MPTP].

    PubMed

    Averkin, R G; Korshunov, V A; Shchegolevskiĭ, N V; Mats, V N; Markevich, V A; Grigor'ian, G A; Bazian, A S

    2010-01-01

    In this paper a structure of a microdialytic cannula inserted into brain areas just before a microdialysis is described. The cannula used allowed to find out a correspondence of behavioral and biochemical changes in C57BL/6 mice at various time intervals after a single dose administration (20 mg/kg) of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, without any additional pharmacological actions enhancing an extracellular striatal dopamine concentration. Immediately after 1-methyl-4-phenyl-1.2,3.6-tetrahydropyridine administration an essential disturbance of mice behavior and a significant reduction of the extracellular concentration of dopamine and homovanillic acid were observed in striatum. A week after the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration neither behavior nor the extracellular dopamine and homovanillic acid striatal concentration substantially differed from those of controls. 30 days after the neurotoxin administration there was again an essential disturbance of behavior and the large reduction of dopamine and its metabolite concentration in striatum. There was suggested that a reduction of the dopamine concentration immediately after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection connected with abnormalities of dopamine synthesis and metabolism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine whereas a reduction of the extracellular striatal dopamine concentration 30 days after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration related to damage of the nigrastriatal dopaminergic system.

  4. Dopamine alleviates nutrient deficiency-induced stress in Malus hupehensis.

    PubMed

    Liang, Bowen; Li, Cuiying; Ma, Changqing; Wei, Zhiwei; Wang, Qian; Huang, Dong; Chen, Qi; Li, Chao; Ma, Fengwang

    2017-10-01

    Dopamine mediates many physiological processes in plants. We investigated its role in regulating growth, root system architecture, nutrient uptake, and responses to nutrient deficiencies in Malus hupehensis Rehd. Under a nutrient deficiency, plants showed significant reductions in growth, chlorophyll concentrations, and net photosynthesis, along with disruptions in nutrient uptake, transport, and distribution. However, pretreatment with 100 μM dopamine markedly alleviated such inhibitions. Supplementation with that compound enabled plants to maintain their photosynthetic capacity and development of the root system while promoting the uptake of N, P, K, Ca, Mg, Fe, Mn, Cu, Zn, and B, altering the way in which those nutrients were partitioned throughout the plant. The addition of dopamine up-regulated genes for antioxidant enzymes involved in the ascorbate-glutathione cycle (MdcAPX, MdcGR, MdMDHAR, MdDHAR-1, and MdDHAR-2) but down-regulated genes for senescence (SAG12, PAO, and MdHXK). These results indicate that exogenous dopamine has an important antioxidant and anti-senescence effect that might be helpful for improving nutrient uptake. Our findings demonstrate that dopamine offers new opportunities for its use in agriculture, especially when addressing the problem of nutrient deficiencies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Dopamine selectively sensitizes dopaminergic neurons to rotenone-induced apoptosis.

    PubMed

    Ahmadi, Ferogh A; Grammatopoulos, Tom N; Poczobutt, Andy M; Jones, Susan M; Snell, Laurence D; Das, Mita; Zawada, W Michael

    2008-05-01

    Among various types of neurons affected in Parkinson's disease, dopamine (DA) neurons of the substantia nigra undergo the most pronounced degeneration. Products of DA oxidation and consequent cellular damage have been hypothesized to contribute to neuronal death. To examine whether elevated intracellular DA will selectively predispose the dopaminergic subpopulation of nigral neurons to damage by an oxidative insult, we first cultured rat primary mesencephalic cells in the presence of rotenone to elevate reactive oxygen species. Although MAP2(+) neurons were more sensitive to rotenone-induced toxicity than type 1 astrocytes, rotenone affected equally both DA (TH(+)) neurons and MAP2(+) neurons. In contrast, when intracellular DA concentration was elevated, DA neurons became selectively sensitized to rotenone. Raising intracellular DA levels in primary DA neurons resulted in dopaminergic neuron death in the presence of subtoxic concentrations of rotenone. Furthermore, mitochondrial superoxide dismutase mimetic, manganese (III) meso-tetrakis (4-benzoic acid) porphyrin, blocked activation of caspase-3, and consequent cell death. Our results demonstrate that an inhibitor of mitochondrial complex I and increased cytosolic DA may cooperatively lead to conditions of elevated oxidative stress and thereby promote selective demise of dopaminergic neurons.

  6. Gene Variants of Brain Dopamine Pathways and Smoking-Induced Dopamine Release in the Ventral Caudate/Nucleus Accumbens

    PubMed Central

    Brody, Arthur L.; Mandelkern, Mark A.; Olmstead, Richard E.; Scheibal, David; Hahn, Emily; Shiraga, Sharon; Zamora-Paja, Eleanor; Farahi, Judah; Saxena, Sanjaya; London, Edythe D.; McCracken, James T.

    2010-01-01

    Context Preclinical studies demonstrate that nicotine administration leads to dopamine release in the ventral striatum. However, human studies reveal considerable interindividual variability in the extent of smoking-induced dopamine release. Objective To determine whether common gene variants of the brain dopamine pathway explain this observed phenotypic variability in humans. Design Blood samples were drawn to determine gene variants of dopamine system components, and positron emission tomography scanning with the radiotracer raclopride labeled with radioactive carbon (11C) was performed to measure smoking-induced dopamine release. Setting Academic brain imaging center. Participants Forty-five tobacco-dependent smokers. Interventions Subjects either smoked a cigarette (n=35) or did not smoke (n=10) during positron emission tomography scanning. Main Outcome Measures Gene variants of dopamine system components (the dopamine transporter variable nucleotide tandem repeat, D2 receptor Taq A1/A2, D4 receptor variable nucleotide tandem repeat, and catechol-O-methyltransferase Val158Met polymorphisms) and change in [11C]raclopride binding potential in the ventral caudate/nucleus accumbens on positron emission tomography scans. Results For subjects who smoked during scanning, those with at least one 9 allele of the dopamine transporter variable nucleotide tandem repeat, fewer than 7 repeats of the D4 variable nucleotide tandem repeat, and the Val/Val catechol-O-methyltransferase genotype had greater decreases in binding potential (an indirect measure of dopamine release) with smoking than those with the alternate genotypes. An overall decrease in ventral caudate/nucleus accumbens binding potential in those who smoked compared with those who did not smoke was also found but was smaller in magnitude than previously reported. Conclusions Smokers with genes associated with low resting dopamine tone have greater smoking-induced (phasic) dopamine release than those with

  7. Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe?

    PubMed

    Lertxundi, Unax; Domingo-Echaburu, Saioa; Peral, Javier; García, Montserrat

    2011-09-15

    Published literature shows that dopamine agonists can reverse antipsychotic-induced hyperprolactinemia without worsening psychotic symptoms in the majority of schizophrenic patients. However, psychiatrists have been reluctant to use drugs with dopaminergic properties for fear of exacerbating psychiatric symptoms. There are reported cases of psychosis worsening published for both cabergoline and bromocriptine. Cabergoline has proven to be more effective and safe when used to treat hyperprolactinemia, but whether cabergoline is also safer than bromocriptine in antipsychotic induced hyperprolactinemia remains unproven.

  8. Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe?

    PubMed Central

    Lertxundi, Unax; Domingo-Echaburu, Saioa; Peral, Javier; García, Montserrat

    2011-01-01

    Published literature shows that dopamine agonists can reverse antipsychotic-induced hyperprolactinemia without worsening psychotic symptoms in the majority of schizophrenic patients. However, psychiatrists have been reluctant to use drugs with dopaminergic properties for fear of exacerbating psychiatric symptoms. There are reported cases of psychosis worsening published for both cabergoline and bromocriptine. Cabergoline has proven to be more effective and safe when used to treat hyperprolactinemia, but whether cabergoline is also safer than bromocriptine in antipsychotic induced hyperprolactinemia remains unproven. PMID:27738363

  9. Taurine infused intrastriatally elevates, but intranigrally decreases striatal extracellular dopamine concentration in anaesthetised rats.

    PubMed

    Ruotsalainen, M; Heikkilä, M; Lillsunde, P; Seppälä, T; Ahtee, L

    1996-01-01

    In the present study we infused taurine (50, 150 or 450 mM, 2 microliters/min for 4h) into the dorsal striatum or into the substantia nigra via microdialysis probe and estimated the extracellular concentrations of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the dorsal striatum of anaesthetised rats. Intrastriatal infusion of taurine elevated striatal dopamine at all concentrations studied. At the 450 mM concentration taurine elevated the extracellular dopamine 10-fold, but only in the first 30 min sample after starting the taurine infusion. At 50 and 150 mM taurine elevated dopamine throughout the 4h infusion maximally up to 3-4-fold the control level. Extracellular DOPAC was increased by 150 and 450 mM taurine (up to about 150-160% of the control level), whereas at all three concentrations taurine decreased HVA to about 85% of the control; however, the decrease caused by 450 mM taurine was short-lasting. At all three concentrations taurine infused into the substantia nigra decreased the extracellular dopamine in the ipsilateral striatum to about 40-50% of the control, and increased extracellular DOPAC and HVA maximally to about 150% and 170% of the control, respectively. These results show that the effects of taurine on the concentrations of extracellular dopamine and its metabolites depend on its administration site on nigrostriatal dopaminergic neurons. It elevates the extracellular dopamine when given into the striatum, but when given into the cell body region of the nigrostriatal dopaminergic pathway it decreases the extracellular dopamine in the ipsilateral striatum.

  10. The dopamine antagonist domperidone increases prolactin concentration and enhances milk production in dairy cows.

    PubMed

    Lacasse, P; Ollier, S

    2015-11-01

    In previous studies, our team showed that the inhibition of prolactin (PRL) secretion by the dopamine agonist quinagolide reduces milk production in dairy cows. The objective of this study was to determine the effects of administration of a dopamine antagonist on basal and milking-induced PRL concentrations in blood and on milk production during positive energy balance and feed restriction in dairy cows. Eighteen mid-lactation Holstein cows received daily s.c. injections of either domperidone (300 mg, DOMP, n=9) or the vehicle, canola oil (CTL, n=9), for 5 wk. During wk 5, all cows were fed at 65% of their dry matter intake in the previous week. Blood and milk samples were collected before (for blood) and during (for milk) the a.m. milking thrice weekly from d -9 to 41 (8d after the last injection). In addition, blood samples were collected during the a.m. milking on d -1 (before the first injection), and on d 1, 28, and 34. Basal PRL concentration was similar in both groups before the start of the treatments. Domperidone injections caused a gradual increase in basal PRL concentration. Feed restriction reduced basal PRL concentration in both the CTL and DOMP cows, but PRL concentration remained higher in the DOMP cows. Prolactin concentration remained elevated in the DOMP cows 7d after the last injection. The milk concentration of PRL increased during the DOMP treatment, but the increase was smaller than that observed in serum. In the CTL cows, the milking-induced PRL release above the premilking concentration was similar on d -1, 1, and 28 but was reduced during feed restriction. In the DOMP cows, the milking-induced PRL release was similar on d -1 and 1 but was reduced on d 28 and 34. Milk production was similar for both groups before the treatments started but was greater in the DOMP cows during the treatment period, at 2.9 ± 0.6 and 2.4 ± 0.6 kg/d greater during wk 3 and 4 of treatment, respectively. Milk production declined in both groups during feed

  11. Implications for glycine receptors and astrocytes in ethanol-induced elevation of dopamine levels in the nucleus accumbens.

    PubMed

    Adermark, Louise; Clarke, Rhona B C; Olsson, Torsten; Hansson, Elisabeth; Söderpalm, Bo; Ericson, Mia

    2011-01-01

    Elevated dopamine levels are believed to contribute to the rewarding sensation of ethanol (EtOH), and previous research has shown that strychnine-sensitive glycine receptors in the nucleus accumbens (nAc) are involved in regulating dopamine release and in mediating the reinforcing effects of EtOH. Furthermore, the osmoregulator taurine, which is released from astrocytes treated with EtOH, can act as an endogenous ligand for the glycine receptor, and increase extracellular dopamine levels. The aim of this study was to address if EtOH-induced swelling of astrocytes could contribute to elevated dopamine levels by increasing the extracellular concentration of taurine. Cell swelling was estimated by optical sectioning of fluorescently labeled astrocytes in primary cultures from rat, and showed that EtOH (25-150 mM) increased astrocyte cell volumes in a concentration- and ion-dependent manner. The EtOH-induced cell swelling was inhibited in cultures treated with the Na(+) /K(+) /2Cl⁻ cotransporter blocker furosemide (1 mM), Na(+) /K(+) -ATPase inhibitor ouabain (0.1 mM), potassium channel inhibitor BaCl₂ (50 µM) and in cultures containing low extracellular sodium concentration (3 mM). In vivo microdialysis performed in the nAc of awake and freely moving rats showed that local treatment with EtOH enhanced the concentrations of dopamine and taurine in the microdialysate, while glycine and β-alanine levels were not significantly modulated. EtOH-induced dopamine release was antagonized by local treatment with the glycine receptor antagonist strychnine (20 µM) or furosemide (100 µM or 1 mM). Furosemide also prevented EtOH-induced taurine release in the nAc. In conclusion, our data suggest that extracellular concentrations of dopamine and taurine are interconnected and that swelling of astrocytes contributes to the acute rewarding sensation of EtOH.

  12. Antipsychotic Induced Dopamine Supersensitivity Psychosis: A Comprehensive Review.

    PubMed

    Yin, John; Barr, Alasdair M; Ramos-Miguel, Alfredo; Procyshyn, Ric M

    2017-01-01

    Chronic prescription of antipsychotics seems to lose its therapeutic benefits in the prevention of recurring psychotic symptoms. In many instances, the occurrence of relapse from initial remission is followed by an increase in dose of the prescribed antipsychotic. The current understanding of why this occurs is still in its infancy, but a controversial idea that has regained attention recently is the notion of iatrogenic dopamine supersensitivity. Studies on cell cultures and animal models have shown that long-term antipsychotic use is linked to both an upregulation of dopamine D2-receptors in the striatum and the emergence of enhanced receptor affinity to endogenous dopamine. These findings have been hypothesized to contribute to the phenomenon known as dopamine supersensitivity psychosis (DSP), which has been clinically typified as the foundation of rebound psychosis, drug tolerance, and tardive dyskinesia. The focus of this review is the update of evidence behind the classification of antipsychotic induced DSP and an investigation of its relationship to treatment resistance. Since antipsychotics are the foundation of illness management, a greater understanding of DSP and its prevention may greatly affect patient outcomes.

  13. Antipsychotic Induced Dopamine Supersensitivity Psychosis: A Comprehensive Review

    PubMed Central

    Yin, John; Barr, Alasdair M.; Ramos-Miguel, Alfredo; Procyshyn, Ric M.

    2017-01-01

    Chronic prescription of antipsychotics seems to lose its therapeutic benefits in the prevention of recurring psychotic symptoms. In many instances, the occurrence of relapse from initial remission is followed by an increase in dose of the prescribed antipsychotic. The current understanding of why this occurs is still in its infancy, but a controversial idea that has regained attention recently is the notion of iatrogenic dopamine supersensitivity. Studies on cell cultures and animal models have shown that long-term antipsychotic use is linked to both an upregulation of dopamine D2-receptors in the striatum and the emergence of enhanced receptor affinity to endogenous dopamine. These findings have been hypothesized to contribute to the phenomenon known as dopamine supersensitivity psychosis (DSP), which has been clinically typified as the foundation of rebound psychosis, drug tolerance, and tardive dyskinesia. The focus of this review is the update of evidence behind the classification of antipsychotic induced DSP and an investigation of its relationship to treatment resistance. Since antipsychotics are the foundation of illness management, a greater understanding of DSP and its prevention may greatly affect patient outcomes. PMID:27264948

  14. Associations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis.

    PubMed

    Andreou, Dimitrios; Söderman, Erik; Axelsson, Tomas; Sedvall, Göran C; Terenius, Lars; Agartz, Ingrid; Jönsson, Erik G

    2016-04-21

    Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder. We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls. We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia.

  15. The decrease in hypothalamic dopamine secretion induced by suckling: comparison of voltammetric and radioisotopic methods of measurement. [Rats

    SciTech Connect

    Plotsky, P.M.; Neill, J.D.

    1982-03-01

    Previous in situ voltammetric microelectrode measurements of median eminence dopamine release during mammary nerve stimulation of anesthetized lactating rats revealed a transient (1-3 min) 70% decline of dopamine concentrations. This dopamine was believed to be destined for secretion into the hypophysial portal circulation, but direct experimental support for this supposition was lacking. Thus, in the present study, (3H)dopamine release into brief sequential samples of hypophysial portal blood was compared with dopamine release in the median eminence measured by voltammetry. Lactating female rats were urethane anesthetized, and the median eminence pituitary region was exposed. (3H)Tyrosine was injected into a jugular cannula (100 microCi) followed by continuous infusion (5 microCi/min). In a preliminary experiment, this regimen produced a steady state level of (3H)dopamine in the portal blood within 45 min. In subsequent experiments, portal blood was collected as sequential 3-min samples, and electrochemical sampling from a microelectrode placed in the median eminence occurred at 1-min intervals. Electrochemical current resulting from the oxidation of dopamine in the medial median eminence was unvarying throughout the 75-min experiment in control rats (n . 4) and during the 30-min control period preceding mammary nerve stimulation in the other group (n . 4). These results were paralled by (3H) dopamine levels in portal blood during the same periods of time. All animals showed simultaneous decreases in oxidation current and (3H)dopamine levels within 1-4 min after initiation of mammary nerve stimulation. These and earlier results demonstrate that mammary nerve stimulation (and by extension, suckling) induces a momentary, but profound, decrease in hypothalamic dopamine secretion which precedes or accompanies the rise in PRL secretion evoked by the same stimulus.

  16. Dopamine inhibits lipopolysaccharide-induced nitric oxide production through the formation of dopamine quinone in murine microglia BV-2 cells.

    PubMed

    Yoshioka, Yasuhiro; Sugino, Yuta; Tozawa, Azusa; Yamamuro, Akiko; Kasai, Atsushi; Ishimaru, Yuki; Maeda, Sadaaki

    2016-02-01

    Dopamine (DA) has been suggested to modulate functions of glial cells including microglial cells. To reveal the regulatory role of DA in microglial function, in the present study, we investigated the effect of DA on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in murine microglial cell line BV-2. Pretreatment with DA for 24 h concentration-dependently attenuated LPS-induced NO production in BV-2 cells. The inhibitory effect of DA on LPS-induced NO production was not inhibited by SCH-23390 and sulpiride, D1-like and D2-like DA receptor antagonists, respectively. In addition, pretreatment with (-)-(6aR,12bR)-4,6,6a,7,8,12b-Hexahydro-7-methylindolo[4,3-a]phenanthridin (CY 208-243) and bromocriptine, D1-like and D2-like DA receptor agonists, respectively, did not affect the LPS-induced NO production. N-Acetylcysteine, which inhibits DA oxidation, completely inhibited the effect of DA. Tyrosinase, which catalyzes the oxidation of DA to DA quionone (DAQ), accelerated the inhibitory effect of DA on LPS-induced NO production. These results suggest that DA attenuates LPS-induced NO production through the formation of DAQ in BV-2 cells.

  17. Demon voltammetry and analysis software: Analysis of cocaine-induced alterations in dopamine signaling using multiple kinetic measures

    PubMed Central

    Yorgason, Jordan T.; España, Rodrigo A.; Jones, Sara R.

    2011-01-01

    The fast sampling rates of fast scan cyclic voltammetry make it a favorable method for measuring changes in brain monoamine release and uptake kinetics in slice, anesthetized, and freely moving preparations. The most common analysis technique for evaluating changes in dopamine signaling uses well-established Michaelis-Menten kinetic methods that can accurately model dopamine release and uptake parameters across multiple experimental conditions. Nevertheless, over the years, many researchers have turned to other measures to estimate changes in dopamine release and uptake, yet to our knowledge no systematic comparison amongst these measures has been conducted. To address this lack of uniformity in kinetic analyses, we have created the Demon Voltammetry and Analysis software suite, which is freely available to academic and non-profit institutions. Here we present an explanation of the Demon Acquisition and Analysis features, and demonstrate its utility for acquiring voltammetric data under in vitro, in vivo anesthetized, and freely moving conditions. Additionally, the software was used to compare the sensitivity of multiple kinetic measures of release and uptake to cocaine-induced changes in electrically evoked dopamine efflux in nucleus accumbens core slices. Specifically, we examined and compared tau, full width at half height, half-life, T20, T80, slope, peak height, calibrated peak dopamine concentration, and area under the curve to the well-characterized Michaelis-Menten parameters, dopamine per pulse, maximal uptake rate, and apparent affinity. Based on observed results we recommend tau for measuring dopamine uptake and calibrated peak dopamine concentration for measuring dopamine release. PMID:21392532

  18. Demon voltammetry and analysis software: analysis of cocaine-induced alterations in dopamine signaling using multiple kinetic measures.

    PubMed

    Yorgason, Jordan T; España, Rodrigo A; Jones, Sara R

    2011-11-15

    The fast sampling rates of fast scan cyclic voltammetry make it a favorable method for measuring changes in brain monoamine release and uptake kinetics in slice, anesthetized, and freely moving preparations. The most common analysis technique for evaluating changes in dopamine signaling uses well-established Michaelis-Menten kinetic methods that can accurately model dopamine release and uptake parameters across multiple experimental conditions. Nevertheless, over the years, many researchers have turned to other measures to estimate changes in dopamine release and uptake, yet to our knowledge no systematic comparison amongst these measures has been conducted. To address this lack of uniformity in kinetic analyses, we have created the Demon Voltammetry and Analysis software suite, which is freely available to academic and non-profit institutions. Here we present an explanation of the Demon Voltammetry acquisition and analysis features, and demonstrate its utility for acquiring voltammetric data under in vitro, in vivo anesthetized, and freely moving conditions. Additionally, the software was used to compare the sensitivity of multiple kinetic measures of release and uptake to cocaine-induced changes in electrically evoked dopamine efflux in nucleus accumbens core slices. Specifically, we examined and compared tau, full width at half height, half-life, T₂₀, T₈₀, slope, peak height, calibrated peak dopamine concentration, and area under the curve to the well-characterized Michaelis-Menten parameters, dopamine per pulse, maximal uptake rate, and apparent affinity. Based on observed results we recommend tau for measuring dopamine uptake and calibrated peak dopamine concentration for measuring dopamine release. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Comparison of extracellular dopamine concentration in awake unstressed and postsurgical nitrous oxide sedated rats.

    PubMed

    Kofke, W A; Stiller, R L; Rose, M E

    1995-10-01

    Nitrous oxide (N2O), 70%, in O2 is often used as a control condition after surgical preparation in rodents undergoing neuroscience investigations. Concern has been expressed that this constitutes a stressful condition. Microdialysis was used in 15 rats to assess extracellular striatal dopamine concentrations during overnight soundproof isolation and on the following day after vascular cannulation and halothane excretion under N2O sedation with concomitant neuromuscular blockade. The overnight dialysate dopamine concentration was 22.8 +/- 8.7 pg/40 microliters. Thirty minutes after stopping halothane, the dialysate concentration was 362.6 +/- 91.6 pg/40 microliters during postsurgical N2O sedation. These data indicate that (a) compared to an unstressed baseline, significant brain dopamine effects occur with N2O sedation after surgery with halothane N2O anesthesia, and (b) baseline conditions can have a major effect on microdialysis data expressed as percentage of baseline.

  20. Enhanced stress-induced dopamine release in the prefrontal cortex of amphetamine-sensitized rats.

    PubMed

    Hamamura, T; Fibiger, H C

    1993-06-11

    This study examined the extent to which chronic d-amphetamine administration sensitizes animals to some behavioral and neurochemical effects of foot shock stress. Rats received daily injections of saline for 14 days or d-amphetamine (2 mg/kg 7 days and 4 mg/kg 7 days). After a 7 day drug abstinent period, extracellular dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations were measured in the medial prefrontal cortex using in vivo microdialysis in freely moving rats. The behavioral responses to mild foot shock stress were enhanced in the d-amphetamine-pretreated subjects. Concomitant with this behavioral sensitization, d-amphetamine-pretreated subjects showed greater stress-induced increases in extracellular dopamine in the medial prefrontal cortex than in controls. d-Amphetamine (2 mg/kg)-induced stereotyped behavior was also enhanced in the amphetamine-pretreated animals compared to controls; however, d-amphetamine-induced increases in extracellular dopamine in the medial prefrontal cortex were not enhanced in the amphetamine-pretreated group. These results suggest that the mesocortical dopaminergic system is involved in cross-sensitization between d-amphetamine and stress, but not in d-amphetamine-induced behavioral sensitization.

  1. Stereospecific antagonism by d-butaclamol of dopamine-induced relaxation of the isolated rabbit mesenteric artery.

    PubMed

    Brodde, O E; Freistühler, J; Meyer, F J

    1981-01-01

    We characterized the properties of vascular dopamine receptors on isolated rabbit mesenteric arteries preincubated with phenoxybenzamine (10(-5) M) and contracted with prostaglandin F2 alpha (PGF2 alpha). The dose-response curve for dopamine-induced relaxation was shifted to the right by the dopamine receptor antagonist d-butaclamol (10(-7)--3 X 10(-6) M) in a concentration-dependent manner. The pA2 value for d-butaclamol was calculated as 6.77. In contrast, even a very high concentration (3 X 10(-6) M) of l-butaclamol had no effect, indicating that vascular dopamine receptors require stereospecificity of antagonists. In the same preparation the mechanism of relaxation by 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN; 3 X 10(-7)--10(-4) M) and bromocriptine (10(-6)--3 X 10(-4) M) was found to be dopaminomimetic, since only the dopamine receptor antagonists droperidol (10(-5) M) and metoclopramide (5 X 10(-5) M) could inhibit relaxations, whereas the beta-adrenoceptor antagonists pindolol (10(-7) M) and propranolol (10(-6) M) were without effect. It is concluded that receptors specific for dopamine exist on the rabbit mesenteric artery, which may tentatively be classified as belonging to the D1-type.

  2. The atypical dopamine D1 receptor agonist SKF 83959 induces striatal Fos expression in rats.

    PubMed

    Wirtshafter, David; Osborn, Catherine V

    2005-12-28

    The effects of dopamine D1 receptor agonists are often presumed to result from an activation of adenylyl cyclase, but dopamine D1 receptors may also be linked to other signal transduction cascades and the relative importance of these various pathways is currently unclear. SKF 83959 is an agonist at dopamine D1 receptors linked to phospholipase C, but has been reported to be an antagonist at receptors linked to adenylyl cyclase. The current report demonstrates that SKF 83959 induces pronounced, nonpatchy, expression of the immediate-early gene product Fos in the striatum of intact rats which can be converted to a patchy pattern by pretreatment with the dopamine D2-like receptor agonist quinpirole. In rats with unilateral 6-hydroxydopamine lesions SKF 83959 induces strong behavioral rotation and a greatly potentiated Fos response. All of the responses to SKF 83959, in both intact and dopamine-depleted animals, can be blocked by pretreatment with the dopamine D1 receptor antagonist SCH-23390. In intact subjects, SKF 83959 induced Fos expression less potently than the standard dopamine D1 receptor agonist SKF 82958, but the two drugs were approximately equipotent in deinnervated animals. These results demonstrate for the first time that possession of full efficacy at dopamine D1 receptors linked to adenylyl cyclase is not a necessary requirement for the induction of striatal Fos expression in intact animals and suggest that alternative signal transduction pathways may play a role in dopamine agonist induced Fos expression, especially in dopamine-depleted subjects.

  3. Cyclooxygenase-independent neuroprotective effects of aspirin against dopamine quinone-induced neurotoxicity.

    PubMed

    Asanuma, Masato; Miyazaki, Ikuko; Kikkawa, Yuri; Kimoto, Naotaka; Takeshima, Mika; Murakami, Shinki; Miyoshi, Ko

    2012-09-01

    Prostaglandin H synthase exerts not only cyclooxygenase activity but also peroxidase activity. The latter activity of the enzyme is thought to couple with oxidation of dopamine to dopamine quinone. Therefore, it has been proposed that cyclooxygenase inhibitors could suppress dopamine quinone formation. In the present study, we examined effects of various cyclooxygenase inhibitors against excess methyl L-3,4-dihydroxyphenylalanine (L-DOPA)-induced quinoprotein (protein-bound quinone) formation and neurotoxicity using dopaminergic CATH.a cells. The treatment with aspirin inhibited excess methyl L-DOPA-induced quinoprotein formation and cell death. However, acetaminophen did not show protective effects, and indomethacin and meloxicam rather aggravated these methyl L-DOPA-induced changes. Aspirin and indomethacin did not affect the level of glutathione that exerts quenching dopamine quinone in dopaminergic cells. In contrast with inhibiting effects of higher dose in the previous reports, relatively lower dose of aspirin that affected methyl L-DOPA-induced quinoprotein formation and cell death failed to prevent cyclooxygenase-induced dopamine chrome generation in cell-free system. Furthermore, aspirin but not acetaminophen or meloxicam showed direct dopamine quinone-scavenging effects in dopamine-semiquinone generating systems. The present results suggest that cyclooxygenase shows little contribution to dopamine oxidation in dopaminergic cells and that protective effects of aspirin against methyl L-DOPA-induced dopamine quinone neurotoxicity are based on its cyclooxygenase-independent property.

  4. Effects of hypoxia on dopamine concentration and the immune response of White Shrimp ( Litopenaeus vannamei)

    NASA Astrophysics Data System (ADS)

    Hu, Fawen; Pan, Luqing; Jing, Futao

    2009-03-01

    Effects of hypoxia on the dopamine concentration and the immune response of White Shrimp Litopenaeus vannamei were studied. The results showed that hypoxia had significant effects on the concentration of dopamine (DA) in the haemolymph, haemocyte count, phenoloxidase activity, phagocytic activity of haemocytes and bacteriolytic and antibacterial activity in the haemolymph ( P<0.05). The concentration of the dopamine in haemolymph reached its maximum in the 3.0 and 1.5 mg L-1 DO groups at 12 h and 6 h, and then returned to normal after 24 h and 12 h, respectively. All immune parameters decreased with the reduction of dissolved oxygen. Total haemocyte count (THC), the hyaline cells and semi-granular cells in the 3.0 mg L-1 DO group became stable after 12 h, while granular cells did so after 24 h. The THC and different haemocyte count (DHC) in the 1.5 mg L-1 DO group became stable after 24 h. Phenoloxidase activity and bacteriolytic activity in the 3.0 and 1.5 mg L-1 DO groups reached their stable levels after 24 h and 12 h respectively, while phagocytic activity and antibacterial activity became stable after 24 and 12, and 36 and 24 h, respectively. It was also indicated that the changes of dopamine concentrations in haemolymph, haemocyte count and phenoloxidase activity were obviously related to the exposure time under hypoxic conditions.

  5. Dopamine as a potent inducer of cellular glutathione and NAD(P)H:quinone oxidoreductase 1 in PC12 neuronal cells: a potential adaptive mechanism for dopaminergic neuroprotection.

    PubMed

    Jia, Zhenquan; Zhu, Hong; Misra, Bhaba R; Li, Yunbo; Misra, Hara P

    2008-11-01

    Dopamine auto-oxidation and the consequent formation of reactive oxygen species and electrophilic quinone molecules have been implicated in dopaminergic neuronal cell death in Parkinson's disease. We reported here that in PC12 dopaminergic neuronal cells dopamine at noncytotoxic concentrations (50-150 muM) potently induced cellular glutathione (GSH) and the phase 2 enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), two critical cellular defenses in detoxification of ROS and electrophilic quinone molecules. Incubation of PC12 cells with dopamine also led to a marked increase in the mRNA levels for gamma-glutamylcysteine ligase catalytic subunit (GCLC) and NQO1. In addition, treatment of PC12 cells with dopamine resulted in a significant elevation of GSH content in the mitochondrial compartment. To determine whether treatment with dopamine at noncytotoxic concentrations, which upregulated the cellular defenses could protect the neuronal cells against subsequent lethal oxidative and electrophilic injury, PC12 cells were pretreated with dopamine (150 muM) for 24 h and then exposed to various cytotoxic concentrations of dopamine or 6-hydroxydopamine (6-OHDA). We found that pretreatment of PC12 cells with dopamine at a noncytotoxic concentration led to a remarkable protection against cytotoxicity caused by dopamine or 6-OHDA at lethal concentrations, as detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium reduction assay. In view of the critical roles of GSH and NQO1 in protecting against dopaminergic neuron degeneration, the above findings implicate that upregulation of both GSH and NQO1 by dopamine at noncytotoxic concentrations may serve as an important adaptive mechanism for dopaminergic neuroprotection.

  6. Mitochondrial stress-induced dopamine efflux and neuronal damage by malonate involves the dopamine transporter.

    PubMed

    Moy, Lily Y; Wang, Sheng-Ping; Sonsalla, Patricia K

    2007-02-01

    Endogenous striatal dopamine (DA) overflow has been associated with neuropathological conditions resulting from ischemia, psychostimulants, and metabolic inhibition. Malonate, a reversible inhibitor of succinate dehydrogenase, models the effects of energy impairment in neurodegenerative disorders. We have previously reported that the striatal DA efflux and damage to DA nerve terminals resulting from intrastriatal malonate infusions is prevented by prior DA depletion, suggesting that DA plays a role in the neuronal damage. We presently report that the malonate-induced DA efflux is partially mediated by reverse transport of DA from the cytosol to the extracellular space via the DA transporter (DAT). Pharmacological blockade of the DAT with a series of structurally different inhibitors [cocaine, mazindol, 1-(2-(bis(4-fluophenyl methoxy) ethyl)-4-(3-(4-fluorophenyl)-propyl)piperazine) dimethane sulfonate (GBR 13098) and methyl(-)-3beta-(p-fluorophenyl)-1alphaH,5alphaH-tropane-2beta-carboxylate1,5-naphthalene (Win 35,428)] attenuated malonate-induced DA overflow in vivo and protected mice against subsequent damage to DA nerve terminals. Consistent with these findings, the DAT inhibitors prevented malonate-induced damage to DA neurons in mesencephalic cultures and also protected against the loss of GABA neurons in this system. The DAT inhibitors did not modify malonate-induced formation of reactive oxygen species or lactate production, indicating that the DAT inhibitors neither exert antioxidant effects nor interfere with the actions of malonate. Taken together, these findings provide direct evidence that mitochondrial impairment and metabolic stress cause striatal DA efflux via the DAT and suggest that disruptions in DA homeostasis resulting from energy impairment may contribute to the pathogenesis of neurodegenerative diseases.

  7. The relationship between the plasma concentration of blonanserin, and its plasma anti-serotonin 5-HT(2A) activity/anti-dopamine D₂ activity ratio and drug-induced extrapyramidal symptoms.

    PubMed

    Suzuki, Hidenobu; Gen, Keishi

    2012-03-01

     Blonanserin is a second-generation antipsychotic that was developed in Japan. We investigated the relationships between plasma concentration, the plasma anti-5-HT(2A) activity/anti-D₂ activity (S/D) ratio and extrapyramidal symptoms (EPS) in blonanserin dosing.  The subjects were 29 outpatients with schizophrenia. We assessed EPS using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The plasma concentrations were measured by high performance liquid chromatography, and the plasma anti-D₂ and anti-5-HT(2A) activities were measured by [³H]-spiperone and [³H]-ketanserin radioreceptor assays. The results revealed that there were significant correlations between both the plasma concentration and the DIEPSS total score (P<0.05). A negative correlative tendency was found between the S/D ratio and the DIEPSS total score. Furthermore, the plasma concentrations were divided into a low plasma concentration group and a high plasma concentration group, and the S/D ratios were divided into a low S/D ratio group and a high S/D ratio group. We then compared each group based on the DIEPSS total scores. The score in the high plasma concentration-low S/D ratio group was significantly higher than in the high plasma concentration-high S/D ratio, low plasma concentration-high S/D ratio and low plasma concentration-low S/D ratio groups (P<0.05 for all).  These findings indicate that the incidence of EPS during treatment with blonanserin is mainly determined by plasma concentration, but the incidence of EPS may be inhibited when anti-5HT(2A) activity is predominant over anti-D₂ activity. © 2012 The Authors. Psychiatry and Clinical Neurosciences © 2012 Japanese Society of Psychiatry and Neurology.

  8. Testosterone Induces Molecular Changes in Dopamine Signaling Pathway Molecules in the Adolescent Male Rat Nigrostriatal Pathway

    PubMed Central

    Purves-Tyson, Tertia D.; Owens, Samantha J.; Double, Kay L.; Desai, Reena; Handelsman, David J.; Weickert, Cynthia Shannon

    2014-01-01

    Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase), breakdown (catechol-O-methyl transferase; monoamine oxygenase), transport [vesicular monoamine transporter (VMAT), dopamine transporter (DAT)] and receptors (DRD1-D5)] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen receptor

  9. The protective effect of dopamine against OGD/R injury-induced cell death in HT22 mouse hippocampal cells.

    PubMed

    Wang, Wenzhu; Zhao, Lixi; Bai, Fan; Zhang, Tong; Dong, Hao; Liu, Lixu

    2016-03-01

    Previous studies have shown that levo-dopamine (L-dopa) can improve the consciousness of certain patients with prolonged coma after cerebral ischemia-reperfusion injury, and promote cell growth in vivo. This study aimed to investigate whether L-dopa, which is used clinically to treat Parkinson's disease, might also ameliorate ischemia-reperfusion injury-induced cell death. The oxygen-glucose deprivation and re-oxygenation (OGD/R) model was used to mimic the ischemia-reperfusion pathological process in vitro. HT22 cells were treated with dopamine hydrochloride at different times (i.e., 2 h prior to OGD, during the period of OGD, during the period of R, and throughout the period of OGD/R) and at different concentrations (i.e., 25 μM, 50 μM, 100 μM). Lactate dehydrogenase (LDH) release, flow cytometry-annexin V, and propidium iodide staining with light microscopy showed that dopamine hydrochloride (added during re-oxygenation) promoted cell proliferation and facilitated maintenance of normal cell morphology. However, when present during oxygen-glucose deprivation for 18 h and present throughout OGD/R, dopamine hydrochloride increased cell damage as manifested by shrinkage, rounding up, and reduced viability. In conclusion, dopamine protected HT22 cells from OGD/R injury-induced cell death only at a particular point in time, suggesting that it may be useful for treating severe ischemia-reperfusion brain injury.

  10. Nicotine decreases ethanol-induced dopamine signaling and increases self-administration via stress hormones.

    PubMed

    Doyon, William M; Dong, Yu; Ostroumov, Alexey; Thomas, Alyse M; Zhang, Tao A; Dani, John A

    2013-08-07

    Tobacco smoking is a well-known risk factor for subsequent alcohol abuse, but the neural events underlying this risk remain largely unknown. Alcohol and nicotine reinforcement involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to nicotine increases alcohol self-administration and decreases alcohol-induced dopamine responses. The blunted dopamine response was due to increased inhibitory synaptic transmission onto dopamine neurons. Blocking stress hormone receptors prior to nicotine exposure prevented all interactions with alcohol that we measured, including the increased inhibition onto dopamine neurons, the decreased dopamine responses, and the increased alcohol self-administration. These results indicate that nicotine recruits neuroendocrine systems to influence neurotransmission and behavior associated with alcohol reinforcement.

  11. Nicotine Decreases Ethanol-induced Dopamine Signaling and Increases Self-administration via Stress Hormones

    PubMed Central

    Doyon, William M.; Dong, Yu; Ostroumov, Alexey; Thomas, Alyse M.; Zhang, Tao A.; Dani, John A.

    2013-01-01

    SUMMARY Tobacco smoking is a well-known risk factor for subsequent alcohol abuse, but the neural events underlying this risk remain largely unknown. Alcohol and nicotine reinforcement involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to nicotine increases alcohol self-administration and decreases alcohol-induced dopamine responses. The blunted dopamine response was due to increased inhibitory synaptic transmission onto dopamine neurons. Blocking stress hormone receptors prior to nicotine exposure prevented all interactions with alcohol that we measured, including the increased inhibition onto dopamine neurons, the decreased dopamine responses, and the increased alcohol self-administration. These results indicate that nicotine recruits neuroendocrine systems to influence neurotransmission and behavior associated with alcohol reinforcement. PMID:23871233

  12. Dopamine Induced Neurodegeneration in a PINK1 Model of Parkinson's Disease

    PubMed Central

    Yao, Zhi; Duchen, Michael R.; Wood, Nicholas W.; Abramov, Andrey Y.

    2012-01-01

    Background Parkinson's disease is a common neurodegenerative disease characterised by progressive loss of dopaminergic neurons, leading to dopamine depletion in the striatum. Mutations in the PINK1 gene cause an autosomal recessive form of Parkinson's disease. Loss of PINK1 function causes mitochondrial dysfunction, increased reactive oxygen species production and calcium dysregulation, which increases susceptibility to neuronal death in Parkinson's disease. The basis of neuronal vulnerability to dopamine in Parkinson's disease is not well understood. Methodology We investigated the mechanism of dopamine induced cell death in transgenic PINK1 knockout mouse neurons. We show that dopamine results in mitochondrial depolarisation caused by mitochondrial permeability transition pore (mPTP) opening. Dopamine-induced mPTP opening is dependent on a complex of reactive oxygen species production and calcium signalling. Dopamine-induced mPTP opening, and dopamine-induced cell death, could be prevented by inhibition of reactive oxygen species production, by provision of respiratory chain substrates, and by alteration in calcium signalling. Conclusions These data demonstrate the mechanism of dopamine toxicity in PINK1 deficient neurons, and suggest potential therapeutic strategies for neuroprotection in Parkinson's disease. PMID:22662171

  13. Ammonia Induces Autophagy through Dopamine Receptor D3 and MTOR.

    PubMed

    Li, Zhiyuan; Ji, Xinmiao; Wang, Wenchao; Liu, Juanjuan; Liang, Xiaofei; Wu, Hong; Liu, Jing; Eggert, Ulrike S; Liu, Qingsong; Zhang, Xin

    2016-01-01

    Hyperammonemia is frequently seen in tumor microenvironments as well as in liver diseases where it can lead to severe brain damage or death. Ammonia induces autophagy, a mechanism that tumor cells may use to protect themselves from external stresses. However, how cells sense ammonia has been unclear. Here we show that culture medium alone containing Glutamine can generate milimolar of ammonia at 37 degrees in the absence of cells. In addition, we reveal that ammonia acts through the G protein-coupled receptor DRD3 (Dopamine receptor D3) to induce autophagy. At the same time, ammonia induces DRD3 degradation, which involves PIK3C3/VPS34-dependent pathways. Ammonia inhibits MTOR (mechanistic target of Rapamycin) activity and localization in cells, which is mediated by DRD3. Therefore, ammonia has dual roles in autophagy: one to induce autophagy through DRD3 and MTOR, the other to increase autophagosomal pH to inhibit autophagic flux. Our study not only adds a new sensing and output pathway for DRD3 that bridges ammonia sensing and autophagy induction, but also provides potential mechanisms for the clinical consequences of hyperammonemia in brain damage, neurodegenerative diseases and tumors.

  14. Ammonia Induces Autophagy through Dopamine Receptor D3 and MTOR

    PubMed Central

    Li, Zhiyuan; Ji, Xinmiao; Wang, Wenchao; Liu, Juanjuan; Liang, Xiaofei; Wu, Hong; Liu, Jing; Eggert, Ulrike S.; Liu, Qingsong

    2016-01-01

    Hyperammonemia is frequently seen in tumor microenvironments as well as in liver diseases where it can lead to severe brain damage or death. Ammonia induces autophagy, a mechanism that tumor cells may use to protect themselves from external stresses. However, how cells sense ammonia has been unclear. Here we show that culture medium alone containing Glutamine can generate milimolar of ammonia at 37 degrees in the absence of cells. In addition, we reveal that ammonia acts through the G protein-coupled receptor DRD3 (Dopamine receptor D3) to induce autophagy. At the same time, ammonia induces DRD3 degradation, which involves PIK3C3/VPS34-dependent pathways. Ammonia inhibits MTOR (mechanistic target of Rapamycin) activity and localization in cells, which is mediated by DRD3. Therefore, ammonia has dual roles in autophagy: one to induce autophagy through DRD3 and MTOR, the other to increase autophagosomal pH to inhibit autophagic flux. Our study not only adds a new sensing and output pathway for DRD3 that bridges ammonia sensing and autophagy induction, but also provides potential mechanisms for the clinical consequences of hyperammonemia in brain damage, neurodegenerative diseases and tumors. PMID:27077655

  15. Alcohol-induced alterations in dopamine modulation of prefrontal activity.

    PubMed

    Trantham-Davidson, Heather; Chandler, L Judson

    2015-12-01

    Long-term alcohol use leads to persistent cognitive deficits that may be associated with maladaptive changes in the neurocircuitry that mediates executive functions. Impairments caused by these changes can persist well into abstinence and have a negative impact on quality of life and job performance, and can increase the probability of relapse. Many of the changes that affect cognitive function appear to involve dysregulation of the mesocortical dopamine system. This includes changes in dopamine release and alterations in dopamine receptor expression and function in the medial prefrontal cortex (PFC). This review summarizes the cellular effects of acute and chronic ethanol exposure on dopamine release and dopamine receptor function in the PFC with the goal of providing greater understanding of the effects of alcohol-use disorders on the dopamine system and how this relates to deficits in the executive function of the PFC.

  16. Alcohol-induced alterations in dopamine modulation of prefrontal activity

    PubMed Central

    Trantham-Davidson, Heather; Chandler, L. Judson

    2015-01-01

    Long-term alcohol use leads to persistent cognitive deficits that may be associated with maladaptive changes in the neurocircuitry that mediates executive functions. Impairments caused by these changes can persist well into abstinence and have a negative impact on quality of life and job performance, and can increase the probability of relapse. Many of the changes that affect cognitive function appear to involve dysregulation of the mesocortical dopamine system. This includes changes in dopamine release and alterations in dopamine receptor expression and function in the medial prefrontal cortex (PFC). This review summarizes the cellular effects of acute and chronic ethanol exposure on dopamine release and dopamine receptor function in the PFC with the goal of providing greater understanding of the effects of alcohol-use disorders on the dopamine system and how this relates to deficits in the executive function of the PFC. PMID:26558348

  17. An acute, epitope-specific modification in the dopamine transporter associated with methamphetamine-induced neurotoxicity.

    PubMed

    Fricks-Gleason, Ashley N; German, Christopher L; Hoonakker, Amanda J; Friend, Danielle M; Ganesh, Kamala K; Carver, Aaron S; Hanson, Glen R; Fleckenstein, Annette E; Keefe, Kristen A

    2016-04-01

    Preclinical studies demonstrate that repeated, high-dose methamphetamine administrations rapidly decrease plasmalemmal dopamine uptake, which may contribute to aberrant dopamine accumulation, reactive species generation, and long-term dopaminergic deficits. The present study extends these findings by demonstrating a heretofore unreported, epitope-specific modification in the dopamine transporter caused by a methamphetamine regimen that induces these deficits. Specifically, repeated, high-dose methamphetamine injections (4 × 10 mg/kg/injection, 2-h intervals) rapidly decreased immunohistochemical detection of striatal dopamine transporter as assessed 1 h after the final methamphetamine exposure. In contrast, neither a single high dose (1 × 10 mg/kg) nor repeated injections of a lower dose (4 × 2 mg/kg/injection) induced this change. The high-dose regimen-induced alteration was only detected using antibodies directed against the N-terminus. Immunohistochemical staining using antibodies directed against the C-terminus did not reveal any changes. The high-dose regimen also did not alter dopamine transporter expression as assessed using [(125) I]RTI-55 autoradiography. These data suggest that the repeated, high-dose methamphetamine regimen alters the N-terminus of the dopamine transporter. Further, these data may be predictive of persistent dopamine deficits caused by the stimulant. Future studies of the signaling cascades involved should provide novel insight into potential mechanisms underlying the physiological and pathophysiological regulation of the dopamine transporter. © 2016 Wiley Periodicals, Inc.

  18. 5-HT2 receptors modulate the expression of antipsychotic-induced dopamine supersensitivity.

    PubMed

    Charron, Alexandra; Hage, Cynthia El; Servonnet, Alice; Samaha, Anne-Noël

    2015-12-01

    Antipsychotic treatment can produce supersensitivity to dopamine receptor stimulation. This compromises the efficacy of ongoing treatment and increases the risk of relapse to psychosis upon treatment cessation. Serotonin 5-HT2 receptors modulate dopamine function and thereby influence dopamine-dependent responses. Here we evaluated the hypothesis that 5-HT2 receptors modulate the behavioural expression of antipsychotic-induced dopamine supersensitivity. To this end, we first treated rats with the antipsychotic haloperidol using a clinically relevant treatment regimen. We then assessed the effects of a 5-HT2 receptor antagonist (ritanserin; 0.01 and 0.1mg/kg) and of a 5-HT2A receptor antagonist (MDL100,907; 0.025-0.1mg/kg) on amphetamine-induced psychomotor activity. Antipsychotic-treated rats showed increased amphetamine-induced locomotion relative to antipsychotic-naïve rats, indicating a dopamine supersensitive state. At the highest dose tested (0.1mg/kg for both antagonists), both ritanserin and MDL100,907 suppressed amphetamine-induced locomotion in antipsychotic-treated rats, while having no effect on this behaviour in control rats. In parallel, antipsychotic treatment decreased 5-HT2A receptor density in the prelimbic cortex and nucleus accumbens core and increased 5-HT2A receptor density in the caudate-putamen. Thus, activation of either 5-HT2 receptors or of 5-HT2A receptors selectively is required for the full expression of antipsychotic-induced dopamine supersensitivity. In addition, antipsychotic-induced dopamine supersensitivity enhances the ability of 5-HT2/5-HT2A receptors to modulate dopamine-dependent behaviours. These effects are potentially linked to changes in 5-HT2A receptor density in the prefrontal cortex and the striatum. These observations raise the possibility that blockade of 5-HT2A receptors might overcome some of the behavioural manifestations of antipsychotic-induced dopamine supersensitivity.

  19. Locally infused taurine, GABA and homotaurine alter differently the striatal extracellular concentrations of dopamine and its metabolites in rats.

    PubMed

    Ruotsalainen, M; Majasaari, M; Salimäki, J; Ahtee, L

    1998-01-01

    We studied in vivo the effects of locally infused taurine (50, 150, and 450 mM) on the striatal dopamine and its metabolites in comparison with those of GABA and homotaurine, a GABAA receptor agonist, in freely moving rats. The extracellular dopamine concentration was elevated maximally 2.5-, 2- and 4-fold by taurine, GABA and homotaurine, respectively. At 150 mM concentration, at which the maximum effects occurred, homotaurine increased the extracellular dopamine more than taurine or GABA. When taurine and GABA were infused simultaneously with tetrodotoxin the output of dopamine did not differ from that in the presence of tetrodotoxin alone. In comparison, tetrodotoxin did not inhibit the increase in extracellular dopamine caused by homotaurine. Furthermore, omission of calcium from the perfusion fluid inhibited the increase of extracellular dopamine caused by GABA. However, it did not block the increase of dopamine caused by taurine or homotaurine. The present study suggests that the effects of intrastriatal taurine, GABA and homotaurine on the striatal extracellular dopamine differ. Thus, these amino acids seem to affect the striatal dopaminergic neurons via more than one mechanism.

  20. Uptake inhibitors but not substrates induce protease resistance in extracellular loop two of the dopamine transporter.

    PubMed

    Gaffaney, Jon D; Vaughan, Roxanne A

    2004-03-01

    Changes in protease sensitivity of extracellular loop two (EL2) of the dopamine transporter (DAT) during inhibitor and substrate binding were examined using trypsin proteolysis and epitope-specific immunoblotting. In control rat striatal membranes, proteolysis of DAT in a restricted region of EL2 was produced by 0.001 to 10 microg/ml trypsin. However, in the presence of the dopamine uptake blockers [2-(diphenylmethoxyl) ethyl]-4-(3phenylpropyl) piperazine (GBR 12909), mazindol, 2beta-carbomethoxy-3beta-(4-flourophenyl)tropane (beta-CFT), nomifensine, benztropine, or (-)-cocaine, 100- to 1000-fold higher concentrations of trypsin were required to produce comparable levels of proteolysis. Protease resistance induced by ligands was correlated with their affinity for DAT binding, was not observed with Zn2+, (+)-cocaine, or inhibitors of norepinephrine or serotonin transporters, and was not caused by altered catalytic activity of trypsin. Together, these results support the hypothesis that the interaction of uptake inhibitors with DAT induces a protease-resistant conformation in EL2. In contrast, binding of substrates did not induce protease resistance in EL2, suggesting that substrates and inhibitors interact with DAT differently during binding. To assess the effects of EL2 proteolysis on DAT function, the binding and transport properties of trypsin-digested DAT were assayed with [3H]CFT and [3H]dopamine. Digestion decreased the Bmax for binding and the Vmax for uptake in amounts that were proportional to the extent of proteolysis, indicating that the structural integrity of EL2 is required for maintenance of both DAT binding and transport functions. Together this data provides novel information about inhibitor and substrate interactions at EL2, possibly relating the protease resistant DAT conformation to a mechanism of transport inhibition.

  1. Dopamine-induced bradycardia in two dogs under isoflurane anaesthesia.

    PubMed

    Tsompanidou, P P; Kazakos, G M; Anagnostou, T L

    2013-12-01

    Dopamine is a commonly used positive inotropic agent for the treatment of hypotension in small animals. Two dogs that had undergone surgery, under isoflurane anaesthesia, developed a sudden and profound bradycardia when a dopamine infusion was administered. Bradycardia was attributed to the activation of the Bezold-Jarisch reflex, an inhibitory reflex, characterised by bradycardia and hypotension. © 2013 British Small Animal Veterinary Association.

  2. JNK inhibition of VMAT2 contributes to rotenone-induced oxidative stress and dopamine neuron death

    PubMed Central

    Choi, Won-Seok; Kim, Hyung-Wook; Xia, Zhengui

    2014-01-01

    Treatment with rotenone, both in vitro and in vivo, is widely used to model dopamine neuron death in Parkinson’s disease upon exposure to environmental neurotoxicants and pesticides. Mechanisms underlying rotenone neurotoxicity are still being defined. Our recent studies suggest that rotenone-induced dopamine neuron death involves microtubule destabilization, which leads to accumulation of cytosolic dopamine and consequently reactive oxygen species (ROS). Furthermore, the c-Jun N-terminal protein kinase (JNK) is required for rotenone-induced dopamine neuron death. Here we report that the neural specific JNK3 isoform of the JNKs, but not JNK1 or JNK2, is responsible for this neuron death in primary cultured dopamine neurons. Treatment with taxol, a microtubule stabilizing agent, attenuates rotenone-induced phosphorylation and presumably activation of JNK. This suggests that JNK is activated by microtubule destabilization upon rotenone exposure. Moreover, rotenone inhibits VMAT2 activity but not VMAT2 protein levels. Significantly, treatment with SP600125, a pharmacological inhibitor of JNKs, attenuates rotenone inhibition of VMAT2. Furthermore, decreased VMAT2 activity following in vitro incubation of recombinant JNK3 protein with purified mesencephalic synaptic vesicles suggests that JNK3 can inhibit VMAT2 activity. Together with our previous findings, these results suggest that rotenone induces dopamine neuron death through a series of sequential events including microtubule destabilization, JNK3 activation, VMAT2 inhibition, accumulation of cytosolic dopamine, and generation of ROS. Our data identify JNK3 as a novel regulator of VMAT2 activity. PMID:25496994

  3. Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours.

    PubMed

    Sim, Hye-Ri; Choi, Tae-Yong; Lee, Hyo Jin; Kang, Eun Young; Yoon, Sehyoun; Han, Pyung-Lim; Choi, Se-Young; Baik, Ja-Hyun

    2013-01-01

    Dopaminergic systems are implicated in stress-related behaviour. Here we investigate behavioural responses to chronic stress in dopamine D2 receptor knockout mice and find that anxiety-like behaviours are increased compared with wild-type mice. Repeated stress exposure suppresses cocaine-induced behavioural sensitization, cocaine-seeking and relapse behaviours in dopamine D2 receptor knockout mice. Cocaine challenge after drug withdrawal in cocaine-experienced wild-type or dopamine D2 receptor knockout mice is associated with inhibition of long-term depression in the nucleus accumbens, and chronic stress during withdrawal prevents inhibition after cocaine challenge in cocaine-experienced dopamine D2 receptor knockout mice, but not in wild-type mice. Lentiviral-induced knockdown of dopamine D2 receptors in the nucleus accumbens of wild-type mice does not affect basal locomotor activity, but confers stress-induced inhibition of the expression of cocaine-induced behavioural sensitization. Stressed mice depleted of dopamine D2 receptors do not manifest long-term depression inhibition. Our results suggest that dopamine D2 receptors have roles in regulating synaptic modification triggered by stress and drug addiction.

  4. Ethanol- and cocaine-induced locomotion are genetically related to increases in accumbal dopamine.

    PubMed

    Meyer, Paul J; Meshul, Charles K; Phillips, Tamara J

    2009-04-01

    Neuroanatomical research suggests that interactions between dopamine and glutamate within the mesolimbic dopamine system are involved in both drug-induced locomotor stimulation and addiction. Therefore, genetically determined differences in the locomotor responses to ethanol and cocaine may be related to differences in the effects of these drugs on this system. To test this, we measured drug-induced changes in dopamine and glutamate within the nucleus accumbens (NAcc), a major target of mesolimbic dopamine neurons, using in vivo microdialysis in selectively bred FAST and SLOW mouse lines, which were bred for extreme sensitivity (FAST) and insensitivity (SLOW) to the locomotor stimulant effects of ethanol. These mice also show a genetically correlated difference in stimulant response to cocaine (FAST > SLOW). Single injections of ethanol (2 g/kg) or cocaine (40 mg/kg) resulted in larger increases in dopamine within the NAcc in FAST compared with SLOW mice. There was no effect of either drug on NAcc glutamate levels. These experiments indicate that response of the mesolimbic dopamine system is genetically correlated with sensitivity to ethanol- and cocaine-induced locomotion. Because increased sensitivity to the stimulating effects of ethanol appears to be associated with greater risk for alcohol abuse, genetically determined differences in the mesolimbic dopamine response to ethanol may represent a critical underlying mechanism for increased genetic risk for alcoholism.

  5. Relationship between psychostimulant-induced "high" and dopamine transporter occupancy.

    PubMed Central

    Volkow, N D; Wang, G J; Fowler, J S; Gatley, S J; Ding, Y S; Logan, J; Dewey, S L; Hitzemann, R; Lieberman, J

    1996-01-01

    The ability of cocaine to inhibit the dopamine transporter (DAT) appears to be crucial for its reinforcing properties. The potential use of drugs that produce long-lasting inhibition of the DAT as a mean of preventing the "high" and reducing drug-seeking behavior has become a major strategy in medication development. However, neither the relation between the high and DAT inhibition nor the ability to block the high by prior DAT blockade have ever been demonstrated. To evaluate if DAT could prevent the high induced by methylphenidate (MP), a drug which like cocaine inhibits the DAT, we compared the responses in eight non-drug-abusing subjects between the first and the second of two MP doses (0.375 mg/kg, i.v.) given 60 min apart. At 60 min the high from MP has returned to baseline, but 75-80% of the drug remains in brain. Positron-emission tomography and [11C]d-threo-MP were used to estimate DAT occupancies at different times after MP. DAT inhibition by MP did not block or attenuate the high from a second dose of MP given 60 min later, despite a 80% residual transporter occupancy from the first dose. Furthermore some subjects did not perceive a high after single or repeated administration despite significant DAT blockade. These results indicate that DAT occupancy is not sufficient to account for the high, and that for DAT inhibitors to be therapeutically effective, occupancies > 80% may be required. Images Fig. 1 PMID:8816810

  6. New Repeat Polymorphism in the AKT1 Gene Predicts Striatal Dopamine D2/D3 Receptor Availability and Stimulant-Induced Dopamine Release in the Healthy Human Brain.

    PubMed

    Shumay, Elena; Wiers, Corinde E; Shokri-Kojori, Ehsan; Kim, Sung Won; Hodgkinson, Colin A; Sun, Hui; Tomasi, Dardo; Wong, Christopher T; Weinberger, Daniel R; Wang, Gene-Jack; Fowler, Joanna S; Volkow, Nora D

    2017-05-10

    The role of the protein kinase Akt1 in dopamine neurotransmission is well recognized and has been implicated in schizophrenia and psychosis. However, the extent to which variants in the AKT1 gene influence dopamine neurotransmission is not well understood. Here we investigated the effect of a newly characterized variant number tandem repeat (VNTR) polymorphism in AKT1 [major alleles: L- (eight repeats) and H- (nine repeats)] on striatal dopamine D2/D3 receptor (DRD2) availability and on dopamine release in healthy volunteers. We used PET and [(11)C]raclopride to assess baseline DRD2 availability in 91 participants. In 54 of these participants, we also measured intravenous methylphenidate-induced dopamine release to measure dopamine release. Dopamine release was quantified as the difference in specific binding of [(11)C]raclopride (nondisplaceable binding potential) between baseline values and values following methylphenidate injection. There was an effect of AKT1 genotype on DRD2 availability at baseline for the caudate (F(2,90) = 8.2, p = 0.001) and putamen (F(2,90) = 6.6, p = 0.002), but not the ventral striatum (p = 0.3). For the caudate and putamen, LL showed higher DRD2 availability than HH; HL were in between. There was also a significant effect of AKT1 genotype on dopamine increases in the ventral striatum (F(2,53) = 5.3, p = 0.009), with increases being stronger in HH > HL > LL. However, no dopamine increases were observed in the caudate (p = 0.1) or putamen (p = 0.8) following methylphenidate injection. Our results provide evidence that the AKT1 gene modulates both striatal DRD2 availability and dopamine release in the human brain, which could account for its association with schizophrenia and psychosis. The clinical relevance of the newly characterized AKT1 VNTR merits investigation.SIGNIFICANCE STATEMENT The AKT1 gene has been implicated in schizophrenia and psychosis. This association is likely to reflect modulation of dopamine signaling by Akt1 kinase

  7. Lobeline effects on tonic and methamphetamine-induced dopamine release

    PubMed Central

    Wilhelm, Clare J.; Johnson, Robert A.; Eshleman, Amy J.; Janowsky, Aaron

    2008-01-01

    The mechanisms of interaction between lobeline and the dopamine transporter (DAT) or the vesicular monoamine transporter (VMAT-2) are not clear. The goal of this study was to elucidate the effects of lobeline on these transporters in a cell system co-expressing the DAT and VMAT-2. Lobeline caused release of [3H]dopamine to a similar extent as reserpine (VMAT-2 inhibitor), but was less efficacious than methamphetamine or dopamine. Additionally, lobeline decreased the [3H]dopamine releasing effects of methamphetamine, unlike reserpine which increased release by methamphetamine. These results suggest that lobeline has unique properties at the DAT and VMAT-2 which may make it useful as a pharmacotherapeutic to treat methamphetamine abuse. PMID:18191815

  8. Association between dopamine-related polymorphisms and plasma concentrations of prolactin during risperidone treatment in schizophrenic patients.

    PubMed

    Yasui-Furukori, Norio; Saito, Manabu; Tsuchimine, Shoko; Nakagami, Taku; Sato, Yasushi; Sugawara, Norio; Kaneko, Sunao

    2008-08-01

    Hyperprolactinemia is an inevitable consequence of treatment with antipsychotic agents to some extent because prolactin response to antipsychotics is related to dopamine blockade. Recent studies have suggested that polymorphisms of the dopamine receptors are associated with therapeutic response to antipsychotics. Thus, we studied the effects of major polymorphisms of dopamine-related genes on plasma concentration of prolactin. Subjects were 174 schizophrenic patients (68 males, 106 females) receiving 3 mg twice daily of risperidone for at least 4 weeks. Sample collections were conducted 12 h after the bedtime dosing. Five dopamine-related polymorphisms (Taq1A, -141C ins/del for DRD2, Ser9Gly for DRD3, 48 bp VNTR for DRD4, Val158Met for COMT) were identified. The mean (+/-SD) plasma concentration of prolactin in females was significantly higher than males (54.3+/-27.2 ng/ml versus 126.8+/-70.2 ng/ml, p<0.001). No dopamine-related polymorphisms differed the plasma concentration of prolactin in males or females. Multiple regression analyses including plasma drug concentration and age revealed that plasma concentration of prolactin correlated with gender (standardized partial correlation coefficients (beta)=0.551, p<0.001) and negatively with age (standardized beta=-0.202, p<0.01). No correlations were found between prolactin concentration and dopamine-related polymorphisms. These findings suggest that plasma prolactin concentrations in females are much higher than in males but the dopamine-related variants are not predominantly associated with plasma concentration of prolactin.

  9. Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers.

    PubMed

    Volkow, N D; Tomasi, D; Wang, G-J; Logan, J; Alexoff, D L; Jayne, M; Fowler, J S; Wong, C; Yin, P; Du, C

    2014-09-01

    Dopamine signaling in nucleus accumbens is essential for cocaine reward. Interestingly, imaging studies have reported blunted dopamine increases in striatum (assessed as reduced binding of [(11)C]raclopride to D2/D3 receptors) in detoxified cocaine abusers. Here, we evaluate whether the blunted dopamine response reflected the effects of detoxification and the lack of cocaine-cues during stimulant exposure. For this purpose we studied 62 participants (43 non-detoxified cocaine abusers and 19 controls) using positron emission tomography and [(11)C]raclopride (radioligand sensitive to endogenous dopamine) to measure dopamine increases induced by intravenous methylphenidate and in 24 of the cocaine abusers, we also compared dopamine increases when methylphenidate was administered concomitantly with a cocaine cue-video versus a neutral-video. In controls, methylphenidate increased dopamine in dorsal (effect size 1.4; P<0.001) and ventral striatum (location of accumbens) (effect size 0.89; P<0.001), but in cocaine abusers methylphenidate's effects did not differ from placebo and were similar whether cocaine-cues were present or not. In cocaine abusers despite the markedly attenuated dopaminergic effects, the methylphenidate-induced changes in ventral striatum were associated with intense drug craving. Our findings are consistent with markedly reduced signaling through D2 receptors during intoxication in active cocaine abusers regardless of cues exposure, which might contribute to compulsive drug use.

  10. Cortical regulation of dopamine depletion-induced dendritic spine loss in striatal medium spiny neurons.

    PubMed

    Neely, M D; Schmidt, D E; Deutch, A Y

    2007-10-26

    The proximate cause of Parkinson's disease is striatal dopamine depletion. Although no overt toxicity to striatal neurons has been reported in Parkinson's disease, one of the consequences of striatal dopamine loss is a decrease in the number of dendritic spines on striatal medium spiny neurons (MSNs). Dendrites of these neurons receive cortical glutamatergic inputs onto the dendritic spine head and dopaminergic inputs from the substantia nigra onto the spine neck. This synaptic arrangement suggests that dopamine gates corticostriatal glutamatergic drive onto spines. Using triple organotypic slice cultures composed of ventral mesencephalon, striatum, and cortex of the neonatal rat, we examined the role of the cortex in dopamine depletion-induced dendritic spine loss in MSNs. The striatal dopamine innervation was lesioned by treatment of the cultures with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) or by removing the mesencephalon. Both MPP+ and mesencephalic ablation decreased MSN dendritic spine density. Analysis of spine morphology revealed that thin spines were preferentially lost after dopamine depletion. Removal of the cortex completely prevented dopamine depletion-induced spine loss. These data indicate that the dendritic remodeling of MSNs seen in parkinsonism occurs secondary to increases in corticostriatal glutamatergic drive, and suggest that modulation of cortical activity may be a useful therapeutic strategy in Parkinson's disease.

  11. Endogenous dopamine is involved in the herbicide paraquat-induced dopaminergic cell death.

    PubMed

    Izumi, Yasuhiko; Ezumi, Masayuki; Takada-Takatori, Yuki; Akaike, Akinori; Kume, Toshiaki

    2014-06-01

    The herbicide paraquat is an environmental factor that may be involved in the etiology of Parkinson's disease (PD). Systemic exposure of mice to paraquat causes a selective loss of dopaminergic neurons in the substantia nigra pars compacta, although paraquat is not selectively incorporated in dopaminergic neurons. Here, we report a contribution of endogenous dopamine to paraquat-induced dopaminergic cell death. Exposure of PC12 cells to paraquat (50μM) caused delayed toxicity from 36 h onward. A decline in intracellular dopamine content achieved by inhibiting tyrosine hydroxylase (TH), an enzyme for dopamine synthesis, conferred resistance to paraquat toxicity on dopaminergic cells. Paraquat increased the levels of cytosolic and vesicular dopamine, accompanied by transiently increased TH activity. Quinone derived from cytosolic dopamine conjugates with cysteine residues in functional proteins to form quinoproteins. Formation of quinoprotein was transiently increased early during exposure to paraquat. Furthermore, pretreatment with ascorbic acid, which suppressed the elevations of intracellular dopamine and quinoprotein, almost completely prevented paraquat toxicity. These results suggest that the elevation of cytosolic dopamine induced by paraquat participates in the vulnerability of dopaminergic cells to delayed toxicity through the formation of quinoproteins.

  12. Cortical Regulation of Dopamine Depletion-Induced Dendritic Spine Loss in Striatal Medium Spiny Neurons

    PubMed Central

    Neely, M. Diana; Schmidt, Dennis E.; Deutch, Ariel Y.

    2007-01-01

    The proximate cause of Parkinson’s Disease is striatal dopamine depletion. Although no overt toxicity to striatal neurons has been reported in Parkinson’s Disease, one of the consequences of striatal dopamine loss is a decrease in the number of dendritic spines on striatal medium spiny neurons (MSNs). Dendrites of these neurons receive cortical glutamatergic inputs onto the dendritic spine head and dopaminergic inputs from the substantia nigra onto the spine neck. This synaptic arrangement suggests that dopamine gates corticostriatal glutamatergic drive onto spines. Using triple organotypic slice cultures comprised of ventral mesencephalon, striatum, and cortex, we examined the role of the cortex in dopamine depletion-induced dendritic spine loss in MSNs. The striatal dopamine innervation was lesioned by treatment of the cultures with the dopaminergic neurotoxin MPP+ or by removing the mesencephalon. Both MPP+ and mesencephalic ablation decreased MSN dendritic spine density. Analysis of spine morphology revealed that thin spines were preferentially lost after dopamine depletion. Removal of the cortex completely prevented dopamine depletion-induced spine loss. These data indicate that the dendritic remodeling of MSNs seen in parkinsonism occurs secondary to increases in corticostriatal glutamatergic drive, and suggest that modulation of cortical activity may be a useful therapeutic strategy in Parkinson’s Disease. PMID:17888581

  13. Intrapallidal dopamine restores motor deficits induced by 6-hydroxydopamine in the rat.

    PubMed

    Galvan, A; Floran, B; Erlij, D; Aceves, J

    2001-01-01

    To explore whether dopamine deficits in the globus pallidus have a role in generating the motor symptoms of Parkinson's disease, we examined the effects of selective intrapallidal administration of dopamine or its antagonists in rats unilaterally lesioned with 6-hydroxydopamine into the medial forebrain bundle. Either the turning behavior induced by apomorphine or the deficit in the performance of a skilled forelimb-reaching task was used as assay for drug action. Microinjection of either the D2 receptor antagonist, sulpiride, or the D1 receptor antagonist, SCH-23390, into the dopamine-denervated pallidum significantly reduced apomorphine induced turning. In animals trained to perform a skilled forelimb-reaching task, 6-OHDA lesions caused a marked motor deficit in the contralateral forelimb. Intrapallidal dopamine applied either intermittently or continuously, restored up to 50% of the motor performance. Continuous application promoted a motor recovery that outlasted dopamine administration. These results show that lack of dopamine in the GP plays an important role in generating the motor symptoms caused by lesion of dopaminergic pathways. Moreover, motor recovery was produced by selectively injecting dopamine into the globus pallidus.

  14. Impact of grafted serotonin and dopamine neurons on development of L-DOPA-induced dyskinesias in parkinsonian rats is determined by the extent of dopamine neuron degeneration.

    PubMed

    Carlsson, Thomas; Carta, Manolo; Muñoz, Ana; Mattsson, Bengt; Winkler, Christian; Kirik, Deniz; Björklund, Anders

    2009-02-01

    Previous studies have shown that serotonin neurons play an important role in the induction and maintenance of L-DOPA-induced dyskinesia in animals with lesion of the nigrostriatal dopamine system. Patients with Parkinson's disease that receive transplants of foetal ventral mesencephalic tissue, the graft cell preparation is likely to contain, in addition to dopamine neurons, serotonin neurons that will vary in number depending on the landmarks used for dissection. Here, we have studied the impact of grafted serotonin neurons--alone or mixed with dopamine neurons--on the development of L-DOPA-induced dyskinesia in rats with a partial 6-hydroxydopamine lesion of the host nigrostriatal projection. In these rats, which showed only low-level dyskinesia at the time of transplantation, serotonin grafts induced a worsening in the severity of dyskinesia that developed during continued L-DOPA treatment, while the dopamine-rich graft had the opposite, dampening effect. The detrimental effect seen in animals with serotonin neuron grafts was dramatically increased when the residual dopamine innervation in the striatum was removed by a second 6-hydroxydopamine lesion. Interestingly, rats with grafts that contained a mixture of dopamine and serotonin neurons (in approximately 2:1) showed a marked reduction in L-DOPA-induced dyskinesia over time, and the appearance of severe dyskinesia induced by the removal of the residual dopamine innervation, seen in the animals with transplants of serotonin neurons alone, was blocked. FosB expression in the striatal projection neurons, which is associated with dyskinesias, was also normalized by the dopamine-rich grafts, but not by the serotonin neuron grafts. These data indicate that as long as a sufficient portion, some 10-20%, of the dopamine innervation still remains, the increased host serotonin innervation generated by the grafted serotonin neurons will have limited effect on the development or severity of L-DOPA-induced dyskinesias. At

  15. Effect of the inhibition of dopamine uptake on the dopamine- and dimethyldopamine-induced-inhibition of the potassium-evoked release of [3H]acetylcholine from striatal slices.

    PubMed

    Farooqui, T; Wallace, R A; Miller, D D; Uretsky, N J

    1989-01-01

    1. Dimethyldopamine was eight times more potent than dopamine in activating the D2 receptor that inhibits the potassium-evoked release of [3H]acetylcholine from striatal slices. 2. Cocaine and mazindol produced an eight-fold shift in the concentration-response curve for dopamine, but not for dimethyldopamine. 3. The IC50 of dimethyldopamine for the inhibition of [3H]dopamine uptake was thirty times greater than that for dopamine. 4. Dopamine may be less potent than dimethyldopamine at the D2 receptor because dopamine has a higher affinity for the dopamine uptake system, resulting in its rapid removal from the vicinity of the receptor.

  16. D-2 dopamine receptor activation reduces free ( sup 3 H)arachidonate release induced by hypophysiotropic peptides in anterior pituitary cells

    SciTech Connect

    Canonico, P.L. )

    1989-09-01

    Dopamine reduces the stimulation of intracellular ({sup 3}H)arachidonate release produced by the two PRL-stimulating peptides angiotensin-II and TRH. This effect is concentration dependent and is mediated by stimulation of D-2 dopamine receptors. D-2 receptor agonists (bromocriptine, dihydroergocryptine, and dihydroergocristine) inhibit the release of fatty acid induced by angiotensin-II with a potency that parallels their ability to inhibit PRL release in vitro. Conversely, the selective D-2 receptor antagonist L-sulpiride completely prevents dopamine's effect, whereas SCH 23390 (a D-1 receptor antagonist) is ineffective. The inhibitory action of dopamine does not seem to be consequent to an action on the adenylate cyclase-cAMP system, as 8-bromo-cAMP (1 mM) does not affect either basal or dopamine-inhibited ({sup 3}H)arachidonate release. However, a 24-h pertussis toxin pretreatment significantly reduces the action of dopamine on fatty acid release. Collectively, these results suggest that D-2 dopamine receptor-mediated inhibition of intracellular ({sup 3}H)arachidonate release requires the action of a GTP-binding protein, but is not a consequence of an inhibitory action on cAMP levels.

  17. Hypoinsulinemia Regulates Amphetamine-Induced Reverse Transport of Dopamine

    PubMed Central

    Williams, Jason M; Owens, W. Anthony; Turner, Gregory H; Saunders, Christine; Dipace, Concetta; Blakely, Randy D; France, Charles P; Gore, John C; Daws, Lynette C; Avison, Malcolm J; Galli, Aurelio

    2007-01-01

    The behavioral effects of psychomotor stimulants such as amphetamine (AMPH) arise from their ability to elicit increases in extracellular dopamine (DA). These AMPH-induced increases are achieved by DA transporter (DAT)-mediated transmitter efflux. Recently, we have shown that AMPH self-administration is reduced in rats that have been depleted of insulin with the diabetogenic agent streptozotocin (STZ). In vitro studies suggest that hypoinsulinemia may regulate the actions of AMPH by inhibiting the insulin downstream effectors phosphotidylinositol 3-kinase (PI3K) and protein kinase B (PKB, or Akt), which we have previously shown are able to fine-tune DAT cell-surface expression. Here, we demonstrate that striatal Akt function, as well as DAT cell-surface expression, are significantly reduced by STZ. In addition, our data show that the release of DA, determined by high-speed chronoamperometry (HSCA) in the striatum, in response to AMPH, is severely impaired in these insulin-deficient rats. Importantly, selective inhibition of PI3K with LY294002 within the striatum results in a profound reduction in the subsequent potential for AMPH to evoke DA efflux. Consistent with our biochemical and in vivo electrochemical data, findings from functional magnetic resonance imaging experiments reveal that the ability of AMPH to elicit positive blood oxygen level–dependent signal changes in the striatum is significantly blunted in STZ-treated rats. Finally, local infusion of insulin into the striatum of STZ-treated animals significantly recovers the ability of AMPH to stimulate DA release as measured by high-speed chronoamperometry. The present studies establish that PI3K signaling regulates the neurochemical actions of AMPH-like psychomotor stimulants. These data suggest that insulin signaling pathways may represent a novel mechanism for regulating DA transmission, one which may be targeted for the treatment of AMPH abuse and potentially other dopaminergic disorders. PMID

  18. Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system

    PubMed Central

    Hatcher, Jaime M.; Richardson, Jason R.; Guillot, Thomas S.; McCormack, Alison L.; Di Monte, Donato A.; Jones, Dean P.; Pennell, Kurt D.; Miller, Gary W.

    2007-01-01

    Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing Parkinson’s disease (PD). Here, we provide evidence that the insecticide dieldrin causes specific oxidative damage in the nigrostriatal dopamine (DA) system. We report that exposure of mice to low levels of dieldrin for 30 days resulted in alterations in dopamine-handling as evidenced by a decrease in dopamine metabolites, DOPAC (31.7% decrease) and HVA (29.2% decrease) and significantly increased cysteinyl-catechol levels in the striatum. Furthermore, dieldrin resulted in a 53% decrease in total glutathione, an increase in the redox potential of glutathione, and a 90% increase in protein carbonyls. α-Synuclein protein expression was also significantly increased in the striatum (25% increase). Finally, dieldrin caused a significant decrease in striatal expression of the dopamine transporter as measured by 3H-WIN 35,428 binding and 3H-dopamine uptake. These alterations occurred in the absence of dopamine neuron loss in the substantia nigra pars compacta. These effects represent the ability of low doses of dieldrin to increase the vulnerability of nigrostriatal dopamine neurons by inducing oxidative stress and suggest that pesticide exposure may act as a promoter of PD. PMID:17291500

  19. Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system.

    PubMed

    Hatcher, Jaime M; Richardson, Jason R; Guillot, Thomas S; McCormack, Alison L; Di Monte, Donato A; Jones, Dean P; Pennell, Kurt D; Miller, Gary W

    2007-04-01

    Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing Parkinson's disease (PD). Here, we provide evidence that the insecticide dieldrin causes specific oxidative damage in the nigrostriatal dopamine (DA) system. We report that exposure of mice to low levels of dieldrin for 30 days resulted in alterations in dopamine-handling as evidenced by a decrease in dopamine metabolites, DOPAC (31.7% decrease) and HVA (29.2% decrease) and significantly increased cysteinyl-catechol levels in the striatum. Furthermore, dieldrin resulted in a 53% decrease in total glutathione, an increase in the redox potential of glutathione, and a 90% increase in protein carbonyls. Alpha-synuclein protein expression was also significantly increased in the striatum (25% increase). Finally, dieldrin caused a significant decrease in striatal expression of the dopamine transporter as measured by (3)H-WIN 35,428 binding and (3)H-dopamine uptake. These alterations occurred in the absence of dopamine neuron loss in the substantia nigra pars compacta. These effects represent the ability of low doses of dieldrin to increase the vulnerability of nigrostriatal dopamine neurons by inducing oxidative stress and suggest that pesticide exposure may act as a promoter of PD.

  20. Modulation of dopamine and noradrenaline release and of intracellular Ca2+ concentration by presynaptic glutamate receptors in hippocampus.

    PubMed

    Malva, J O; Carvalho, A P; Carvalho, C M

    1994-12-01

    1. We studied the release of [3H]-dopamine and [3H]-noradrenaline (NA) from hippocampal synaptosomes induced by glutamate receptors and the associated Ca2+ influx through Ca2+ channels. The release of tritiated neurotransmitters was studied by use of superfusion system and the intracellular free Ca2+ concentration ([Ca2+]i) was determined by a fluorimetric assay with Indo-1 as a probe for Ca2+. 2. Presynaptic glutamate receptor activation induced Ca(2+)-dependent release of [3H]-dopamine and [3H]-NA from rat hippocampal synaptosomes. Thus, L-glutamate induced the release of both neurotransmitters in a dose-dependent manner (EC50 = 5.62 microM), and the effect of 100 microM L-glutamate was inhibited by 83.8% in the presence of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dioxine (CNQX), but was not affected by 1 microM (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine (MK-801). 3. Other glutamate receptor agonists also stimulated the Ca(2+)-dependent release of [3H]-dopamine and [3H]-NA as follows: N-methyl-D-aspartate (NMDA), at 200 microM, released 3.65 +/- 0.23% of the total 3H catecholamines, and this effect was inhibited by 81.2% in the presence of 1 microM MK-801; quisqualate (50 microM), S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionic acid (AMPA) (100 microM) or kainate (100 microM) released 1.57 +/- 0.26%, 1.93 +/- 0.17% and 2.09 +/- 0.22%, of the total 3H catecholamines, respectively. 4. The ionotropic glutamate receptor agonist, AMPA, induced an increase in the [Ca2+]i which was inhibited by 58.6% in the presence of 10 microM CNQX. In contrast, the increase in [Ca2+]i due to stimulation by glutamate was not sensitive to CNQX or MK-801.5. Nitrendipine, at I JAM, did not inhibit the neurotransmitter release induced by AMPA, but, both 0.5 micro M -conotoxin GVIA (w-CgTx) and 100 nM w-Aga IVA reduced catecholamine release to 49.03 +/- 3.79% and 46.06 +/- 10.51% of the control, respectively. In the presence of both toxins the release was

  1. Risk-assessment and risk-taking behavior predict potassium- and amphetamine-induced dopamine response in the dorsal striatum of rats

    PubMed Central

    Palm, Sara; Momeni, Shima; Lundberg, Stina; Nylander, Ingrid; Roman, Erika

    2014-01-01

    Certain personality types and behavioral traits display high correlations to drug use and an increased level of dopamine in the reward system is a common denominator of all drugs of abuse. Dopamine response to drugs has been suggested to correlate with some of these personality types and to be a key factor influencing the predisposition to addiction. This study investigated if behavioral traits can be related to potassium- and amphetamine-induced dopamine response in the dorsal striatum, an area hypothesized to be involved in the shift from drug use to addiction. The open field and multivariate concentric square field™ tests were used to assess individual behavior in male Wistar rats. Chronoamperometric recordings were then made to study the potassium- and amphetamine-induced dopamine response in vivo. A classification based on risk-taking behavior in the open field was used for further comparisons. Risk-taking behavior was correlated between the behavioral tests and high risk takers displayed a more pronounced response to the dopamine uptake blocking effects of amphetamine. Behavioral parameters from both tests could also predict potassium- and amphetamine-induced dopamine responses showing a correlation between neurochemistry and behavior in risk-assessment and risk-taking parameters. In conclusion, the high risk-taking rats showed a more pronounced reduction of dopamine uptake in the dorsal striatum after amphetamine indicating that this area may contribute to the sensitivity of these animals to psychostimulants and proneness to addiction. Further, inherent dopamine activity was related to risk-assessment behavior, which may be of importance for decision-making and inhibitory control, key components in addiction. PMID:25076877

  2. Striatal dopamine and glutamate receptors modulate methamphetamine-induced cortical Fos expression

    PubMed Central

    Gross, Noah B.; Marshall, John F.

    2009-01-01

    Methamphetamine (mAMPH) is a psychostimulant drug that increases extracellular levels of monoamines throughout the brain. It has previously been observed that a single injection of mAMPH increases immediate early gene (IEG) expression in both the striatum and cerebral cortex. Moreover, this effect is modulated by dopamine and glutamate receptors since systemic administration of dopamine or glutamate antagonists has been found to alter mAMPH-induced striatal and cortical IEG expression. However, because dopamine and glutamate receptors are found in extra-striatal as well as striatal brain regions, studies employing systemic injection of dopamine or glutamate antagonists fail to localize the effects of mAMPH-induced activation. In the present experiments, the roles of striatal dopamine and glutamate receptors in mAMPH-induced gene expression in the striatum and cerebral cortex were examined. The nuclear expression of Fos, the protein product of the IEG c-fos, was quantified in both the striatum and the cortex of animals receiving intrastriatal dopamine or glutamate antagonist administration. Intrastriatal infusion of dopamine (D1 or D2) or glutamate [N-methyl-D-aspartic acid (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)] antagonists affected not only mAMPH-induced striatal, but also cortical, Fos expression. Overall, the effects of the antagonists occurred dose-dependently, in both the infused and non-infused hemispheres, with greater influences occurring in the infused hemisphere. Finally, unilateral intrastriatal infusion of dopamine or glutamate antagonists changed the behavior of the rats from characteristic mAMPH-induced stereotypy to rotation ipsilateral to the infusion. These results demonstrate that mAMPH’s actions on striatal dopamine and glutamate receptors modulate the widespread cortical activation induced by mAMPH. It is hypothesized that dopamine release from nigrostriatal terminals modulates activity within striatal

  3. Pyrethroid pesticide-induced alterations in dopamine transporter function

    SciTech Connect

    Elwan, Mohamed A.; Richardson, Jason R.; Guillot, Thomas S.; Caudle, W. Michael; Miller, Gary W. . E-mail: gary.miller@emory.edu

    2006-03-15

    Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies from our laboratory and others have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Here, we report that repeated exposure (3 injections over 2 weeks) of mice to two commonly used pyrethroid pesticides, deltamethrin (3 mg/kg) and permethrin (0.8 mg/kg), increases DAT-mediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, we determined that exposure (10 min) to deltamethrin and permethrin (1 nM-100 {mu}M) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 {mu}M) or 24 h (1, 5, and 10 {mu}M) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD.

  4. Role of 6-monoacetylmorphine in the acute release of striatal dopamine induced by intravenous heroin.

    PubMed

    Gottås, A; Boix, F; Øiestad, E L; Vindenes, V; Mørland, J

    2014-09-01

    After injection, heroin is rapidly metabolized to 6-monoacetylmorphine (6-MAM) and further to morphine. As morphine has been shown to increase striatal dopamine, whereas 6-MAM has not been studied in this respect, we gave i.v. injections of 3 μmol 6-MAM, morphine or heroin to rats. Opioids were measured in blood, and dopamine and opioids in microdialysate from brain striatal extracellular fluid (ECF), by UPLC-MS/MS. After 6-MAM injection, 6-MAM ECF concentrations increased rapidly, and reached Cmax of 4.4 μM after 8 min. After heroin injection, 6-MAM increased rapidly in blood and reached Cmax of 6.4 μM in ECF after 8 min, while ECF Cmax for heroin was 1.2 μM after 2 min. T max for morphine in ECF was 29 and 24 min following 6-MAM and heroin administration, respectively, with corresponding Cmax levels of 1 and 2 μM. Dopamine levels peaked after 8 and 14 min following 6-MAM and heroin administration, respectively. The dopamine responses were equal, indicating no dopamine release by heroin per se. Furthermore, 6-MAM, and not morphine, appeared to mediate the early dopamine response, whereas morphine administration, giving rise to morphine ECF concentrations similar to those observed shortly after 6-MAM injection, did not increase ECF dopamine. 6-MAM appeared accordingly to be the substance responsible for the early increase in dopamine observed after heroin injection. As 6-MAM was formed rapidly from heroin in blood, and was the major substance reaching the brain after heroin administration, this also indicates that factors influencing blood 6-MAM concentrations might change the behavioural effects of heroin.

  5. Phasic-like stimulation of the medial forebrain bundle augments striatal gene expression despite methamphetamine-induced partial dopamine denervation.

    PubMed

    Howard, Christopher D; Pastuzyn, Elissa D; Barker-Haliski, Melissa L; Garris, Paul A; Keefe, Kristen A

    2013-05-01

    Methamphetamine-induced partial dopamine depletions are associated with impaired basal ganglia function, including decreased preprotachykinin mRNA expression and impaired transcriptional activation of activity-regulated, cytoskeleton-associated (Arc) gene in striatum. Recent work implicates deficits in phasic dopamine signaling as a potential mechanism linking methamphetamine-induced dopamine loss to impaired basal ganglia function. This study thus sought to establish a causal link between phasic dopamine transmission and altered basal ganglia function by determining whether the deficits in striatal neuron gene expression could be restored by increasing phasic dopamine release. Three weeks after pretreatment with saline or a neurotoxic regimen of methamphetamine, rats underwent phasic- or tonic-like stimulation of ascending dopamine neurons. Striatal gene expression was examined using in situ hybridization histochemistry. Phasic-like, but not tonic-like, stimulation induced immediate-early genes Arc and zif268 in both groups, despite the partial striatal dopamine denervation in methamphetamine-pretreated rats, with the Arc expression occurring in presumed striatonigral efferent neurons. Phasic-like stimulation also restored preprotachykinin mRNA expression. These results suggest that disruption of phasic dopamine signaling likely underlies methamphetamine-induced impairments in basal ganglia function, and that restoring phasic dopamine signaling may be a viable approach to manage long-term consequences of methamphetamine-induced dopamine loss on basal ganglia functions. © 2013 International Society for Neurochemistry.

  6. Modulatory effects of sesamin on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells.

    PubMed

    Zhang, Min; Lee, Hak Ju; Park, Keun Hong; Park, Hyun Jin; Choi, Hyun Sook; Lim, Sung Cil; Lee, Myung Koo

    2012-06-01

    The effects of sesamin on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells were investigated. Sesamin at concentration ranges of 20-75 μM exhibited a significant increase in intracellular dopamine levels at 24 h: 50 μM sesamin increased dopamine levels to 133% and tyrosine hydroxylase (TH) activity to 128.2% of control levels. Sesamin at 20-100 μM rapidly increased the intracellular levels of cyclic AMP (cAMP) to 158.3%-270.3% of control levels at 30 min. At 50 μM, sesamin combined with L-DOPA (50, 100 and 200 μM) further increased the intracellular dopamine levels for 24 h compared to L-DOPA alone. In the absence or presence of L-DOPA (100 and 200 μM), sesamin (50 μM) increased the phosphorylation of TH, cAMP-dependent protein kinase (PKA), and cAMP-response element-binding protein (CREB), as well as the mRNA levels of TH and CREB for 24 h, an effect which was reduced by L-DOPA (100 and 200 μM). In addition, 50 μM sesamin exhibited a protective effect against L-DOPA (100 and 200 μM)-induced cytotoxicity via the inhibition of reactive oxygen species (ROS) production and superoxide dismutase reduction, induction of extracellular signal-regulated kinase (ERK)1/2 and BadSer112 phosphorylation and Bcl-2 expression, and inhibition of cleaved-caspase-3 formation. These results suggested that sesamin enhanced dopamine biosynthesis and L-DOPA-induced increase in dopamine levels by inducing TH activity and TH gene expression, which was mediated by cAMP-PKA-CREB systems. Sesamin also protected against L-DOPA (100-200 μM)-induced cytotoxicity through the suppression of ROS activity via the modulation of ERK1/2, BadSer112, Bcl-2, and caspase-3 pathways in PC12 cells. Therefore, sesamin might serve as an adjuvant phytonutrient for neurodegenerative diseases.

  7. Lineweaver-Burk analysis for the blocking effects of mammalian dopamine receptor antagonists on dopamine-induced currents in Achatina giant neurones.

    PubMed

    Emaduddin, M; Takeuchi, H

    1996-10-01

    1. We had demonstrated (Emaduddin et al., 1995) the blocking effects of the three mammalian dopamine receptor antagonists, (+/-)-SKF83566 (mammalian dopamine D1-like receptor antagonist), (+)-UH232 (D2 and D3-like receptor antagonist) and (+/-)-sulpiride (D2-like receptor antagonist) on the dose (pressure duration)-response curves of dopamine in the three giant neurone types, LVMN (left visceral multiple spike neurone), d-RPeAN (dorsal-right pedal anterior neurone) and v-LCDN (ventral-left cerebral distinct neurone), of Achatina fulica Férussac under voltage clamp. In the present study, we analyzed these data by Lineweaver-Burk plot. 2. Dopamine-induced inward currents (Iin) of the two neurone types, LVMN and d-RPeAN, were blocked by (+/-)-SKF83566 and (+)-UH232 in partly noncompetitive and partly uncompetitive manners. (+/-)-Sulpiride had no effect on these currents. 3. In contrast, dopamine-induced outward current (Iout) of v-LCDN was inhibited competitively by (+/-)-sulpiride and noncompetitively by (+)-UH232. (+/-)-SKF83566 had no effect on this current. 4. Therefore, we consider that the pharmacological features of the dopamine receptors of Achatina neurones are not identical in detail to those of the mammalian dopamine receptors.

  8. Endomorphins 1 and 2 induce amnesia via selective modulation of dopamine receptors in mice.

    PubMed

    Ukai, Makoto; Lin, Hui Ping

    2002-06-20

    The involvement of dopamine receptors in the amnesic effects of the endogenous micro-opioid receptor agonists endomorphins 1 and 2 was investigated by observing step-down type passive avoidance learning in mice. Although the dopamine D1 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol hydrochloride (R(+)-SKF38393) (0.05 and 0.1 mg/kg), the dopamine D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (R(+)-SCH23390) (2.5 and 5 microg/kg) or the dopamine D2 receptor agonist N-n-phenethyl-N-propylethyl-p-(3-hydroxyphenyl)-ethylamine (RU24213) (0.3 and 1 mg/kg) had no significant effects on the endomorphin-1 (10 microg)- or endomorphin-2 (10 microg)-induced decrease in step-down latency of passive avoidance learning, (-)-sulpiride (10 mg/kg), a dopamine D2 receptor antagonist, significantly reversed the decrease in step-down latency evoked by endomorphin-2 (10 microg), but not by endomorphin-1 (10 microg). Taken together, it is likely that stimulation of dopamine D2 receptors results in the endomorphin-2-but not endomorphin-1-induced impairment of passive avoidance learning.

  9. Dopamine-induced silica-polydopamine hybrids with controllable morphology.

    PubMed

    Ho, Chia-Che; Ding, Shinn-Jyh

    2014-04-07

    Novel silica-polydopamine hybrids, with controllable morphology, are facilely fabricated in an emulsion system consisting of tetraethyl orthosilicate, dopamine, water, and NaOH under weakly basic conditions (pH 8.5-10). An increase in initial pH favors the formation of nano-structured spherical silica-PDA hybrids from a flocculated structure.

  10. JNK inhibition of VMAT2 contributes to rotenone-induced oxidative stress and dopamine neuron death.

    PubMed

    Choi, Won-Seok; Kim, Hyung-Wook; Xia, Zhengui

    2015-02-03

    Treatment with rotenone, both in vitro and in vivo, is widely used to model dopamine neuron death in Parkinson's disease upon exposure to environmental neurotoxicants and pesticides. Mechanisms underlying rotenone neurotoxicity are still being defined. Our recent studies suggest that rotenone-induced dopamine neuron death involves microtubule destabilization, which leads to accumulation of cytosolic dopamine and consequently reactive oxygen species (ROS). Furthermore, the c-Jun N-terminal protein kinase (JNK) is required for rotenone-induced dopamine neuron death. Here we report that the neural specific JNK3 isoform of the JNKs, but not JNK1 or JNK2, is responsible for this neuron death in primary cultured dopamine neurons. Treatment with taxol, a microtubule stabilizing agent, attenuates rotenone-induced phosphorylation and presumably activation of JNK. This suggests that JNK is activated by microtubule destabilization upon rotenone exposure. Moreover, rotenone inhibits VMAT2 activity but not VMAT2 protein levels. Significantly, treatment with SP600125, a pharmacological inhibitor of JNKs, attenuates rotenone inhibition of VMAT2. Furthermore, decreased VMAT2 activity following in vitro incubation of recombinant JNK3 protein with purified mesencephalic synaptic vesicles suggests that JNK3 can inhibit VMAT2 activity. Together with our previous findings, these results suggest that rotenone induces dopamine neuron death through a series of sequential events including microtubule destabilization, JNK3 activation, VMAT2 inhibition, accumulation of cytosolic dopamine, and generation of ROS. Our data identify JNK3 as a novel regulator of VMAT2 activity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. l-Theanine protects against excess dopamine-induced neurotoxicity in the presence of astrocytes

    PubMed Central

    Takeshima, Mika; Miyazaki, Ikuko; Murakami, Shinki; Kita, Taizo; Asanuma, Masato

    2016-01-01

    l-Theanine (γ-glutamylethylamide), a component of green tea, is considered to have regulatory and neuroprotective roles in the brain. The present study was designed to determine the effect of l-theanine on excess dopamine-induced neurotoxicity in both cell culture and animal experiments. The primary cultured mesencephalic neurons or co-cultures of mesencephalic neurons and striatal astrocytes were pretreated with l-theanine for 72 h, and then treated with excess dopamine for further 24 h. The cell viability of dopamine neurons and levels of glutathione were evaluated. Excess dopamine-induced neurotoxicity was significantly attenuated by 72 h preincubation with l-theanine in neuron-astrocyte co-cultures but not in neuron-rich cultures. Exposure to l-theanine increased the levels of glutathione in both astrocytes and glial conditioned medium. The glial conditioned medium from l-theanine-pretreated striatal astrocytes attenuated dopamine-induced neurotoxicity and quinoprotein formation in mesencephalic neurons. In addition, replacement of l-glutamate with l-theanine in an in vitro cell-free glutathione-synthesis system produced glutathione-like thiol compounds. Furthermore, l-theanine administration (4 mg/kg, p.o.) for 14 days significantly increased glutathione levels in the striatum of mice. The results suggest that l-theanine provides neuroprotection against oxidative stress-induced neuronal damage by humoral molecules released from astrocytes, probably including glutathione. PMID:27698535

  12. l-Theanine protects against excess dopamine-induced neurotoxicity in the presence of astrocytes.

    PubMed

    Takeshima, Mika; Miyazaki, Ikuko; Murakami, Shinki; Kita, Taizo; Asanuma, Masato

    2016-09-01

    l-Theanine (γ-glutamylethylamide), a component of green tea, is considered to have regulatory and neuroprotective roles in the brain. The present study was designed to determine the effect of l-theanine on excess dopamine-induced neurotoxicity in both cell culture and animal experiments. The primary cultured mesencephalic neurons or co-cultures of mesencephalic neurons and striatal astrocytes were pretreated with l-theanine for 72 h, and then treated with excess dopamine for further 24 h. The cell viability of dopamine neurons and levels of glutathione were evaluated. Excess dopamine-induced neurotoxicity was significantly attenuated by 72 h preincubation with l-theanine in neuron-astrocyte co-cultures but not in neuron-rich cultures. Exposure to l-theanine increased the levels of glutathione in both astrocytes and glial conditioned medium. The glial conditioned medium from l-theanine-pretreated striatal astrocytes attenuated dopamine-induced neurotoxicity and quinoprotein formation in mesencephalic neurons. In addition, replacement of l-glutamate with l-theanine in an in vitro cell-free glutathione-synthesis system produced glutathione-like thiol compounds. Furthermore, l-theanine administration (4 mg/kg, p.o.) for 14 days significantly increased glutathione levels in the striatum of mice. The results suggest that l-theanine provides neuroprotection against oxidative stress-induced neuronal damage by humoral molecules released from astrocytes, probably including glutathione.

  13. Tremor analysis separates Parkinson's disease and dopamine receptor blockers induced parkinsonism.

    PubMed

    Shaikh, Aasef G

    2017-05-01

    Parkinson's disease, the most common cause of parkinsonism is often difficult to distinguish from its second most common etiology due to exposure to dopamine receptor blocking agents such as antiemetics and neuroleptics. Dual axis accelerometry was used to quantify tremor in 158 patients with parkinsonism; 62 had Parkinson's disease and 96 were clinically diagnosed with dopamine receptor blocking agent-induced parkinsonism. Tremor was measured while subjects rested arms (resting tremor), outstretched arms in front (postural tremor), and reached a target (kinetic tremor). Cycle-by-cycle analysis was performed to measure cycle duration, oscillation amplitude, and inter-cycle variations in the frequency. Patients with dopamine receptor blocker induced parkinsonism had lower resting and postural tremor amplitude. There was a substantial increase of kinetic tremor amplitude in both disorders. Postural and resting tremor in subjects with dopamine receptor blocking agent-induced parkinsonism was prominent in the abduction-adduction plane. In contrast, the Parkinson's disease tremor had equal amplitude in all three planes of motion. Tremor frequency was comparable in both groups. Remarkable variability in the width of the oscillatory cycles suggested irregularity in the oscillatory waveforms in both subtypes of parkinsonism. Quantitative tremor analysis can distinguish Parkinson's disease from dopamine receptor blocking agent-induced parkinsonism.

  14. Intracellular Methamphetamine Prevents the Dopamine-induced Enhancement of Neuronal Firing*

    PubMed Central

    Saha, Kaustuv; Sambo, Danielle; Richardson, Ben D.; Lin, Landon M.; Butler, Brittany; Villarroel, Laura; Khoshbouei, Habibeh

    2014-01-01

    The dysregulation of the dopaminergic system is implicated in multiple neurological and neuropsychiatric disorders such as Parkinson disease and drug addiction. The primary target of psychostimulants such as amphetamine and methamphetamine is the dopamine transporter (DAT), the major regulator of extracellular dopamine levels in the brain. However, the behavioral and neurophysiological correlates of methamphetamine and amphetamine administration are unique from one another, thereby suggesting these two compounds impact dopaminergic neurotransmission differentially. We further examined the unique mechanisms by which amphetamine and methamphetamine regulate DAT function and dopamine neurotransmission; in the present study we examined the impact of extracellular and intracellular amphetamine and methamphetamine on the spontaneous firing of cultured midbrain dopaminergic neurons and isolated DAT-mediated current. In dopaminergic neurons the spontaneous firing rate was enhanced by extracellular application of amphetamine > dopamine > methamphetamine and was DAT-dependent. Amphetamine > methamphetamine similarly enhanced DAT-mediated inward current, which was sensitive to isosmotic substitution of Na+ or Cl− ion. Although isosmotic substitution of extracellular Na+ ions blocked amphetamine and methamphetamine-induced DAT-mediated inward current similarly, the removal of extracellular Cl− ions preferentially blocked amphetamine-induced inward current. The intracellular application of methamphetamine, but not amphetamine, prevented the dopamine-induced increase in the spontaneous firing of dopaminergic neurons and the corresponding DAT-mediated inward current. The results reveal a new mechanism for methamphetamine-induced dysregulation of dopaminergic neurons. PMID:24962577

  15. Intracellular methamphetamine prevents the dopamine-induced enhancement of neuronal firing.

    PubMed

    Saha, Kaustuv; Sambo, Danielle; Richardson, Ben D; Lin, Landon M; Butler, Brittany; Villarroel, Laura; Khoshbouei, Habibeh

    2014-08-08

    The dysregulation of the dopaminergic system is implicated in multiple neurological and neuropsychiatric disorders such as Parkinson disease and drug addiction. The primary target of psychostimulants such as amphetamine and methamphetamine is the dopamine transporter (DAT), the major regulator of extracellular dopamine levels in the brain. However, the behavioral and neurophysiological correlates of methamphetamine and amphetamine administration are unique from one another, thereby suggesting these two compounds impact dopaminergic neurotransmission differentially. We further examined the unique mechanisms by which amphetamine and methamphetamine regulate DAT function and dopamine neurotransmission; in the present study we examined the impact of extracellular and intracellular amphetamine and methamphetamine on the spontaneous firing of cultured midbrain dopaminergic neurons and isolated DAT-mediated current. In dopaminergic neurons the spontaneous firing rate was enhanced by extracellular application of amphetamine > dopamine > methamphetamine and was DAT-dependent. Amphetamine > methamphetamine similarly enhanced DAT-mediated inward current, which was sensitive to isosmotic substitution of Na(+) or Cl(-) ion. Although isosmotic substitution of extracellular Na(+) ions blocked amphetamine and methamphetamine-induced DAT-mediated inward current similarly, the removal of extracellular Cl(-) ions preferentially blocked amphetamine-induced inward current. The intracellular application of methamphetamine, but not amphetamine, prevented the dopamine-induced increase in the spontaneous firing of dopaminergic neurons and the corresponding DAT-mediated inward current. The results reveal a new mechanism for methamphetamine-induced dysregulation of dopaminergic neurons.

  16. Malonate-induced generation of reactive oxygen species in rat striatum depends on dopamine release but not on NMDA receptor activation.

    PubMed

    Ferger, B; Eberhardt, O; Teismann, P; de Groote, C; Schulz, J B

    1999-09-01

    Intrastriatal injection of the reversible succinate dehydrogenase inhibitor malonate produces both energy depletion and striatal lesions similar to that seen in cerebral ischemia and Huntington's disease. The mechanisms of neuronal cell death involve secondary excitotoxicity and the generation of reactive oxygen species. Here, we investigated the effects of dopamine on malonate-induced generation of hydroxyl radicals and striatal lesion volumes. Using in vivo microdialysis, we found that malonate induced a 94-fold increase in extracellular striatal dopamine concentrations. This was paralleled by an increase in the generation of hydroxyl radicals. Prior unilateral lesioning of the nigrostriatal dopaminergic pathway by focal injection of 6-hydroxydopamine blocked the malonate-induced increase in dopamine concentrations and the generation of hydroxyl radicals and attenuated the lesion volume. In contrast, the NMDA receptor antagonist MK-801 attenuated malonate-induced lesion volumes but did not block the generation of hydroxyl radicals. Thus, the dopaminergic and glutamatergic pathways are essential in the pathogenesis of malonate-induced striatal lesions. Our results suggest that the malonate-induced release of dopamine but not NMDA receptor activation mediates hydroxyl radical formation.

  17. Functional recovery of locus coeruleus noradrenergic neurons after DSP-4 lesion: effects on dopamine levels and neuroleptic induced-parkinsonian symptoms in rats.

    PubMed

    Srinivasan, J; Schmidt, W J

    2004-01-01

    Noradrenaline has been shown to control dopamine turnover and release in rat brain. Noradrenergic lesion with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) decreases dopamine release in the striatum and enhances catalepsy in experimental models of Parkinson's disease. However, in due course, sprouting of remaining noradrenergic axons, to compensate for the decreased noradrenaline is said to occur in specific brain regions. Though this is to some extent understood, the longstanding effects of noradrenergic lesion on dopaminergic neurons of the basal ganglia and in Parkinsonian behavior is not known. Here the question is addressed, whether locus coeruleus lesion with DSP-4 in rats alters dopamine concentration of the basal ganglia and influences Parkinsonian behavior in a long term (6 months). Parkinsonian behavior was assessed by catalepsy and activity cage after challenging with subthreshold dose of haloperidol (0.2 mg/kg), on 7, 30, 90, 120 and 180 days after DSP-4 lesion. The concentrations of noradrenaline and dopamine and its metabolites were estimated by HPLC. 6 months after DSP-4 lesion, increased concentration of noradrenaline was found in prefrontal cortex and hippocampus. Other regions remain unaffected. The concentration of dopamine remained unchanged. However, dopamine turnover appeared to be increased in prefrontal cortex and reduced in striatum and nucleus accumbens. Catalepsy and hypoactivity were observed in DSP-4 lesioned animals after haloperidol challenge on 7th, 30th and 60th day. Though dopamine turnover was reduced after 6 months in the striatum, haloperidol-induced catalepsy was not observed after 60 days. These results indicate a gradual functional recovery, perhaps hyperinnervation of noradrenergic neurons after DSP-4 treatment and the reversal of its effects on dopaminergic neurons and on Parkinsonian symptoms.

  18. Buprenorphine modulates methamphetamine-induced dopamine dynamics in the rat caudate nucleus.

    PubMed

    Pereira, Frederico C; Gough, Bobby; Macedo, Tice R; Ribeiro, Carlos F; Ali, Syed F; Binienda, Zbigniew K

    2011-01-01

    Methamphetamine (METH) abuse and addiction present a major problem in the United States and globally. Oxidative stress associated with exposure to METH mediates to the large extent METH-evoked neurotoxicity. While there are currently no medications approved for treating METH addiction, its pharmacology provides opportunities for potential pharmacotherapeutic adjuncts to behavioral therapy in the treatment of METH addiction. Opioid receptor agonists can modulate the activity of dopamine neurons and could, therefore, modify the pharmacodynamic effects of METH in the dopaminergic system. Efficacy of the adjunctive medication with buprenorphine has been demonstrated in the treatment of cocaine addiction extending beyond opiate addiction. We investigated the interactions of morphine (10 mg/kg) and buprenorphine (0.01 and 10 mg/kg) with METH (2 mg/kg) affecting striatal dopaminergic transmission. The extracellular concentration of dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined using brain microdialysis coupled with high performance liquid chromatography with electrochemical detection (HPLC-ED) in the caudate nucleus of adult, awake, male Sprague-Dawley rats. Compared to METH alone, extracellular DA release was prolonged for 140 min without changes in DA peak-effect by combined treatment with morphine/METH. Morphine did not change DOPAC efflux evoked by METH. On the other hand, both buprenorphine doses attenuated the METH-induced DA peak-effect. However, whereas high buprenorphine dose extended DA outflow for 190 min, the low-dose abbreviated DA release. High buprenorphine dose also shortened METH-induced decrease in DOPAC efflux. Data confirm that opiates modulate dopaminergic neurotransmission evoked by METH. Alteration of dopaminergic response to METH challenge under buprenorphine may suggest effectiveness of buprenorphine treatment in METH addiction.

  19. Medial prefrontal cortex inversely regulates toluene-induced changes in markers of synaptic plasticity of mesolimbic dopamine neurons

    PubMed Central

    Beckley, Jacob T.; Evins, Caitlin E.; Fedarovich, Hleb; Gilstrap, Meghin J.; Woodward, John J.

    2013-01-01

    Toluene is a volatile solvent that is intentionally inhaled by children, adolescents and adults for its intoxicating effects. While voluntary use of toluene suggests that it possesses rewarding properties and abuse potential, it is unknown whether toluene alters excitatory synaptic transmission in reward sensitive dopamine neurons like other drugs of abuse. Here, using a combination of retrograde labeling and slice electrophysiology, we show that a brief in vivo exposure of rats to a behaviorally relevant concentration of toluene vapor enhances glutamatergic synaptic strength of dopamine (DA) neurons projecting to nucleus accumbens core and medial shell neurons. This effect persisted for up to 3 days in mesoaccumbens core DA neurons and for at least 21 days in those projecting to the medial shell. In contrast, toluene vapor exposure had no effect on synaptic strength of DA neurons that project to the medial prefrontal cortex (mPFC). Furthermore, infusion of GABAergic modulators into the mPFC prior to vapor exposure to pharmacologically manipulate output, inhibited or potentiated toluene's action on mesoaccumbens DA neurons. Taken together, the results of these studies indicate that toluene induces a target-selective increase in mesolimbic DA neuron synaptic transmission and strongly implicates the mPFC as an important regulator of drug-induced plasticity of mesolimbic dopamine neurons. PMID:23303956

  20. A transgenic mouse model of neuroepithelial cell specific inducible overexpression of dopamine D1-receptor

    PubMed Central

    Fujimoto, Kumiko; Araki, Kiyomi; McCarthy, Deirdre M.; Sims, John R.; Ren, Jia-Qian; Zhang, Xuan; Bhide, Pradeep G.

    2010-01-01

    Dopamine and its receptors appear in the brain during early embryonic period suggesting a role for dopamine in brain development. In fact, dopamine receptor imbalance resulting from impaired physiological balance between D1- and D2-receptor activities can perturb brain development and lead to persisting changes in brain structure and function. Dopamine receptor imbalance can be produced experimentally using pharmacological or genetic methods. Pharmacological methods tend to activate or antagonize the receptors in all cell types. In the traditional gene knockout models the receptor imbalance occurs during development and also at maturity. Therefore, assaying the effects of dopamine imbalance on specific cell types (e.g. precursor versus postmitotic cells) or at specific periods of brain development (e.g. pre- or postnatal periods) is not feasible in these models. We describe a novel transgenic mouse model based on the tetracycline dependent inducible gene expression system in which dopamine D1-receptor transgene expression is induced selectively in neuroepithelial cells of the embryonic brain at experimenter-chosen intervals of brain development. In this model, doxycycline-induced expression of the transgene causes significant overexpression of the D1-receptor and significant reductions in the incorporation of the S-phase marker bromodeoxyuridine into neuroepithelial cells of the basal and dorsal telencephalon indicating marked effects on telencephalic neurogenesis. The D1-receptor overexpression occurs at higher levels in the medial ganglionic eminence than the lateral ganglionic eminence or cerebral wall. Moreover, although the transgene is induced selectively in the neuroepithelium, D1-receptor protein overexpression appears to persist in postmitotic cells. The mouse model can be modified for neuroepithelial cell-specific inducible expression of other transgenes or induction of the D1-receptor transgene in other cells in specific brain regions by crossbreeding

  1. Acute amphetamine-induced subsensitivity of A10 dopamine autoreceptors in vitro.

    PubMed

    Seutin, V; Verbanck, P; Massotte, L; Dresse, A

    1991-08-30

    Extracellular recordings were obtained from spontaneously active, presumed dopamine (DA) neurons of the ventral tegmental area (VTA) of the rat in a slice preparation. Bath-applied (+)-amphetamine (AMPH) (1-30 microM) induced a concentration-dependent decrease in the firing rate of these neurons, which tended to saturate with the highest concentrations used (n = 11). This inhibitory effect was dependent on the activation of D2 receptors since it was reversed by the D2 antagonist sulpiride (n = 8). However, the most striking effect of AMPH was the induction of a prominent subsensitivity of DA autoreceptors: whereas in 18 out of 20 control neurons, the D2 agonist BHT 920 (100 nM) produced a rapid and complete inhibition of the firing, this was observed in none out of 11 neurons 10 min after the end of the application of AMPH (1-30 microM) (P less than 0.001). In these cells, the mean percent inhibition produced by BHT 920 was only 47 +/- 8%. This subsensitivity remained unchanged after 20 min and declined after one hour. This effect was specific, since the sensitivity of GABAB receptors to baclofen (500 nM-1 microM) was not modified by the application of AMPH (n = 12). These results suggest that AMPH-induced DA autoreceptor subsensitivity can be produced acutely and may be the first step in a cascade of events leading to behavioral sensitization to this compound.

  2. [Protective effect of verapamil and dopamine against cyclosporine-induced vasoconstriction in isolated glomeruli in rats].

    PubMed

    L'Azou, B; Lagroye, I; Plande, J; Lakhdar, B; Cambar, J

    1992-12-02

    Cyclosporin A (CsA)-induced nephrotoxicity is characterized by dramatic changes in glomerular filtration rate and renal plasma flow, largely limiting the clinical use of this drug. The vasoconstrictive response of CsA could explain, in part, these hemodynamic alterations. The present study compares the area changes in rat-isolated glomeruli incubated with CsA alone or after pre-treatment with verapamil and dopamine. In verapamil-pretreated CsA-intoxicated glomeruli, size decrease was reduced (-1.5 percent at T10, -3.1 percent at T20 and -4.8 percent at T30), when compared with CsA alone (-4.7 percent at T10, -10.1 percent at T20 and -12 percent at T30). The results obtained with dopamine were similar. In conclusion, verapamil and dopamine can be regarded as fair protective agents against CsA-induced vasoconstriction in rat-isolated glomeruli.

  3. Lipopolysaccharide mitagates methamphetamine-induced striatal dopamine depletion via modulating local TNF-alpha and dopamine transporter expression.

    PubMed

    Lai, Yu-Ting; Tsai, Yen-Ping N; Cherng, Chianfang G; Ke, Jing-Jer; Ho, Ming-Che; Tsai, Chia-Wen; Yu, Lung

    2009-04-01

    Systemic lipopolysaccharide (LPS) treatment may affect methamphetamine (MA)-induced nigrostriatal dopamine (DA) depletion. This study was undertaken to determine the critical time window for the protective effects of LPS treatment and the underlying mechanisms. An LPS injection (1 mg/kg) 72 h before or 2 h after MA treatment [three consecutive, subcutaneous injections of MA (10 mg/kg each) at 2-h intervals] diminished the MA-induced DA depletion in mouse striatum. Such an LPS-associated effect was independent of MA-produced hyperthermia. TNF-alpha, IL-1beta, IL-6 expressions were all elevated in striatal tissues following a systemic injection with LPS, indicating that peripheral LPS treatment affected striatal pro-inflammatory cytokine expression. Striatal TNF-alpha expression was dramatically increased at 72 and 96 h after the MA treatment, while such TNF-alpha elevation was abolished by the LPS pretreatment protocol. Moreover, MA-produced activation of nuclear NFkappaB, a transcription factor following TNF-alpha activation, in striatum was abolished by the LPS (1 mg/kg) pretreatment. Furthermore, thalidomide, a TNF-alpha antagonist, treatment abolished the LPS pretreatment-associated protective effects. Pretreatment with mouse recombinant TNF-alpha in striatum diminished the MA-produced DA depletion. Finally, single LPS treatment caused a rapid down-regulation of dopamine transporter (DAT) in striatum. Taken together, we conclude that peripheral LPS treatment protects nigrostriatal DA neurons against MA-induced toxicity, in part, by reversing elevated TNF-alpha expression and subsequent signaling cascade and causing a rapid DAT down-regulation in striatum.

  4. Phasic dopamine release in appetitive behaviors and drug abuse

    PubMed Central

    Wanat, Matthew J.; Willuhn, Ingo; Clark, Jeremy J.; Phillips, Paul E. M.

    2010-01-01

    Short phasic bursts of neuronal activity in dopamine neurons produce rapid and transient increases in extracellular dopamine concentrations throughout the mesocorticolimbic system, which are associated with the initiation of goal-directed behaviors. It is well established that acute exposure to many addictive drugs produce increases in tonic dopamine levels that occur on the order of minutes. However, recent studies suggest that abused drugs similarly enhance phasic dopamine release events that occur on a subsecond time scale. Furthermore, drug experience modulates the synaptic and intrinsic properties of dopamine neurons, which could affect dopamine burst firing and phasic dopamine release. This review will provide a general introduction to the mesolimbic dopamine system, as well as the primary methods used to detect dopamine neurons and dopamine release. We present the role of phasic dopamine release in appetitive behaviors in the context of contemporary theories regarding the function of dopamine. Next we discuss the known drug-induced changes to dopamine neurons and phasic release in both in vitro and in vivo preparations. Finally, we offer a simple model that chronic drug experience attenuates tonic/basal dopamine levels but promotes phasic dopamine release, which may result in aberrant goal-directed behaviors contributing to the development of addiction. PMID:19630749

  5. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND.

    PubMed

    Gaskill, Peter J; Calderon, Tina M; Coley, Jacqueline S; Berman, Joan W

    2013-06-01

    Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70 % of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers.

  6. Response contingency directs long-term cocaine-induced neuroplasticity in prefrontal and striatal dopamine terminals.

    PubMed

    Wiskerke, Joost; Schoffelmeer, Anton N M; De Vries, Taco J

    2016-10-01

    Exposure to addictive substances such as cocaine is well-known to alter brain organisation. Cocaine-induced neuroadaptations depend on several factors, including drug administration paradigm. To date, studies addressing the consequences of cocaine exposure on dopamine transmission have either not been designed to investigate the role of response contingency or focused only on short-term neuroplasticity. We demonstrate a key role of response contingency in directing long-term cocaine-induced neuroplasticity throughout projection areas of the mesocorticolimbic dopamine system. We found enhanced electrically-evoked [(3)H]dopamine release from superfused brain slices of nucleus accumbens shell and core, dorsal striatum and medial prefrontal cortex three weeks after cessation of cocaine self-administration. In yoked cocaine rats receiving the same amount of cocaine passively, sensitised dopamine terminal reactivity was only observed in the nucleus accumbens core. Control sucrose self-administration experiments demonstrated that the observed neuroadaptations were not the result of instrumental learning per se. Thus, long-term withdrawal from cocaine self-administration is associated with widespread sensitisation of dopamine terminals throughout frontostriatal circuitries.

  7. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND

    PubMed Central

    Gaskill, Peter J.; Calderon, Tina M.; Coley, Jacqueline S.; Berman, Joan W.

    2013-01-01

    Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70% of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID:23456305

  8. Dopamine is a key regulator in the signalling pathway underlying predator-induced defences in Daphnia.

    PubMed

    Weiss, Linda C; Leese, Florian; Laforsch, Christian; Tollrian, Ralph

    2015-10-07

    The waterflea Daphnia is a model to investigate the genetic basis of phenotypic plasticity resulting from one differentially expressed genome. Daphnia develops adaptive phenotypes (e.g. morphological defences) thwarting predators, based on chemical predator cue perception. To understand the genomic basis of phenotypic plasticity, the description of the precedent cellular and neuronal mechanisms is fundamental. However, key regulators remain unknown. All neuronal and endocrine stimulants were able to modulate but not induce defences, indicating a pathway of interlinked steps. A candidate able to link neuronal with endocrine responses is the multi-functional amine dopamine. We here tested its involvement in trait formation in Daphnia pulex and Daphnia longicephala using an induction assay composed of predator cues combined with dopaminergic and cholinergic stimulants. The mere application of both stimulants was sufficient to induce morphological defences. We determined dopamine localization in cells found in close association with the defensive trait. These cells serve as centres controlling divergent morphologies. As a mitogen and sclerotization agent, we anticipate that dopamine is involved in proliferation and structural formation of morphological defences. Furthermore, dopamine pathways appear to be interconnected with endocrine pathways, and control juvenile hormone and ecdysone levels. In conclusion, dopamine is suggested as a key regulator of phenotypic plasticity. © 2015 The Author(s).

  9. Dopamine is a key regulator in the signalling pathway underlying predator-induced defences in Daphnia

    PubMed Central

    Weiss, Linda C.; Leese, Florian; Laforsch, Christian; Tollrian, Ralph

    2015-01-01

    The waterflea Daphnia is a model to investigate the genetic basis of phenotypic plasticity resulting from one differentially expressed genome. Daphnia develops adaptive phenotypes (e.g. morphological defences) thwarting predators, based on chemical predator cue perception. To understand the genomic basis of phenotypic plasticity, the description of the precedent cellular and neuronal mechanisms is fundamental. However, key regulators remain unknown. All neuronal and endocrine stimulants were able to modulate but not induce defences, indicating a pathway of interlinked steps. A candidate able to link neuronal with endocrine responses is the multi-functional amine dopamine. We here tested its involvement in trait formation in Daphnia pulex and Daphnia longicephala using an induction assay composed of predator cues combined with dopaminergic and cholinergic stimulants. The mere application of both stimulants was sufficient to induce morphological defences. We determined dopamine localization in cells found in close association with the defensive trait. These cells serve as centres controlling divergent morphologies. As a mitogen and sclerotization agent, we anticipate that dopamine is involved in proliferation and structural formation of morphological defences. Furthermore, dopamine pathways appear to be interconnected with endocrine pathways, and control juvenile hormone and ecdysone levels. In conclusion, dopamine is suggested as a key regulator of phenotypic plasticity. PMID:26423840

  10. Repeated Exposure to Methamphetamine, Cocaine or Morphine Induces Augmentation of Dopamine Release in Rat Mesocorticolimbic Slice Co-Cultures

    PubMed Central

    Nakagawa, Takayuki; Suzuki, Yuichi; Nagayasu, Kazuki; Kitaichi, Maiko; Shirakawa, Hisashi; Kaneko, Shuji

    2011-01-01

    Repeated intermittent exposure to psychostimulants and morphine leads to progressive augmentation of its locomotor activating effects in rodents. Accumulating evidence suggests the critical involvement of the mesocorticolimbic dopaminergic neurons, which project from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex, in the behavioral sensitization. Here, we examined the acute and chronic effects of psychostimulants and morphine on dopamine release in a reconstructed mesocorticolimbic system comprised of a rat triple organotypic slice co-culture of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex regions. Tyrosine hydroxylase-positive cell bodies were localized in the ventral tegmental area, and their neurites projected to the nucleus accumbens and medial prefrontal cortex regions. Acute treatment with methamphetamine (0.1–1000 µM), cocaine (0.1–300 µM) or morphine (0.1–100 µM) for 30 min increased extracellular dopamine levels in a concentration-dependent manner, while 3,4-methylenedioxyamphetamine (0.1–1000 µM) had little effect. Following repeated exposure to methamphetamine (10 µM) for 30 min every day for 6 days, the dopamine release gradually increased during the 30-min treatment. The augmentation of dopamine release was maintained even after the withdrawal of methamphetamine for 7 days. Similar augmentation was observed by repeated exposure to cocaine (1–300 µM) or morphine (10 and 100 µM). Furthermore, methamphetamine-induced augmentation of dopamine release was prevented by an NMDA receptor antagonist, MK-801 (10 µM), and was not observed in double slice co-cultures that excluded the medial prefrontal cortex slice. These results suggest that repeated psychostimulant- or morphine-induced augmentation of dopamine release, i.e. dopaminergic sensitization, was reproduced in a rat triple organotypic slice co-cultures. In addition, the slice co-culture system revealed that the NMDA

  11. Reversal of Alcohol-Induced Dysregulation in Dopamine Network Dynamics May Rescue Maladaptive Decision-making.

    PubMed

    Schindler, Abigail G; Soden, Marta E; Zweifel, Larry S; Clark, Jeremy J

    2016-03-30

    Alcohol is the most commonly abused substance among adolescents, promoting the development of substance use disorders and compromised decision-making in adulthood. We have previously demonstrated, with a preclinical model in rodents, that adolescent alcohol use results in adult risk-taking behavior that positively correlates with phasic dopamine transmission in response to risky options, but the underlying mechanisms remain unknown. Here, we show that adolescent alcohol use may produce maladaptive decision-making through a disruption in dopamine network dynamics via increased GABAergic transmission within the ventral tegmental area (VTA). Indeed, we find that increased phasic dopamine signaling after adolescent alcohol use is attributable to a midbrain circuit, including the input from the pedunculopontine tegmentum to the VTA. Moreover, we demonstrate that VTA dopamine neurons from adult rats exhibit enhanced IPSCs after adolescent alcohol exposure corresponding to decreased basal dopamine levels in adulthood that negatively correlate with risk-taking. Building on these findings, we develop a model where increased inhibitory tone on dopamine neurons leads to a persistent decrease in tonic dopamine levels and results in a potentiation of stimulus-evoked phasic dopamine release that may drive risky choice behavior. Based on this model, we take a pharmacological approach to the reversal of risk-taking behavior through normalization of this pattern in dopamine transmission. These results isolate the underlying circuitry involved in alcohol-induced maladaptive decision-making and identify a novel therapeutic target. One of the primary problems resulting from chronic alcohol use is persistent, maladaptive decision-making that is associated with ongoing addiction vulnerability and relapse. Indeed, studies with the Iowa Gambling Task, a standard measure of risk-based decision-making, have reliably shown that alcohol-dependent individuals make riskier, more maladaptive

  12. Graft-induced dyskinesias in Parkinson's disease: High striatal serotonin/dopamine transporter ratio.

    PubMed

    Politis, Marios; Oertel, Wolfgang H; Wu, Kit; Quinn, Niall P; Pogarell, Oliver; Brooks, David J; Bjorklund, Anders; Lindvall, Olle; Piccini, Paola

    2011-09-01

    Graft-induced dyskinesias are a serious complication after neural transplantation in Parkinson's disease. One patient with Parkinson's disease, treated with fetal grafts 14 years ago and deep brain stimulation 6 years ago, showed marked improvement of motor symptoms but continued to suffer from OFF-medication graft-induced dyskinesias. The patient received a series of clinical and imaging assessments. Positron emission tomography and single-photon emission computed tomography 14 years posttransplantation revealed an elevated serotonin/dopamine transporter ratio in the grafted striatum compatible with serotonergic hyperinnervation. Inhibition of serotonin neuron activity by systemic administration of a 5-HT(1A) agonist suppressed graft-induced dyskinesias. Our data provide further evidence that serotonergic neurons mediate graft-induced dyskinesias in Parkinson's disease. Achieving a normal striatal serotonin/dopamine transporter ratio following transplantation of fetal tissue or stem cells should be necessary to avoid the development of graft-induced dyskinesias.

  13. Selective 6OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats.

    PubMed

    Kelly, P H; Iversen, S D

    1976-11-01

    Selective large scale destruction of mesolimbic dopamine-containing terminals is produced by bilateral injection of 8 mug of 6-hydroxydopamine (6OHDA) into the nucleus accumbens septi (NAS) of rats pretreated with pargyline and desipramine (DMI). The DMI prevents the destruction of the noradrenergic innervation of the forebrain normally produced by the NAS 6OHDA lesion, without affecting the destruction of dopamine-containing neurons. The locomotor stimulation produced by the psychostimulants d-amphetamine (1.5 mg/kg) and cocaine (20 mg/kg) is blocked in rats with selective destruction of the mesolimbic dopamine system. In contrast the locomotor stimulation produced by the directly acting dopamine agonist apomorphine (1.0 mg/kg) is enhanced, which may indicate supersensitivity of the denervated dopamine receptors. These results lend further support to the view that psychostimulant-induced locomotr stimulation in rats results from effects on mesolimbic dopamine neurons. In addition, the protection by DMI of noradrenergic neurons from the toxic effects of 6OHDA is evidence that 6OHDA, as used here, destroys catecholamine neurons mainly by an uptake-dependent specific mechanism.

  14. Sequential Loss of LC Noradrenergic and Dopaminergic Neurons Results in a Correlation of Dopaminergic Neuronal Number to Striatal Dopamine Concentration.

    PubMed

    Szot, Patricia; Franklin, Allyn; Sikkema, Carl; Wilkinson, Charles W; Raskind, Murray A

    2012-01-01

    Noradrenergic neurons in the locus coeruleus (LC) are significantly reduced in Parkinson's disease (PD) and the LC exhibits neuropathological changes early in the disease process. It has been suggested that a loss of LC neurons can enhance the susceptibility of dopaminergic neurons to damage. To determine if LC noradrenergic innervation protects dopaminergic neurons from damage, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered to adult male C57Bl/6 mice 3 days after bilateral LC administration of 6-hydroxydopamine (6OHDA), a time when there is a significant reduction in LC neuronal number and innervation to forebrain regions. To assess if LC loss can affect dopaminergic loss four groups of animals were studied: control, 6OHDA, MPTP, and 6OHDA + MPTP; animals sacrificed 3 weeks after MPTP administration. The number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA), and noradrenergic neurons in the LC were determined. Catecholamine levels in striatum were measured by high-pressure liquid chromatography. The loss of LC neurons did not affect the number of dopaminergic neurons in the SN and VTA compared to control; however, LC 6OHDA significantly reduced striatal dopamine (DA; 29% reduced) but not norepinephrine (NE) concentration. MPTP significantly reduced SN and VTA neuronal number and DA concentration in the striatum compared to control; however, there was not a correlation of striatal DA concentration with SN or VTA neuronal number. Administration of 6OHDA prior to MPTP did not enhance MPTP-induced damage despite an effect of LC loss on striatal DA concentration. However, the loss of LC neurons before MPTP resulted now in a correlation between SN and VTA neuronal number to striatal DA concentration. These results demonstrate that the loss of either LC or DA neurons can affect the function of each others systems, indicating the importance of both the noradrenergic and

  15. Sequential Loss of LC Noradrenergic and Dopaminergic Neurons Results in a Correlation of Dopaminergic Neuronal Number to Striatal Dopamine Concentration

    PubMed Central

    Szot, Patricia; Franklin, Allyn; Sikkema, Carl; Wilkinson, Charles W.; Raskind, Murray A.

    2012-01-01

    Noradrenergic neurons in the locus coeruleus (LC) are significantly reduced in Parkinson’s disease (PD) and the LC exhibits neuropathological changes early in the disease process. It has been suggested that a loss of LC neurons can enhance the susceptibility of dopaminergic neurons to damage. To determine if LC noradrenergic innervation protects dopaminergic neurons from damage, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered to adult male C57Bl/6 mice 3 days after bilateral LC administration of 6-hydroxydopamine (6OHDA), a time when there is a significant reduction in LC neuronal number and innervation to forebrain regions. To assess if LC loss can affect dopaminergic loss four groups of animals were studied: control, 6OHDA, MPTP, and 6OHDA + MPTP; animals sacrificed 3 weeks after MPTP administration. The number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA), and noradrenergic neurons in the LC were determined. Catecholamine levels in striatum were measured by high-pressure liquid chromatography. The loss of LC neurons did not affect the number of dopaminergic neurons in the SN and VTA compared to control; however, LC 6OHDA significantly reduced striatal dopamine (DA; 29% reduced) but not norepinephrine (NE) concentration. MPTP significantly reduced SN and VTA neuronal number and DA concentration in the striatum compared to control; however, there was not a correlation of striatal DA concentration with SN or VTA neuronal number. Administration of 6OHDA prior to MPTP did not enhance MPTP-induced damage despite an effect of LC loss on striatal DA concentration. However, the loss of LC neurons before MPTP resulted now in a correlation between SN and VTA neuronal number to striatal DA concentration. These results demonstrate that the loss of either LC or DA neurons can affect the function of each others systems, indicating the importance of both the noradrenergic and

  16. Neurotensin Induces Presynaptic Depression of D2 Dopamine Autoreceptor-Mediated Neurotransmission in Midbrain Dopaminergic Neurons.

    PubMed

    Piccart, Elisabeth; Courtney, Nicholas A; Branch, Sarah Y; Ford, Christopher P; Beckstead, Michael J

    2015-08-05

    Increased dopaminergic signaling is a hallmark of severe mesencephalic pathologies such as schizophrenia and psychostimulant abuse. Activity of midbrain dopaminergic neurons is under strict control of inhibitory D2 autoreceptors. Application of the modulatory peptide neurotensin (NT) to midbrain dopaminergic neurons transiently increases activity by decreasing D2 dopamine autoreceptor function, yet little is known about the mechanisms that underlie long-lasting effects. Here, we performed patch-clamp electrophysiology and fast-scan cyclic voltammetry in mouse brain slices to determine the effects of NT on dopamine autoreceptor-mediated neurotransmission. Application of the active peptide fragment NT8-13 produced synaptic depression that exhibited short- and long-term components. Sustained depression of D2 autoreceptor signaling required activation of the type 2 NT receptor and the protein phosphatase calcineurin. NT application increased paired-pulse ratios and decreased extracellular levels of somatodendritic dopamine, consistent with a decrease in presynaptic dopamine release. Surprisingly, we observed that electrically induced long-term depression of dopaminergic neurotransmission that we reported previously was also dependent on type 2 NT receptors and calcineurin. Because electrically induced depression, but not NT-induced depression, was blocked by postsynaptic calcium chelation, our findings suggest that endogenous NT may act through a local circuit to decrease presynaptic dopamine release. The current research provides a mechanism through which augmented NT release can produce a long-lasting increase in membrane excitability of midbrain dopamine neurons. Whereas plasticity of glutamate synapses in the brain has been studied extensively, demonstrations of plasticity at dopaminergic synapses have been more elusive. By quantifying inhibitory neurotransmission between midbrain dopaminergic neurons in brain slices from mice we have discovered that the modulatory

  17. Dopamine depletion of the prefrontal cortex induces dendritic spine loss: reversal by atypical antipsychotic drug treatment.

    PubMed

    Wang, Hui-Dong; Deutch, Ariel Y

    2008-05-01

    Dystrophic changes in dendrites of cortical neurons are present in several neuro-psychiatric disorders, including schizophrenia. The mechanisms that account for dendritic changes in the prefrontal cortex (PFC) in schizophrenia are unclear. Cognitive deficits in schizophrenia have been linked to compromised cortical dopamine function, and the density of the PFC dopamine innervation is decreased in schizophrenia. We determined if 6-hydroxydopamine lesions of the ventral tegmental area that disrupt the PFC dopamine innervation cause dystrophic changes in cortical neurons. Three weeks post-operatively we observed a marked decrease in basal dendritic length and spine density of layer V pyramidal cells in the prelimbic cortex; no change was seen in neurons of the motor cortex. We then examined rats in which the PFC dopamine innervation was lesioned and 3 weeks later were started on chronic treatment with an atypical (olanzapine) or typical (haloperidol) antipsychotic drug. Olanzapine but not haloperidol reversed lesion-induced changes in PFC pyramidal cell dendrites. These data suggest that dopamine regulates dendritic structure in PFC neurons. Moreover, the findings are consistent with a decrease in cortical dopaminergic tone contributing to the pathological changes in the cortex of schizophrenia, and suggest that the progressive cortical loss in schizophrenia may be slowed or reversed by treatment with atypical antipsychotic drugs.

  18. Adaptations of Presynaptic Dopamine Terminals Induced by Psychostimulant Self-Administration

    PubMed Central

    2015-01-01

    A great deal of research has focused on investigating neurobiological alterations induced by chronic psychostimulant use in an effort to describe, understand, and treat the pathology of psychostimulant addiction. It has been known for several decades that dopamine neurotransmission in the nucleus accumbens is integrally involved in the selection and execution of motivated and goal-directed behaviors, and that psychostimulants act on this system to exert many of their effects. As such, a large body of work has focused on defining the consequences of psychostimulant use on dopamine signaling in the striatum as it relates to addictive behaviors. Here, we review presynaptic dopamine terminal alterations observed following self-administration of cocaine and amphetamine, as well as possible mechanisms by which these alterations occur and their impact on the progression of addiction. PMID:25491345

  19. DOPAMINE D1 RECEPTORS WITHIN THE BASOLATERAL AMYGDALA MEDIATE HEROIN-INDUCED CONDITIONED IMMUNOMODULATION

    PubMed Central

    Szczytkowski, Jennifer L.; Lysle, Donald T.

    2012-01-01

    This study investigates the role of basolateral amygdala (BLA) dopamine in heroin-induced conditioned immunomodulation. Animals underwent conditioning in which heroin administration was repeatedly paired with placement into a conditioning chamber. Six days after the final conditioning session animals were returned to the chamber and received intra-BLA microinfusions of dopamine, D1 or D2, antagonist. Antagonism of D1, but not D2, receptors within the BLA blocked the suppressive effect of heroin-associated environmental stimuli on iNOS, TNF-α and IL-1β. This study is the first to demonstrate that the expression of heroin’s conditioned effects on proinflammatory mediators require dopamine D1 receptors within the BLA. PMID:20605224

  20. Microdialysis and SPECT measurements of amphetamine-induced dopamine release in nonhuman primates.

    PubMed

    Laruelle, M; Iyer, R N; al-Tikriti, M S; Zea-Ponce, Y; Malison, R; Zoghbi, S S; Baldwin, R M; Kung, H F; Charney, D S; Hoffer, P B; Innis, R B; Bradberry, C W

    1997-01-01

    The competition between endogenous transmitters and radiolabeled ligands for in vivo binding to neuroreceptors might provide a method to measure endogenous transmitter release in the living human brain with noninvasive techniques such as positron emission tomography (PET) or single photon emission computerized tomography (SPECT). In this study, we validated the measure of amphetamine-induced dopamine release with SPECT in nonhuman primates. Microdialysis experiments were conducted to establish the dose-response curve of amphetamine-induced dopamine release and to document how pretreatment with the dopamine depleter alpha-methyl-para-tyrosine (alpha MPT) affects this response. SPECT experiments were performed with two iodinated benzamides, [123I]IBZM and [123I]IBF, under sustained equilibrium condition. Both radio-tracers are specific D2 antagonists, but the affinity of [123I]IBZM (KD-0.4 nM) is lower than that of [123I]IBF (KD 0.1 nM). With both tracers, we observed a prolonged reduction in binding to D2 receptors following amphetamine injection. [123I]IBZM binding to D2 receptors was more affected than [123I]IBF by high doses of amphetamine, indicating that a lower affinity increases the vulnerability of a tracer to endogenous competition. With [123I]IBZM, we observed an excellent correlation between reduction of D2 receptor binding measured with SPECT and peak dopamine release measured with microdialysis after various doses of amphetamine. Pretreatment with alpha MPT significantly reduced the effect of amphetamine on [123I]IBZM binding to D2 receptors, confirming that this effect was mediated by intrasynaptic dopamine release. Together, these results validate the use of this SPECT paradigm as a noninvasive measurement of intrasynaptic dopamine release in the living brain.

  1. Dopamine and paraquat enhance α-synuclein-induced alterations in membrane conductance

    PubMed Central

    Feng, Li Rebekah; Maguire-Zeiss, Kathleen A.

    2011-01-01

    We have previously demonstrated that α-synuclein overexpression increases the membrane conductance of dopaminergic-like cells. Although α-synuclein is thought to play a central role in the pathogenesis of several neurodegenerative diseases including Parkinson’s disease, multiple system atrophy and diffuse Lewy body disease the mechanism of action is not completely understood. In this study we sought to determine whether multiple factors act together with α-synuclein to engender cell vulnerability through an augmentation of membrane conductance. Here we employed a cell model that mimics dopaminergic neurons coupled with α-synuclein overexpression and oxidative stressors. We demonstrate an enhancement of α-synuclein-induced toxicity in the presence of combined treatment with dopamine and paraquat, two molecules known to incite oxidative stress. In addition we show that combined dopamine and paraquat treatment increases the expression of heme oxygenase-1, an antioxidant response protein. Finally, we demonstrate for the first time that combined treatment of dopaminergic cells with paraquat and dopamine enhances α-synuclein-induced leak channel properties resulting in increased membrane conductance. Importantly, these increases are most robust when both paraquat and dopamine are present suggesting the need for multiple oxidative insults to augment α-synuclein-induced disruption of membrane integrity. PMID:21735318

  2. Chronic Nicotine Mitigates Aberrant Inhibitory Motor Learning Induced by Motor Experience under Dopamine Deficiency.

    PubMed

    Koranda, Jessica L; Krok, Anne C; Xu, Jian; Contractor, Anis; McGehee, Daniel S; Beeler, Jeff A; Zhuang, Xiaoxi

    2016-05-11

    Although dopamine receptor antagonism has long been associated with impairments in motor performance, more recent studies have shown that dopamine D2 receptor (D2R) antagonism, paired with a motor task, not only impairs motor performance concomitant with the pharmacodynamics of the drug, but also impairs future motor performance once antagonism has been relieved. We have termed this phenomenon "aberrant motor learning" and have suggested that it may contribute to motor symptoms in movement disorders such as Parkinson's disease (PD). Here, we show that chronic nicotine (cNIC), but not acute nicotine, treatment mitigates the acquisition of D2R-antagonist-induced aberrant motor learning in mice. Although cNIC mitigates D2R-mediated aberrant motor learning, cNIC has no effect on D1R-mediated motor learning. β2-containing nicotinic receptors in dopamine neurons likely mediate the protective effect of cNIC against aberrant motor learning, because selective deletion of β2 nicotinic subunits in dopamine neurons reduced D2R-mediated aberrant motor learning. Finally, both cNIC treatment and β2 subunit deletion blunted postsynaptic responses to D2R antagonism. These results suggest that a chronic decrease in function or a downregulation of β2-containing nicotinic receptors protects the striatal network against aberrant plasticity and aberrant motor learning induced by motor experience under dopamine deficiency. Increasingly, aberrant plasticity and aberrant learning are recognized as contributing to the development and progression of movement disorders. Here, we show that chronic nicotine (cNIC) treatment or specific deletion of β2 nicotinic receptor subunits in dopamine neurons mitigates aberrant motor learning induced by dopamine D2 receptor (D2R) blockade in mice. Moreover, both manipulations also reduced striatal dopamine release and blunt postsynaptic responses to D2R antagonists. These results suggest that chronic downregulation of function and/or receptor

  3. Intratracheal dopamine attenuates pulmonary edema and improves survival after ventilator-induced lung injury in rats

    PubMed Central

    Chamorro-Marín, Virginia; García-Delgado, Manuel; Touma-Fernández, Angel; Aguilar-Alonso, Eduardo; Fernández-Mondejar, Enrique

    2008-01-01

    Intoduction Clearance of alveolar oedema depends on active transport of sodium across the alveolar-epithelial barrier. β-Adrenergic agonists increase clearance of pulmonary oedema, but it has not been established whether β-agonist stimulation achieves sufficient oedema clearance to improve survival in animals. The objective of this study was to determine whether the increased pulmonary oedema clearance produced by intratracheal dopamine improves the survival of rats after mechanical ventilation with high tidal volume (HVT). Methods This was a randomized, controlled, experimental study. One hundred and thirty-two Wistar-Kyoto rats, weighing 250 to 300 g, were anaesthetized and cannulated via endotracheal tube. Pulmonary oedema was induced by endotracheal instillation of saline solution and mechanical ventilation with HVT. Two types of experiment were carried out. The first was an analysis of pulmonary oedema conducted in six groups of 10 rats ventilated with low (8 ml/kg) or high (25 ml/kg) tidal volume for 30 or 60 minutes with or without intratracheally instilled dopamine. At the end of the experiment the animals were exsanguinated and pulmonary oedema analysis performed. The second experiment was a survival analysis, which was conducted in two groups of 36 animals ventilated with HVT for 60 minutes with or without intratracheal dopamine; survival of the animals was monitored for up to 7 days after extubation. Results In animals ventilated at HVT with or without intratracheal dopamine, oxygen saturation deteriorated over time and was significantly higher at 30 minutes than at 60 minutes. After 60 minutes, a lower wet weight/dry weight ratio was observed in rats ventilated with HVT and instilled with dopamine than in rats ventilated with HVT without dopamine (3.9 ± 0.27 versus 4.9 ± 0.29; P = 0.014). Survival was significantly (P = 0.013) higher in animals receiving intratracheal dopamine and ventilated with HVT, especially at 15 minutes after extubation, when

  4. Effects of hypothalamic dopamine (DA) on salsolinol (SAL)-induced prolactin (PRL) secretion in male goats.

    PubMed

    Jin, Jin; Hara, Sayaka; Sawai, Ken; Fülöp, Ferenc; Nagy, György Miklos; Hashizume, Tsutomu

    2014-04-01

    The aim of the present study was to clarify the effects of hypothalamic dopamine (DA) on salsolinol (SAL)-induced prolactin (PRL) release in goats. The PRL-releasing response to an intravenous (i.v.) injection of SAL was examined after treatment with augmentation of central DA using carbidopa (carbi) and L-dopa in male goats under 8-h (8 h light, 16 h dark) or 16-h (16 h light, 8 h dark) photoperiod conditions. The carbi and L-dopa treatments reduced basal PRL concentrations in the 16-h photoperiod group (P < 0.05), while a reduction was not observed in the 8-h photoperiod group. The mean basal plasma PRL concentration in the control group for the 8-h photoperiod was lower than that for the 16-h photoperiod (P < 0.05). SAL significantly stimulated the release of PRL promptly after the injection in both the 8- and 16-h photoperiod groups (P < 0.05). PRL-releasing responses for the 16-h photoperiod were greater than those for the 8-h photoperiod (P < 0.05). The carbi and L-dopa treatments blunted SAL-induced PRL release in both the 8- and 16-h photoperiods (P < 0.05). These results indicate that hypothalamic DA blunts the SAL-induced release of PRL in male goats, regardless of the photoperiod, which suggests that both SAL and DA are involved in regulating the secretion of PRL in goats.

  5. The interaction of manganese nanoparticles with PC-12 cells induces dopamine depletion.

    PubMed

    Hussain, Saber M; Javorina, Amanda K; Schrand, Amanda M; Duhart, Helen M; Ali, Syed F; Schlager, John J

    2006-08-01

    This investigation was designed to determine whether nano-sized manganese oxide (Mn-40 nm) particles would induce dopamine (DA) depletion in a cultured neuronal phenotype, PC-12 cells, similar to free ionic manganese (Mn(2+)). Cells were exposed to Mn-40 nm, Mn(2+) (acetate), or known cytotoxic silver nanoparticles (Ag-15 nm) for 24 h. Phase-contrast microscopy studies show that Mn-40 nm or Mn(2+) exposure did not greatly change morphology of PC-12 cells. However, Ag-15 nm and AgNO(3) produce cell shrinkage and irregular membrane borders compared to control cells. Further microscopic studies at higher resolution demonstrated that Mn-40 nm nanoparticles and agglomerates were effectively internalized by PC-12 cells. Mitochondrial reduction activity, a sensitive measure of particle and metal cytotoxicity, showed only moderate toxicity for Mn-40 nm compared to similar Ag-15 nm and Mn(2+) doses. Mn-40 nm and Mn(2+) dose dependently depleted DA and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), while Ag-15 nm only significantly reduced DA and DOPAC at concentrations of 50 mug/ml. Therefore, the DA depletion of Mn-40 nm was most similar to Mn(2+), which is known to induce concentration-dependent DA depletion. There was a significant increase (> 10-fold) in reactive oxygen species (ROS) with Mn-40 nm exposure, suggesting that increased ROS levels may participate in DA depletion. These results clearly demonstrate that nanoscale manganese can deplete DA, DOPAC, and HVA in a dose-dependent manner. Further study is required to evaluate the specific intracellular distribution of Mn-40 nm nanoparticles, metal dissolution rates in cells and cellular matrices, if DA depletion is induced in vivo, and the propensity of Mn nanoparticles to cross the blood-brain barrier or be selectively uptaken by nasal epithelium.

  6. 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

  7. Methylphenidate-Induced Increases in Vesicular Dopamine Sequestration and Dopamine Release in the Striatum: The Role of Muscarinic and Dopamine D2 Receptors

    PubMed Central

    Volz, Trent J.; Farnsworth, Sarah J.; Rowley, Shane D.; Hanson, Glen R.; Fleckenstein, Annette E.

    2008-01-01

    Methylphenidate (MPD) administration alters the subcellular distribution of vesicular monoamine transporter-2 (VMAT-2)-containing vesicles in rat striatum. This report reveals previously undescribed pharmacological features of MPD by elucidating its receptor-mediated effects on VMAT-2-containing vesicles that co-fractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles) and on striatal dopamine (DA) release. MPD administration increased DA transport into, and decreased the VMAT-2 immunoreactivity of, the membrane-associated vesicle subcellular fraction. These effects were mimicked by the D2 receptor agonist, quinpirole, and blocked by the D2 receptor antagonist, eticlopride. Both MPD and quinpirole increased vesicular DA content. However, MPD increased, whereas quinpirole decreased, K+-stimulated DA release from striatal suspensions. Like MPD, the muscarinic receptor agonist, oxotremorine, increased K+-stimulated DA release. Both eticlopride and the muscarinic receptor antagonist, scopolamine, blocked MPD-induced increases in K+-stimulated DA release while the N-methyl-D-aspartate receptor antagonist, MK-801, was without effect. This suggests that D2 receptors mediate both the MPD-induced redistribution of vesicles away from synaptosomal membranes and the MPD-induced upregulation of vesicles remaining at the membrane. This results in a redistribution of DA within the striatum from the cytoplasm into vesicles, leading to increased DA release. However, D2 receptor activation alone is not sufficient to mediate the MPD-induced increases in striatal DA release as muscarinic receptor activation is also required. These novel findings provide insight into the mechanism of action of MPD, regulation of DA sequestration/release, and treatment of disorders affecting DA disposition including attention-deficit hyperactivity disorder, substance abuse, and Parkinson's disease. PMID:18591219

  8. Ca2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism.

    PubMed

    Antkiewicz-Michaluk, L; Románska, I; Vetulani, J

    1997-07-30

    To investigate the effect of a single and multiple administration of lysergic acid diethylamide (LSD) on cerebral metabolism of dopamine and serotonin, male Wistar rats were treated with low and high doses (0.1 and 2.0 mg/kg i.p.) of LSD and the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, serotonin and 5-hydroxyindoleacetic acid were assayed by HPLC in the nucleus accumbens, striatum and frontal cortex. Some rats received nifedipine, 5 mg/kg i.p., before each injection of LSD to assess the effect of a Ca2+ channel blockade. High-dose LSD treatment (8 x 2 mg/kg per day) caused a strong stimulation of dopamine metabolism in the nucleus accumbens and striatum, and serotonin metabolism in the nucleus accumbens: the changes were observed 24 (but not 1 h) after the last dose. The changes induced by the low-dose treatment (8 x 0.1 mg/kg per day) had a different pattern, suggesting the release of dopamine from vesicles to cytoplasm. Co-administration of nifedipine completely prevented the LSD-induced biochemical changes. The results suggest that Ca2+ channel blocking agents may prevent development of some behavioral consequences of chronically used LSD.

  9. Effects of dronabinol on morphine-induced dopamine-related behavioral effects in animals.

    PubMed

    Mori, Tomohisa; Shibasaki, Masahiro; Abe, Minako; Udagawa, Yuya; Suzuki, Tsutomu

    2012-11-01

    The present study examined the effects of dronabinol, a United States FDA-approved synthetic cannabinoid receptor agonist, on morphine (a prototypic μ-opioid receptor agonist)-induced dopamine-related behaviors in animals. Dronabinol suppressed the rewarding effects of morphine in rats and its emetic effects in ferrets. Furthermore, the morphine-induced increase in dopamine release from the nucleus accumbens was significantly attenuated by dronabinol, which indicated that the suppressive effects of dronabinol on morphine-induced behaviors are at least in part mediated by regulation of the dopaminergic system. Since cannabinoid receptor agonists have been shown to enhance the antinociceptive effects of morphine, the use of dronabinol as an adjuvant could be useful for preventing the adverse effects of μ-opioid receptor agonists when used to control pain.

  10. /sup 3/H-imipramine uptake into rat striatal slices and imipramine-induced /sup 3/H-dopamine efflux

    SciTech Connect

    Saito, R.; Kawasaki, K.; Ono, N.; Kamiya, H.

    1983-04-01

    The effect of imipramine on spontaneous efflux of radiolabelled dopamine (DA) from slices of rat striatum was examined by a superfusion method. Imipramine at concentrations of 10 - 100 microM enhanced the efflux of DA accumulated in a high-affinity uptake system in a concentration-dependent manner. This efflux of /sup 3/H-DA was not affected by conditions (Ca/sup 2 +/-free medium, 100 microM bretylium and 30 microM tetrodotoxin) which inhibited the release of /sup 3/H-DA by electrical stimulation. Furthermore, this imipramine-induced /sup 3/H-DA efflux was temperature-dependent. The uptake of /sup 3/H-imipramine into striatal slices was determined. This uptake was concentration- and temperature-dependent and increased linearly. These results are discussed in relation to the hypothesis that /sup 3/H-DA efflux by imipramine is connected with uptake of imipramine.

  11. Correlation of individual differences in schizotypal personality traits with amphetamine-induced dopamine release in striatal and extrastriatal brain regions.

    PubMed

    Woodward, Neil D; Cowan, Ronald L; Park, Sohee; Ansari, M Sib; Baldwin, Ronald M; Li, Rui; Doop, Mikisha; Kessler, Robert M; Zald, David H

    2011-04-01

    Schizotypal personality traits are associated with schizophrenia spectrum disorders, and individuals with schizophrenia spectrum disorders demonstrate increased dopamine transmission in the striatum. The authors sought to determine whether individual differences in normal variation in schizotypal traits are correlated with dopamine transmission in the striatum and in extrastriatal brain regions. Sixty-three healthy volunteers with no history of psychiatric illness completed the Schizotypal Personality Questionnaire and underwent positron emission tomography imaging with [(18)F]fallypride at baseline and after administration of oral d-amphetamine (0.43 mg/kg). Dopamine release, quantified by subtracting each participant's d-amphetamine scan from his or her baseline scan, was correlated with Schizotypal Personality Questionnaire total and factor scores using region-of-interest and voxel-wise analyses. Dopamine release in the striatum was positively correlated with overall schizotypal traits. The association was especially robust in the associative subdivision of the striatum. Voxel-wise analyses identified additional correlations between dopamine release and schizotypal traits in the left middle frontal gyrus and left supramarginal gyrus. Exploratory analyses of Schizotypal Personality Questionnaire factor scores revealed correlations between dopamine release and disorganized schizotypal traits in the striatum, thalamus, medial prefrontal cortex, temporal lobe, insula, and inferior frontal cortex. The association between dopamine signaling and psychosis phenotypes extends to individual differences in normal variation in schizotypal traits and involves dopamine transmission in both striatal and extrastriatal brain regions. Amphetamine-induced dopamine release may be a useful endophenotype for investigating the genetic basis of schizophrenia spectrum disorders.

  12. Caffeic acid, tyrosol and p-coumaric acid are potent inhibitors of 5-S-cysteinyl-dopamine induced neurotoxicity.

    PubMed

    Vauzour, David; Corona, Giulia; Spencer, Jeremy P E

    2010-09-01

    Parkinson's disease is characterized by a progressive and selective loss of dopaminergic neurons in the substantia nigra. Recent investigations have shown that conjugates such as the 5-S-cysteinyl-dopamine, possess strong neurotoxicity and may contribute to the underlying progression of the disease pathology. Although the neuroprotective actions of flavonoids are well reported, that of hydroxycinnamates and other phenolic acids is less established. We show that the hydroxycinnamates caffeic acid and p-coumaric acid, the hydroxyphenethyl alcohol, tyrosol, and a Champagne wine extract rich in these components protect neurons against injury induced by 5-S-cysteinyl-dopamine in vitro. The protection induced by these polyphenols was equal to or greater than that observed for the flavonoids, (+)-catechin, (-)-epicatechin and quercetin. For example, p-coumaric acid evoked significantly more protection at 1muM (64.0+/-3.1%) than both (-)-epicatechin (46.0+/-4.1%, p<0.05) and (+)-catechin (13.1+/-3.0%, p<0.001) at the same concentration. These data indicate that hydroxycinnamates, phenolic acids and phenolic alcohol are also capable of inducing neuroprotective effects to a similar extent to that seen with flavonoids.

  13. Concentration-dependent activation of dopamine receptors differentially modulates GABA release onto orexin neurons

    PubMed Central

    Linehan, Victoria; Trask, Robert B.; Briggs, Chantalle; Rowe, Todd M.; Hirasawa, Michiru

    2017-01-01

    Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups, where orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying DA action on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using whole cell patch clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration dependent, bidirectional manner. Low (1 μM) and high concentrations (100 μM) of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors, whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours. PMID:26036709

  14. Concentration-dependent activation of dopamine receptors differentially modulates GABA release onto orexin neurons.

    PubMed

    Linehan, Victoria; Trask, Robert B; Briggs, Chantalle; Rowe, Todd M; Hirasawa, Michiru

    2015-08-01

    Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups: orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying the action of DA on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using the whole-cell patch-clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration-dependent bidirectional manner. Low (1 μM) and high (100 μM) concentrations of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G-protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours.

  15. Multiple functions of Na/K-ATPase in dopamine-induced salivation of the Blacklegged tick, Ixodes scapularis

    PubMed Central

    Kim, Donghun; Urban, Joshua; Boyle, Daniel L.; Park, Yoonseong

    2016-01-01

    Control of salivary secretion in ticks involves autocrine dopamine activating two dopamine receptors: D1 and Invertebrate-specific D1-like dopamine receptors. In this study, we investigated Na/K-ATPase as an important component of the secretory process. Immunoreactivity for Na/K-ATPase revealed basal infolding of lamellate cells in type-I, abluminal interstitial (epithelial) cells in type-II, and labyrinth-like infolding structures opening towards the lumen in type-III acini. Ouabain (10 μmol l−1), a specific inhibitor of Na/K-ATPase, abolished dopamine-induced salivary secretion by suppressing fluid transport in type III acini. At 1 μmol l−1, ouabain, the secreted saliva was hyperosmotic. This suggests that ouabain also inhibits an ion resorptive function of Na/K-ATPase in the type I acini. Dopamine/ouabain were not involved in activation of protein secretion, while dopamine-induced saliva contained constitutively basal level of protein. We hypothesize that the dopamine-dependent primary saliva formation, mediated by Na/K-ATPase in type III and type II acini, is followed by a dopamine-independent resorptive function of Na/K-ATPase in type I acini located in the proximal end of the salivary duct. PMID:26861075

  16. Multiple functions of Na/K-ATPase in dopamine-induced salivation of the Blacklegged tick, Ixodes scapularis.

    PubMed

    Kim, Donghun; Urban, Joshua; Boyle, Daniel L; Park, Yoonseong

    2016-02-10

    Control of salivary secretion in ticks involves autocrine dopamine activating two dopamine receptors: D1 and Invertebrate-specific D1-like dopamine receptors. In this study, we investigated Na/K-ATPase as an important component of the secretory process. Immunoreactivity for Na/K-ATPase revealed basal infolding of lamellate cells in type-I, abluminal interstitial (epithelial) cells in type-II, and labyrinth-like infolding structures opening towards the lumen in type-III acini. Ouabain (10 μmol l(-1)), a specific inhibitor of Na/K-ATPase, abolished dopamine-induced salivary secretion by suppressing fluid transport in type III acini. At 1 μmol l(-1), ouabain, the secreted saliva was hyperosmotic. This suggests that ouabain also inhibits an ion resorptive function of Na/K-ATPase in the type I acini. Dopamine/ouabain were not involved in activation of protein secretion, while dopamine-induced saliva contained constitutively basal level of protein. We hypothesize that the dopamine-dependent primary saliva formation, mediated by Na/K-ATPase in type III and type II acini, is followed by a dopamine-independent resorptive function of Na/K-ATPase in type I acini located in the proximal end of the salivary duct.

  17. The protective effect of dopamine on ventilator-induced lung injury via the inhibition of NLRP3 inflammasome.

    PubMed

    Yang, Xiaomei; Sun, Xiaotong; Chen, Hongli; Xi, Guangmin; Hou, Yonghao; Wu, Jianbo; Liu, Dejie; Wang, Huanliang; Hou, Yuedong; Yu, Jingui

    2017-04-01

    Dopamine (DA), a neurotransmitter, was previously shown to have anti-inflammatory effects. However, its role in ventilator-induced lung injury (VILI) has not been explicitly demonstrated. This study aimed to investigate the therapeutic efficacy and molecular mechanisms of dopamine in VILI. Rats were treated with dopamine during mechanical ventilation. Afterwards, the influence of dopamine on histological changes, pulmonary edema, the lung wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, polymorphonuclear(PMN)counts, inflammatory cytokine levels, and NLRP3 inflammasome protein expression were examined. Our results showed that dopamine significantly attenuated lung tissue injury, the lung W/D ratio, MPO activity and neutrophil infiltration. Moreover, it inhibited inflammatory cytokine levels in the Bronchoalveolar lavage fluid (BAL). In addition, dopamine significantly inhibited ventilation-induced NLRP3 activation. Our experimental findings demonstrate that dopamine exerted protective effects in VILI by alleviating the inflammatory response through inhibition of NLRP3 signaling pathways. The present study indicated that dopamine could be a potential effective therapeutic strategy for the treatment of VILI. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Central dopamine modulates anapyrexia but not hyperventilation induced by hypoxia.

    PubMed

    Barros, Renata C H; Branco, Luiz G S

    2002-03-01

    Hypoxia causes hyperventilation and decreases body temperature (T(b)) and metabolism [O(2) consumption (VO(2))]. Because dopamine (DA) is released centrally in response to peripheral chemoreceptor stimulation, we tested the hypothesis that central DA mediates the ventilatory, thermal, and metabolic responses to hypoxia. Thus we predicted that injection of haloperidol (a DA D(2)-receptor antagonist) into the third ventricle would augment hyperventilation and attenuate the drop in T(b) and VO(2) in conscious rats. We measured ventilation, T(b), and VO(2) before and after intracerebroventricular injection of haloperidol or vehicle (5% DMSO in saline), followed by a 30-min period of hypoxia exposure. Haloperidol did not change T(b) or VO(2) during normoxia; however, breathing frequency was decreased. During hypoxia, haloperidol significantly attenuated the falls in T(b) and VO(2), although hyperventilation persisted. The present study shows that central DA participates in the thermal and metabolic responses to hypoxia without affecting hyperventilation, showing that DA is not a common mediator of this interaction.

  19. A role for D1 dopamine receptors in striatal methamphetamine-induced neurotoxicity.

    PubMed

    Friend, Danielle M; Keefe, Kristen A

    2013-10-25

    Methamphetamine (METH) exposure results in long-term damage to the dopamine system in both human METH abusers and animal models. One factor that has been heavily implicated in this METH-induced damage to the dopaminergic system is the activation of D1 dopamine (DA) receptors. However, a significant caveat to the studies investigating the role of the receptor in such toxicity is that genetic and pharmacological manipulations of the D1 DA receptor also mitigate METH-induced hyperthermia. Importantly, METH-induced hyperthermia is tightly associated with the neurotoxicity, such that simply cooling animals during METH exposure protects against the neurotoxicity. Therefore, it is difficult to determine whether D1 DA receptors per se play an important role in METH-induced neurotoxicity or whether the protection observed simply resulted from a mitigation of METH-induced hyperthermia. To answer this important question, the current study infused a D1 DA receptor antagonist into striatum during METH exposure while controlling for METH-induced hyperthermia. Here we found that even when METH-induced hyperthermia is maintained, the coadministration of a D1 DA receptor antagonist protects against METH-induced neurotoxicity, strongly suggesting that D1 DA receptors play an important role in METH-induced neurotoxicity apart from the mitigation of METH-induced hyperthermia. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  20. A Role for D1 Dopamine Receptors in Striatal Methamphetamine-Induced Neurotoxicity

    PubMed Central

    Friend, Danielle M.; Keefe, Kristen A.

    2015-01-01

    Methamphetamine (METH) exposure results in long-term damage to the dopamine system in both human METH abusers and animal models. One factor that has been heavily implicated in this METH-induced damage to the dopaminergic system is the activation of D1 Dopamine (DA) receptors. However, a significant caveat to the studies investigating the role of the receptor in such toxicity is that genetic and pharmacological manipulations of the D1 DA receptor also mitigate METH-induced hyperthermia. Importantly, METH-induced hyperthermia is tightly associated with the neurotoxicity, such that simply cooling animals during METH exposure protects against the neurotoxicity. Therefore, it is difficult to determine whether D1 DA receptors per se play an important role in METH-induced neurotoxicity or whether the protection observed simply resulted from a mitigation of METH-induced hyperthermia. To answer this important question, the current study infused a D1 DA receptor antagonist into striatum during METH exposure while controlling for METH-induced hyperthermia. Here we found that even when METH-induced hyperthermia is maintained, the coadministration of a D1 DA receptor antagonist protects against METH-induced neurotoxicity, strongly suggesting that D1 DA receptors play an important role in METH-induced neurotoxicity apart from the mitigation of METH-induced hyperthermia. PMID:23994061

  1. PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity

    PubMed Central

    Madeo, G.; Schirinzi, T.; Martella, G.; Latagliata, E.C.; Puglisi, F.; Shen, J.; Valente, E.M.; Federici, M.; Mercuri, N.B.; Puglisi-Allegra, S.; Bonsi, P.; Pisani, A.

    2014-01-01

    Background Homozygous or compound heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene are causative of autosomal recessive, early onset PD. Single heterozygous mutations have been repeatedly detected in a subset of patients as well as in non-affected subjects, and their significance has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have shown the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. Methods In the present study, we performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knock-out (PINK1+/−) mice by a multidisciplinary approach. Results We found that, despite a normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression (LTD) was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, we measured a significantly lower dopamine release in the striatum of PINK1+/−, compared to control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored a normal LTP in heterozygous mice. Moreover, MAO-B inhibitors rescued a physiological LTP and a normal dopamine release. Conclusions Our results provide novel evidence for striatal plasticity abnormalities even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of PD, and a valid tool to characterize early disease stage and design possible disease-modifying therapies. PMID:24167038

  2. Vitamin D3: A Role in Dopamine Circuit Regulation, Diet-Induced Obesity, and Drug Consumption.

    PubMed

    Trinko, Joseph R; Land, Benjamin B; Solecki, Wojciech B; Wickham, Robert J; Tellez, Luis A; Maldonado-Aviles, Jaime; de Araujo, Ivan E; Addy, Nii A; DiLeone, Ralph J

    2016-01-01

    The influence of micronutrients on dopamine systems is not well defined. Using mice, we show a potential role for reduced dietary vitamin D3 (cholecalciferol) in promoting diet-induced obesity (DIO), food intake, and drug consumption while on a high fat diet. To complement these deficiency studies, treatments with exogenous fully active vitamin D3 (calcitriol, 10 µg/kg, i.p.) were performed. Nondeficient mice that were made leptin resistant with a high fat diet displayed reduced food intake and body weight after an acute treatment with exogenous calcitriol. Dopamine neurons in the midbrain and their target neurons in the striatum were found to express vitamin D3 receptor protein. Acute calcitriol treatment led to transcriptional changes of dopamine-related genes in these regions in naive mice, enhanced amphetamine-induced dopamine release in both naive mice and rats, and increased locomotor activity after acute amphetamine treatment (2.5 mg/kg, i.p.). Alternatively, mice that were chronically fed either the reduced D3 high fat or chow diets displayed less activity after acute amphetamine treatment compared with their respective controls. Finally, high fat deficient mice that were trained to orally consume liquid amphetamine (90 mg/L) displayed increased consumption, while nondeficient mice treated with calcitriol showed reduced consumption. Our findings suggest that reduced dietary D3 may be a contributing environmental factor enhancing DIO as well as drug intake while eating a high fat diet. Moreover, these data demonstrate that dopamine circuits are modulated by D3 signaling, and may serve as direct or indirect targets for exogenous calcitriol.

  3. Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD.

    PubMed

    Cherkasova, Mariya V; Faridi, Nazlie; Casey, Kevin F; O'Driscoll, Gillian A; Hechtman, Lily; Joober, Ridha; Baker, Glen B; Palmer, Jennifer; Dagher, Alain; Leyton, Marco; Benkelfat, Chawki

    2014-05-01

    Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [(11)C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87 ± 8.65) and 18 healthy male controls (age: 25.44 ± 6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [(11)C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [(11)C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.

  4. Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement.

    PubMed

    Huang, Mei; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Miyauchi, Masanori; Meltzer, Herbert Y

    2015-11-01

    Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Coincident postsynaptic activity gates presynaptic dopamine release to induce plasticity in Drosophila mushroom bodies

    PubMed Central

    Ueno, Kohei; Suzuki, Ema; Naganos, Shintaro; Ofusa, Kyoko; Horiuchi, Junjiro; Saitoe, Minoru

    2017-01-01

    Simultaneous stimulation of the antennal lobes (ALs) and the ascending fibers of the ventral nerve cord (AFV), two sensory inputs to the mushroom bodies (MBs), induces long-term enhancement (LTE) of subsequent AL-evoked MB responses. LTE induction requires activation of at least three signaling pathways to the MBs, mediated by nicotinic acetylcholine receptors (nAChRs), NMDA receptors (NRs), and D1 dopamine receptors (D1Rs). Here, we demonstrate that inputs from the AL are transmitted to the MBs through nAChRs, and inputs from the AFV are transmitted by NRs. Dopamine signaling occurs downstream of both nAChR and NR activation, and requires simultaneous stimulation of both pathways. Dopamine release requires the activity of the rutabaga adenylyl cyclase in postsynaptic MB neurons, and release is restricted to MB neurons that receive coincident stimulation. Our results indicate that postsynaptic activity can gate presynaptic dopamine release to regulate plasticity. DOI: http://dx.doi.org/10.7554/eLife.21076.001 PMID:28117664

  6. Modulation of PC12 cell viability by forskolin-induced cyclic AMP levels through ERK and JNK pathways: an implication for L-DOPA-induced cytotoxicity in nigrostriatal dopamine neurons.

    PubMed

    Park, Keun Hong; Park, Hyun Jin; Shin, Keon Sung; Choi, Hyun Sook; Kai, Masaaki; Lee, Myung Koo

    2012-07-01

    The intracellular levels of cyclic AMP (cAMP) increase in response to cytotoxic concentrations of L-DOPA in PC12 cells, and forskolin that induces intracellular cAMP levels either protects PC12 cells from L-DOPA-induced cytotoxicity or enhances cytotoxicity in a concentration-dependent manner. This study investigated the effects of cAMP induced by forskolin on cell viability of PC12 cells, relevant to L-DOPA-induced cytotoxicity in Parkinson's disease therapy. The low levels of forskolin (0.01 and 0.1 μM)-induced cAMP increased dopamine biosynthesis and tyrosine hydroxylase (TH) phosphorylation, and induced transient phosphorylation of ERK1/2 within 1 h. However, at the high levels of forskolin (1.0 and 10 μM)-induced cAMP, dopamine biosynthesis and TH phosphorylation did not increase, but rapid differentiation in neurite-like formation was observed with a steady state. The high levels of forskolin-induced cAMP also induced sustained increase in ERK1/2 phosphorylation within 0.25-6 h and then led to apoptosis, which was apparently mediated by JNK1/2 and caspase-3 activation. Multiple treatment of PC12 cells with nontoxic L-DOPA (20 μM) for 4-6 days induced neurite-like formation and decreased intracellular dopamine levels by reducing TH phosphorylation. These results suggest that the low levels of forskolin-induced cAMP increased dopamine biosynthesis in cell survival via transient ERK1/2 phosphorylation. In contrast, the high levels of forskolin-induced cAMP induced differentiation via sustained ERK1/2 phosphorylation and then led to apoptosis. Taken together, the intracellular levels of cAMP play a dual role in cell survival and death through the ERK1/2 and JNK1/2 pathways in PC12 cells.

  7. Running Reduces Uncontrollable Stress-Evoked Serotonin and Potentiates Stress-Evoked Dopamine Concentrations in the Rat Dorsal Striatum

    PubMed Central

    Clark, Peter J.; Amat, Jose; McConnell, Sara O.; Ghasem, Parsa R.; Greenwood, Benjamin N.; Maier, Steven F.; Fleshner, Monika

    2015-01-01

    Accumulating evidence from both the human and animal literature indicates that exercise reduces the negative consequences of stress. The neurobiological etiology for this stress protection, however, is not completely understood. Our lab reported that voluntary wheel running protects rats from expressing depression-like instrumental learning deficits on the shuttle box escape task after exposure to unpredictable and inescapable tail shocks (uncontrollable stress). Impaired escape behavior is a result of stress-sensitized serotonin (5-HT) neuron activity in the dorsal raphe (DRN) and subsequent excessive release of 5-HT into the dorsal striatum following exposure to a comparatively mild stressor. However, the possible mechanisms by which exercise prevents stress-induced escape deficits are not well characterized. The purpose of this experiment was to test the hypothesis that exercise blunts the stress-evoked release of 5-HT in the dorsal striatum. Changes to dopamine (DA) levels were also examined, since striatal DA signaling is critical for instrumental learning and can be influenced by changes to 5-HT activity. Adult male F344 rats, housed with or without running wheels for 6 weeks, were either exposed to tail shock or remained undisturbed in laboratory cages. Twenty-four hours later, microdialysis was performed in the medial (DMS) and lateral (DLS) dorsal striatum to collect extracellular 5-HT and DA before, during, and following 2 mild foot shocks. We report wheel running prevents foot shock-induced elevation of extracellular 5-HT and potentiates DA concentrations in both the DMS and DLS approximately 24 h following exposure to uncontrollable stress. These data may provide a possible mechanism by which exercise prevents depression-like instrumental learning deficits following exposure to acute stress. PMID:26555633

  8. Wireless Instantaneous Neurotransmitter Concentration System–based amperometric detection of dopamine, adenosine, and glutamate for intraoperative neurochemical monitoring

    PubMed Central

    Agnesi, Filippo; Tye, Susannah J.; Bledsoe, Jonathan M.; Griessenauer, Christoph J.; Kimble, Christopher J.; Sieck, Gary C.; Bennet, Kevin E.; Garris, Paul A.; Blaha, Charles D.; Lee, Kendall H.

    2009-01-01

    Object In a companion study, the authors describe the development of a new instrument named the Wireless Instantaneous Neurotransmitter Concentration System (WINCS), which couples digital telemetry with fast-scan cyclic voltammetry (FSCV) to measure extracellular concentrations of dopamine. In the present study, the authors describe the extended capability of the WINCS to use fixed potential amperometry (FPA) to measure extracellular concentrations of dopamine, as well as glutamate and adenosine. Compared with other electrochemical techniques such as FSCV or high-speed chronoamperometry, FPA offers superior temporal resolution and, in combination with enzyme-linked biosensors, the potential to monitor nonelectroactive analytes in real time. Methods The WINCS design incorporated a transimpedance amplifier with associated analog circuitry for FPA; a microprocessor; a Bluetooth transceiver; and a single, battery-powered, multilayer, printed circuit board. The WINCS was tested with 3 distinct recording electrodes: 1) a carbon-fiber microelectrode (CFM) to measure dopamine; 2) a glutamate oxidase enzyme-linked electrode to measure glutamate; and 3) a multiple enzyme-linked electrode (adenosine deaminase, nucleoside phosphorylase, and xanthine oxidase) to measure adenosine. Proof-of-principle analyses included noise assessments and in vitro and in vivo measurements that were compared with similar analyses by using a commercial hardwired electrochemical system (EA161 Picostat, eDAQ; Pty Ltd). In urethane-anesthetized rats, dopamine release was monitored in the striatum following deep brain stimulation (DBS) of ascending dopaminergic fibers in the medial forebrain bundle (MFB). In separate rat experiments, DBS-evoked adenosine release was monitored in the ventrolateral thalamus. To test the WINCS in an operating room setting resembling human neurosurgery, cortical glutamate release in response to motor cortex stimulation (MCS) was monitored using a large-mammal animal

  9. Changes in stress-stimulated allopregnanolone levels induced by neonatal estradiol treatment are associated with enhanced dopamine release in adult female rats: reversal by progesterone administration.

    PubMed

    Porcu, Patrizia; Lallai, Valeria; Locci, Andrea; Catzeddu, Sandro; Serra, Valeria; Pisu, Maria Giuseppina; Serra, Mariangela; Dazzi, Laura; Concas, Alessandra

    2017-03-01

    Allopregnanolone plays a role in the stress response and homeostasis. Alterations in the estrogen milieu during the perinatal period influence brain development in a manner that persists into adulthood. Accordingly, we showed that a single administration of estradiol benzoate (EB) on the day of birth decreases brain allopregnanolone concentrations in adult female rats. We examined whether the persistent decrease in allopregnanolone concentrations, induced by neonatal EB treatment, might affect sensitivity to stress during adulthood. Female rats were treated with 10 μg of EB or vehicle on the day of birth. During adulthood, the response to acute foot shock stress was assessed by measuring changes in brain allopregnanolone and corticosterone levels, as well as extracellular dopamine output in the medial prefrontal cortex (mPFC). Neonatal EB treatment enhanced stress-stimulated allopregnanolone levels in the hypothalamus, as well as extracellular dopamine output in the mPFC; this latest effect is reverted by subchronic progesterone treatment. By contrast, neonatal EB treatment did not alter stress-induced corticosterone levels, sensitivity to hypothalamic-pituitary-adrenal (HPA) axis negative feedback, or abundance of glucocorticoid and mineralocorticoid receptors. The persistent decrease in brain allopregnanolone concentrations, induced by neonatal EB treatment, enhances stress-stimulated allopregnanolone levels and extracellular dopamine output during adulthood. These effects are not associated to an impairment in HPA axis activity. Heightened sensitivity to stress is a risk factor for several neuropsychiatric disorders; these results suggest that exposure to estrogen during development may predispose individuals to such disorders.

  10. Beta-endorphin-induced increases in plasma epinephrine, norepinephrine and dopamine in rats: inhibition of adrenomedullary response by intracerebral somatostatin.

    PubMed

    Van Loon, G R; Appel, N M; Ho, D

    1981-05-11

    Synthetic human beta-endorphin, 7.25 nmol intracisternally, in unanesthetized, freely moving, chronically cannulated, adult male rats increased plasma concentrations of all 3 catecholamines: epinephrine, norepinephrine and dopamine, for the 2 h period studied. Blockade of these endorphin effects by the prior systemic administration of naloxone supports mediation of the effects at opioid receptors. Acute systemic administration of guanethidine, which decreases norepinephrine release induced by sympathetic nerve stimulation, blunted the plasma norepinephrine response to intracerebral beta-endorphin. Thus, it seems likely that in addition to secretion by adrenal medulla a considerable portion of the beta-endorphin-induced increase in norepinephrine is derived from sympathetic nerve endings. Simultaneous intracisternal administration of another neuropeptide, somatostatin, together with beta-endorphin markedly inhibited the plasma epinephrine response to beta-endorphin, while decreasing the dopamine and norepinephrine responses to a much lesser degree. The dats suggest that beta-endorphin stimulates central sympathetic outflow to both adrenal medulla and sympathetic nerve endings, and further that somatostatin inhibits the effect of endorphin to stimulate outflow to adrenal medulla but does not affect outflow to sympathetic nerve endings.

  11. Amantadine preserves dopamine level and attenuates depression-like behavior induced by traumatic brain injury in rats.

    PubMed

    Tan, Liang; Ge, Hongfei; Tang, Jun; Fu, Chuhua; Duanmu, Wangsheng; Chen, Yujie; Hu, Rong; Sui, Jianfeng; Liu, Xin; Feng, Hua

    2015-02-15

    Traumatic brain injury (TBI) often results in multiple neuropsychiatric sequelae, including cognitive, emotional, and behavioral problems. Among them, depression is a common psychiatric symptom, and links to poorer recovery. Amantadine, as an antiparkinsonian, increases dopamine release, and blocks dopamine reuptake, but has recently received attention for its effectiveness as an antidepressant. In the present study, we first induced a post-TBI depression rat model to probe the efficacy of amantadine therapy in reducing post-TBI depression. The DA concentration in the striatum of the injured rats, as well as the degeneration and apoptosis of dopaminergic neurons in the substantia nigra (SN), were checked along with the depression-like behavior. The results showed that amantadine therapy could significantly ameliorate the depression-like behavior, improving the DA level in the striatum and decreasing the degeneration and apoptosis of dopaminergic neurons in the SN. The results indicated that the anti-depression effect may result from the increase of extracellular DA concentration in the striatum and/or the indirect neuroprotection on the dopaminergic neurons in the SN. We conclude that DA plays a critical role in post-TBI depression, and that amantadine shows its potential value in anti-depression treatment for TBI.

  12. Effect of dopamine and serotonin receptor antagonists on fencamfamine-induced abolition of latent inhibition.

    PubMed

    de Aguiar, Cilene Rejane Ramos Alves; de Aguiar, Marlison José Lima; DeLucia, Roberto; Silva, Maria Teresa Araujo

    2013-01-05

    The purpose of this investigation was to verify the role of dopamine and serotonin receptors in the effect of fencamfamine (FCF) on latent inhibition. FCF is a psychomotor stimulant with an indirect dopaminergic action. Latent inhibition is a model of attention. Latent inhibition is blocked by dopaminergic agents and facilitated by dopamine receptor agonists. FCF has been shown to abolish latent inhibition. The serotonergic system may also participate in the neurochemical mediation of latent inhibition. The selective dopamine D(1) receptor antagonist SCH 23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), D(2) receptor antagonists pimozide (PIM) and methoclopramide (METH), and serotonin 5-HT(2A/C) receptor antagonist ritanserin (RIT) were used in the present study. Latent inhibition was evaluated using a conditioned emotional response procedure. Male Wistar rats that were water-restricted were subjected to a three-phase procedure: preexposure to a tone, tone-shock conditioning, and a test of the effect of the tone on licking frequency. All of the drugs were administered before the preexposure and conditioning phases. The results showed that FCF abolished latent inhibition, and this effect was clearly antagonized by PIM and METH and moderately attenuated by SCH 23390. At the doses used in the present study, RIT pretreatment did not affect latent inhibition and did not eliminate the effect of FCF, suggesting that the FCF-induced abolition of latent inhibition is not mediated by serotonin 5-HT(2A/C) receptors. These results suggest that the effect of FCF on latent inhibition is predominantly related to dopamine D(2) receptors and that dopamine D(2) receptors participate in attention processes.

  13. Baclofen antagonizes nicotine-, cocaine-, and morphine-induced dopamine release in the nucleus accumbens of rat.

    PubMed

    Fadda, Paola; Scherma, Maria; Fresu, Alessandra; Collu, Maria; Fratta, Walter

    2003-10-01

    Evidence recently provided has suggested a specific involvement of the GABAergic system in modulating positive reinforcing properties of several drugs of abuse through an action on mesolimbic dopaminergic neurons. The GABA(B) receptor agonist baclofen has been proposed as a potential therapeutic agent for the clinical treatment of several forms of drug addiction. In the present study, using the in vivo microdialysis technique, we investigated the effect of baclofen on nicotine, cocaine, and morphine-induced increase in extracellular dopamine (DA) levels in the shell of the nucleus accumbens, a brain area supposedly involved in the modulation of the central effects of several drugs of abuse, of freely moving rats. As expected, nicotine (0.6 mg/kg s.c.), morphine (5 mg/kg s.c.), and cocaine (7.5 mg/kg i.p.) administration in rats induced a marked increase in extracellular DA concentrations in the nucleus accumbens, reaching a maximum value of +205 +/- 8.4%, +300 +/- 22.2%, and +370 +/- 30.7%, respectively. Pretreatment with baclofen (1.25 and 2.5 mg/kg i.p.) dose-dependently reduced the nicotine-, morphine-, and cocaine-evoked DA release in the shell of the nucleus accumbens. Furthermore, baclofen alone did not elicit changes in basal DA extracellular levels up to 180 min. Taken together, our data are in line with previous reports demonstrating the ability of baclofen to modulate the mesolimbic DAergic transmission and indicate baclofen as a putative candidate in the pharmacotherapy of polydrug abuse.

  14. Comparison of the MK-801-induced increase in non-rewarded appetitive responding with dopamine agonists and locomotor activity in rats.

    PubMed

    Davis-MacNevin, Parnell L; Dekraker, Jordan; LaDouceur, Liane; Holahan, Matthew R

    2013-09-01

    Systemic administration of the noncompetitive N-methyl-D-aspartate (NMDA)- receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. Evidence has shown that MK-801 increases the probability of operant responding during extinction, possibly modeling perseveration, as would be seen in patients with schizophrenia. This MK-801-induced behavioral perseveration is reversed by dopamine receptor antagonism. To further explore the role of dopamine in this behavioral change, the current study sought to determine if the MK-801-induced increase in non-rewarded operant responding could be mimicked by dopamine agonism and determine how it was related to locomotor activity. Male Long Evans rats were treated systemically with MK-801, cocaine, GBR12909 or apomorphine (APO) and given a single trial operant extinction session, followed by a separate assessment of locomotor activity. Both MK-801 (0.05 mg/kg) and cocaine (10 mg/kg) significantly increased responding during the extinction session and both increased horizontal locomotor activity. No dose of GBR-12909 (5, 10 or 20 mg/kg) was found to effect non-rewarded operant responding or locomotor activity. APO (0.05, 0.5, 2 or 5 mg/kg) treatment produced a dose-dependent decrease in both operant responding and locomotor activity. These results suggest the possibility that, rather than a primary influence of increased dopamine concentration on elevating bar-pressing responses during extinction, other neurotransmitter systems may be involved.

  15. Effects of indomethacin on plasma homovanillic acid concentration in normal subjects: a study of prostaglandin-dopamine interactions.

    PubMed

    Kahn, R S; Davidson, M; Kanof, P; McQueeney, R T; Singh, R R; Davis, K L

    1991-01-01

    In laboratory animals, prostaglandins have been shown to act as endogenous neuromodulators of central dopamine (DA) activity. To examine the interaction between prostaglandins and DA in man, the effect of a prostaglandin synthesis inhibitor, indomethacin, was studied on plasma concentrations of the DA metabolite, homovanillic acid (pHVA). Indomethacin (150 mg PO) as compared to placebo significantly elevated mean pHVA concentrations in eight normal subjects. Results of this study support the hypothesis that, as in animals, inhibition of prostaglandin synthesis increases central DA turnover in man.

  16. Mode of action of dopamine in inducing hyperglycemia in the fresh water edible crab, Oziothelphusa senex senex.

    PubMed

    Swetha, Ch; Sainath, S B; Reddy, P Sreenivasula

    2014-11-01

    The objective of this study was to investigate the mode of action of dopamine in regulating hemolymph sugar level in the fresh water edible crab, Oziothelphusa senex senex. Injection of dopamine produced hyperglycemia in a dose-dependent manner in intact crabs but not in eyestalkless crabs. Administration of dopamine resulted in a significant decrease in total carbohydrates and glycogen levels with a significant increase in glycogen phosphorylase activity levels in hepatopancreas and muscle of intact crabs, indicating dopamine-induced glycogenolysis resulting in hyperglycemia. Bilateral eyestalk ablation resulted in significant increase in the total carbohydrates and glycogen levels with a significant decrease in the activity levels of phosphorylase in the hepatopancreas and muscle of the crabs. Eyestalk ablation resulted in significant decrease in hemolymph hyperglycemic hormone levels. The levels of hyperglycemic hormone in the hemolymph of dopamine injected crabs were significantly higher than in control crabs. However, no significant changes in the levels of hemolymph hyperglycemic hormone and sugar and tissue carbohydrate and phosphorylase activity were observed in dopamine injected eyestalk ablated crabs when compared with eyestalk ablated crabs. These results support an earlier hypothesis in crustaceans that dopamine acts as a neurotransmitter and induces hyperglycemia by triggering the release of hyperglycemic hormone in the crab, O. senex senex. © 2014 Wiley Periodicals, Inc.

  17. Expression and Activity of Nitric Oxide Synthase Isoforms in Methamphetamine-Induced Striatal Dopamine Toxicity

    PubMed Central

    Friend, Danielle M.; Son, Jong H.; Keefe, Kristen A.

    2013-01-01

    Nitric oxide is implicated in methamphetamine (METH)-induced neurotoxicity; however, the source of the nitric oxide has not been identified. Previous work has also revealed that animals with partial dopamine loss induced by a neurotoxic regimen of methamphetamine fail to exhibit further decreases in striatal dopamine when re-exposed to methamphetamine 7–30 days later. The current study examined nitric oxide synthase expression and activity and protein nitration in striata of animals administered saline or neurotoxic regimens of methamphetamine at postnatal days 60 and/or 90, resulting in four treatment groups: Saline:Saline, METH:Saline, Saline:METH, and METH:METH. Acute administration of methamphetamine on postnatal day 90 (Saline:METH and METH:METH) increased nitric oxide production, as evidenced by increased protein nitration. Methamphetamine did not, however, change the expression of endothelial or inducible isoforms of nitric oxide synthase, nor did it change the number of cells positive for neuronal nitric oxide synthase mRNA expression or the amount of neuronal nitric oxide synthase mRNA per cell. However, nitric oxide synthase activity in striatal interneurons was increased in the Saline:METH and METH:METH animals. These data suggest that increased nitric oxide production after a neurotoxic regimen of methamphetamine results from increased nitric oxide synthase activity, rather than an induction of mRNA, and that constitutively expressed neuronal nitric oxide synthase is the most likely source of nitric oxide after methamphetamine administration. Of interest, animals rendered resistant to further methamphetamine-induced dopamine depletions still show equivalent degrees of methamphetamine-induced nitric oxide production, suggesting that nitric oxide production alone in response to methamphetamine is not sufficient to induce acute neurotoxic injury. PMID:23230214

  18. Dopamine antagonists and brief vision distinguish lens-induced- and form-deprivation-induced myopia.

    PubMed

    Nickla, Debora L; Totonelly, Kristen

    2011-11-01

    In eyes wearing negative lenses, the D2 dopamine antagonist spiperone was only partly effective in preventing the ameliorative effects of brief periods of vision (Nickla et al., 2010), in contrast to reports from studies using form-deprivation. The present study was done to directly compare the effects of spiperone, and the D1 antagonist SCH-23390, on the two different myopiagenic paradigms. 12-day old chickens wore monocular diffusers (form-deprivation) or -10 D lenses attached to the feathers with matching rings of Velcro. Each day for 4 days, 10 μl intravitreal injections of the dopamine D2/D4 antagonist spiperone (5 nmoles) or the D1 antagonist SCH-23390, were given under isoflurane anesthesia, and the diffusers (n = 16; n = 5, respectively) or lenses (n = 20; n = 6) were removed for 2 h immediately after. Saline injections prior to vision were done as controls (form-deprivation: n = 11; lenses: n = 10). Two other saline-injected groups wore the lenses (n = 12) or diffusers (n = 4) continuously. Axial dimensions were measured by high frequency A-scan ultrasonography at the start, and on the last day immediately prior to, and 3 h after the injection. Refractive errors were measured at the end of the experiment using a Hartinger's refractometer. In form-deprived eyes, spiperone, but not SCH-23390, prevented the ocular growth inhibition normally effected by the brief periods of vision (change in vitreous chamber depth, spiperone vs saline: 322 vs 211 μm; p = 0.01). By contrast, neither had any effect on negative lens-wearing eyes given similar unrestricted vision (210 and 234 μm respectively, vs 264 μm). The increased elongation in the spiperone-injected form-deprived eyes did not, however, result in a myopic shift, probably due to the inhibitory effect of the drug on anterior chamber growth (drug vs saline: 96 vs 160 μm; p < 0.01). Finally, spiperone inhibited the vision-induced transient choroidal thickening in form-deprived eyes, while SCH-23390 did not

  19. Differential subcellular distribution of rat brain dopamine receptors and subtype-specific redistribution induced by cocaine

    PubMed Central

    Voulalas, Pamela J.; Schetz, John; Undieh, Ashiwel S.

    2011-01-01

    We investigated the subcellular distribution of dopamine D1, D2 and D5 receptor subtypes in rat frontal cortex, and examined whether psychostimulant-induced elevation of synaptic dopamine could alter the receptor distribution. Differential detergent solubilization and density gradient centrifugation were used to separate various subcellular fractions, followed by semi-quantitative determination of the relative abundance of specific receptor proteins in each fraction. D1 receptors were predominantly localized to detergent-resistant membranes, and a portion of these receptors also floated on sucrose gradients. These properties are characteristic of proteins found in lipid rafts and caveolae. D2 receptors exhibited variable distribution between cytoplasmic, detergent-soluble and detergent-resistant membrane fractions, yet were not present in buoyant membranes. Most D5 receptor immunoreactivity was distributed into the cytoplasmic fraction, failing to sediment at forces up to 300,000g, while the remainder was localized to detergent-soluble membranes in cortex. D5 receptors were undetectable in detergent-resistant fractions or raft-like subdomains. Following daily cocaine administration for seven days, a significant portion of D1 receptors translocated from detergent-resistant membranes to detergent-soluble membranes and the cytoplasmic fraction. The distributions of D5 and D2 receptor subtypes were not significantly altered by cocaine treatment. These data imply that D5 receptors are predominantly cytoplasmic, D2 receptors are diffusely distributed within the cell, whereas D1 receptors are mostly localized to lipid rafts within the rat frontal cortex. Dopamine receptor subtype localization is susceptible to modulation by pharmacological manipulations that elevate synaptic dopamine, however the functional implications of such drug-induced receptor warrant further investigation. PMID:21236347

  20. Sertraline induced parkinsonism. A case report and an in-vivo study of the effect of sertraline on dopamine metabolism.

    PubMed

    Di Rocco, A; Brannan, T; Prikhojan, A; Yahr, M D

    1998-01-01

    We report a patient with a parkinsonian syndrome induced by sertraline (Zoloft), an SSRI antidepressant, whose symptoms resolved after the drug was discontinued. This case prompted us to investigate the effect of sertraline on dopamine metabolism in animals. Sertraline (30 mg/kg, i.p.) or placebo (vehicle) was administered to two groups of six normal, anesthetized rats and using cerebral microdyalisis extracellular striatal levels of dopamine, the dopamine metabolites (HVA and DOPAC), as well as the serotonin metabolite 5-HIIA were monitored. In animals pre-treated with sertraline, DOPAC, HVA, and 5-HIAA levels were significantly decreased compared to control animals (p < 0.01). These data indicate that sertraline has an effect on dopamine metabolism, which may alter function in the striatum and induce a parkinsonian syndrome.

  1. Antagonism of bromocriptine-induced cage climbing behaviour in mice by the selective D-2 dopamine receptor antagonists, metoclopramide and molindone.

    PubMed

    Balsara, J J; Nandal, N V; Gada, V P; Bapat, T R; Chandorkar, A G

    1986-01-01

    Bromocriptine (5-30 mg/kg, ip), 2 hr after administration, induced cage climbing behaviour in mice. Pretreatment with haloperidol, an antagonist of both D-1 and D-2 dopamine receptors, metoclopramide and molindone, the selective D-2 dopamine receptor antagonists, effectively antagonised bromocriptine-induced climbing behaviour. The results indicate that bromocriptine most probably induces climbing behaviour in mice by stimulating the postsynaptic striatal D-2 dopamine receptors.

  2. BDNF interacts with endocannabinoids to regulate cocaine-induced synaptic plasticity in mouse midbrain dopamine neurons.

    PubMed

    Zhong, Peng; Liu, Yong; Hu, Ying; Wang, Tong; Zhao, Yong-ping; Liu, Qing-song

    2015-03-11

    Brain-derived neurotrophic factor (BDNF) and endocannabinoids (eCBs) have been individually implicated in behavioral effects of cocaine. The present study examined how BDNF-eCB interaction regulates cocaine-induced synaptic plasticity in the ventral tegmental area and behavioral effects. We report that BDNF and selective tyrosine kinase receptor B (TrkB) agonist 7,8-dihydroxyflavone (DHF) activated the TrkB receptor to facilitate two forms of eCB-mediated synaptic depression, depolarization-induced suppression of inhibition (DSI), and long-term depression (I-LTD) of IPSCs in ventral tegmental area dopamine neurons in mouse midbrain slices. The facilitation appears to be mediated by an increase in eCB production via phospholipase Cγ pathway, but not by an increase in CB1 receptor responsiveness or a decrease in eCB hydrolysis. Using Cre-loxP technology to specifically delete BDNF in dopamine neurons, we showed that eCB-mediated I-LTD, cocaine-induced reduction of GABAergic inhibition, and potentiation of glutamatergic excitation remained intact in wild-type control mice, but were impaired in BDNF conditional knock-out mice. We also showed that cocaine-induced conditioned place preference was attenuated in BDNF conditional knock-out mice, in vivo pretreatments with DHF before place conditioning restored cocaine conditioned place preference in these mice, and the behavioral effect of DHF was blocked by a CB₁ receptor antagonist. Together, these results suggest that BDNF in dopamine neurons regulates eCB responses, cocaine-induced synaptic plasticity, and associative learning. Copyright © 2015 the authors 0270-6474/15/354469-13$15.00/0.

  3. BDNF Interacts with Endocannabinoids to Regulate Cocaine-Induced Synaptic Plasticity in Mouse Midbrain Dopamine Neurons

    PubMed Central

    Zhong, Peng; Liu, Yong; Hu, Ying; Wang, Tong; Zhao, Yong-ping

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) and endocannabinoids (eCBs) have been individually implicated in behavioral effects of cocaine. The present study examined how BDNF-eCB interaction regulates cocaine-induced synaptic plasticity in the ventral tegmental area and behavioral effects. We report that BDNF and selective tyrosine kinase receptor B (TrkB) agonist 7,8-dihydroxyflavone (DHF) activated the TrkB receptor to facilitate two forms of eCB-mediated synaptic depression, depolarization-induced suppression of inhibition (DSI), and long-term depression (I-LTD) of IPSCs in ventral tegmental area dopamine neurons in mouse midbrain slices. The facilitation appears to be mediated by an increase in eCB production via phospholipase Cγ pathway, but not by an increase in CB1 receptor responsiveness or a decrease in eCB hydrolysis. Using Cre-loxP technology to specifically delete BDNF in dopamine neurons, we showed that eCB-mediated I-LTD, cocaine-induced reduction of GABAergic inhibition, and potentiation of glutamatergic excitation remained intact in wild-type control mice, but were impaired in BDNF conditional knock-out mice. We also showed that cocaine-induced conditioned place preference was attenuated in BDNF conditional knock-out mice, in vivo pretreatments with DHF before place conditioning restored cocaine conditioned place preference in these mice, and the behavioral effect of DHF was blocked by a CB1 receptor antagonist. Together, these results suggest that BDNF in dopamine neurons regulates eCB responses, cocaine-induced synaptic plasticity, and associative learning. PMID:25762688

  4. Studies, using in vivo microdialysis, on the effect of the dopamine uptake inhibitor GBR 12909 on 3,4-methylenedioxymethamphetamine ('ecstasy')-induced dopamine release and free radical formation in the mouse striatum.

    PubMed

    Camarero, Jorge; Sanchez, Veronica; O'Shea, Esther; Green, A Richard; Colado, M Isabel

    2002-06-01

    The present study examined the mechanisms by which 3,4-methylenedioxymethamphetamine (MDMA) produces long-term neurotoxicity of striatal dopamine neurones in mice and the protective action of the dopamine uptake inhibitor GBR 12909. MDMA (30 mg/kg, i.p.), given three times at 3-h intervals, produced a rapid increase in striatal dopamine release measured by in vivo microdialysis (maximum increase to 380 +/- 64% of baseline). This increase was enhanced to 576 +/- 109% of baseline by GBR 12909 (10 mg/kg, i.p.) administered 30 min before each dose of MDMA, supporting the contention that MDMA enters the terminal by diffusion and not via the dopamine uptake site. This, in addition to the fact that perfusion of the probe with a low Ca(2+) medium inhibited the MDMA-induced increase in extracellular dopamine, indicates that the neurotransmitter may be released by a Ca(2+) -dependent mechanism not related to the dopamine transporter. MDMA (30 mg/kg x 3) increased the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA) from salicylic acid perfused through a probe implanted in the striatum, indicating that MDMA increased free radical formation. GBR 12909 pre-treatment attenuated the MDMA-induced increase in 2,3-DHBA formation by approximately 50%, but had no significant intrinsic radical trapping activity. MDMA administration increased lipid peroxidation in striatal synaptosomes, an effect reduced by approximately 60% by GBR 12909 pre-treatment. GBR 12909 did not modify the MDMA-induced changes in body temperature. These data suggest that MDMA-induced toxicity of dopamine neurones in mice results from free radical formation which in turn induces an oxidative stress process. The data also indicate that the free radical formation is probably not associated with the MDMA-induced dopamine release and that MDMA does not induce dopamine release via an action at the dopamine transporter.

  5. Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction

    PubMed Central

    Hiday, Andrew C.; Edler, Michael C.; Salek, Asma B.; Morris, Cameron W.; Thang, Morrent; Rentz, Tyler J.; Rose, Kristie L.; Jones, Lisa M.

    2017-01-01

    Signaling changes that occur in the striatum following the loss of dopamine neurons in the Parkinson disease (PD) are poorly understood. While increases in the activity of kinases and decreases in the activity of phosphatases have been observed, the specific consequences of these changes are less well understood. Phosphatases, such as protein phosphatase 1 (PP1), are highly promiscuous and obtain substrate selectivity via targeting proteins. Spinophilin is the major PP1-targeting protein enriched in the postsynaptic density of striatal dendritic spines. Spinophilin association with PP1 is increased concurrent with decreases in PP1 activity in an animal model of PD. Using proteomic-based approaches, we observed dopamine depletion-induced decreases in spinophilin binding to multiple protein classes in the striatum. Specifically, there was a decrease in the association of spinophilin with neurofilament medium (NF-M) in dopamine-depleted striatum. Using a heterologous cell line, we determined that spinophilin binding to NF-M required overexpression of the catalytic subunit of protein kinase A and was decreased by cyclin-dependent protein kinase 5. Functionally, we demonstrate that spinophilin can decrease NF-M phosphorylation. Our data determine mechanisms that regulate, and putative consequences of, pathological changes in the association of spinophilin with NF-M that are observed in animal models of PD. PMID:28634551

  6. Visualization and ligand-induced modulation of dopamine receptor dimerization at the single molecule level

    PubMed Central

    Tabor, Alina; Weisenburger, Siegfried; Banerjee, Ashutosh; Purkayastha, Nirupam; Kaindl, Jonas M.; Hübner, Harald; Wei, Luxi; Grömer, Teja W.; Kornhuber, Johannes; Tschammer, Nuska; Birdsall, Nigel J. M.; Mashanov, Gregory I.; Sandoghdar, Vahid; Gmeiner, Peter

    2016-01-01

    G protein–coupled receptors (GPCRs), including dopamine receptors, represent a group of important pharmacological targets. An increased formation of dopamine receptor D2 homodimers has been suggested to be associated with the pathophysiology of schizophrenia. Selective labeling and ligand-induced modulation of dimerization may therefore allow the investigation of the pathophysiological role of these dimers. Using TIRF microscopy at the single molecule level, transient formation of homodimers of dopamine receptors in the membrane of stably transfected CHO cells has been observed. The equilibrium between dimers and monomers was modulated by the binding of ligands; whereas antagonists showed a ratio that was identical to that of unliganded receptors, agonist-bound D2 receptor-ligand complexes resulted in an increase in dimerization. Addition of bivalent D2 receptor ligands also resulted in a large increase in D2 receptor dimers. A physical interaction between the protomers was confirmed using high resolution cryogenic localization microscopy, with ca. 9 nm between the centers of mass. PMID:27615810

  7. Dopamine-Induced Changes in Gαolf Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice

    PubMed Central

    Morigaki, Ryoma; Okita, Shinya; Goto, Satoshi

    2017-01-01

    The dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), exerts powerful therapeutic effects but eventually generates l-DOPA-induced dyskinesia (LID) in patients with Parkinson’s disease (PD). LID has a close link with deregulation of striatal dopamine/cAMP signaling, which is integrated by medium spiny neurons (MSNs). Olfactory type G-protein α subunit (Gαolf), a stimulatory GTP-binding protein encoded by the GNAL gene, is highly concentrated in the striatum, where it positively couples with dopamine D1 (D1R) receptor and adenosine A2A receptor (A2AR) to increase intracellular cAMP levels in MSNs. In the striatum, D1Rs are mainly expressed in the MSNs that form the striatonigral pathway, while D2Rs and A2ARs are expressed in the MSNs that form the striatopallidal pathway. Here, we examined the association between striatal Gαolf protein levels and the development of LID. We used a hemi-parkinsonian mouse model with nigrostriatal lesions induced by 6-hydroxydopamine (6-OHDA). Using quantitative immunohistochemistry (IHC) and a dual-antigen recognition in situ proximity ligation assay (PLA), we here found that in the dopamine-depleted striatum, there appeared increased and decreased levels of Gαolf protein in striatonigral and striatopallidal MSNs, respectively, after a daily pulsatile administration of l-DOPA. This leads to increased responsiveness to dopamine stimulation in both striatonigral and striatopallidal MSNs. Because Gαolf protein levels serve as a determinant of cAMP signal-dependent activity in striatal MSNs, we suggest that l-DOPA-induced changes in striatal Gαolf levels in the dopamine-depleted striatum could be a key event in generating LID. PMID:28239340

  8. Dopamine-Induced Changes in Gαolf Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice.

    PubMed

    Morigaki, Ryoma; Okita, Shinya; Goto, Satoshi

    2017-01-01

    The dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), exerts powerful therapeutic effects but eventually generates l-DOPA-induced dyskinesia (LID) in patients with Parkinson's disease (PD). LID has a close link with deregulation of striatal dopamine/cAMP signaling, which is integrated by medium spiny neurons (MSNs). Olfactory type G-protein α subunit (Gαolf), a stimulatory GTP-binding protein encoded by the GNAL gene, is highly concentrated in the striatum, where it positively couples with dopamine D1 (D1R) receptor and adenosine A2A receptor (A2AR) to increase intracellular cAMP levels in MSNs. In the striatum, D1Rs are mainly expressed in the MSNs that form the striatonigral pathway, while D2Rs and A2ARs are expressed in the MSNs that form the striatopallidal pathway. Here, we examined the association between striatal Gαolf protein levels and the development of LID. We used a hemi-parkinsonian mouse model with nigrostriatal lesions induced by 6-hydroxydopamine (6-OHDA). Using quantitative immunohistochemistry (IHC) and a dual-antigen recognition in situ proximity ligation assay (PLA), we here found that in the dopamine-depleted striatum, there appeared increased and decreased levels of Gαolf protein in striatonigral and striatopallidal MSNs, respectively, after a daily pulsatile administration of l-DOPA. This leads to increased responsiveness to dopamine stimulation in both striatonigral and striatopallidal MSNs. Because Gαolf protein levels serve as a determinant of cAMP signal-dependent activity in striatal MSNs, we suggest that l-DOPA-induced changes in striatal Gαolf levels in the dopamine-depleted striatum could be a key event in generating LID.

  9. 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.

  10. Rapid induction of dopamine sensitization in the nucleus accumbens shell induced by a single injection of cocaine.

    PubMed

    Singer, Bryan F; Bryan, Myranda A; Popov, Pavlo; Robinson, Terry E; Aragona, Brandon J

    2017-05-01

    Repeated intermittent exposure to cocaine results in the neurochemical sensitization of dopamine (DA) transmission within the nucleus accumbens (NAc). Indeed, the excitability of DA neurons in the ventral tegmental area (VTA) is enhanced within hours of initial psychostimulant exposure. However, it is not known if this is accompanied by a comparably rapid change in the ability of cocaine to increase extracellular DA concentrations in the ventral striatum. To address this question we used fast-scan cyclic voltammetry (FSCV) in awake-behaving rats to measure DA responses in the NAc shell following an initial intravenous cocaine injection, and then again 2-h later. Both injections quickly elevated DA levels in the NAc shell, but the second cocaine infusion produced a greater effect than the first, indicating sensitization. This suggests that a single injection of cocaine induces sensitization-related plasticity very rapidly within the mesolimbic DA system.

  11. Prenatal Inflammation-Induced Hypoferremia Alters Dopamine Function in the Adult Offspring in Rat: Relevance for Schizophrenia

    PubMed Central

    Aguilar-Valles, Argel; Flores, Cecilia; Luheshi, Giamal N.

    2010-01-01

    Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans. PMID:20532043

  12. Prenatal inflammation-induced hypoferremia alters dopamine function in the adult offspring in rat: relevance for schizophrenia.

    PubMed

    Aguilar-Valles, Argel; Flores, Cecilia; Luheshi, Giamal N

    2010-06-04

    Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans.

  13. Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons

    PubMed Central

    Ehrich, Jonathan M.; Messinger, Daniel I.; Knakal, Cerise R.; Kuhar, Jamie R.; Schattauer, Selena S.; Bruchas, Michael R.; Zweifel, Larry S.; Kieffer, Brigitte L.; Phillips, Paul E.M.

    2015-01-01

    The endogenous dynorphin-κ opioid receptor (KOR) system encodes the dysphoric component of the stress response and controls the risk of depression-like and addiction behaviors; however, the molecular and neural circuit mechanisms are not understood. In this study, we report that KOR activation of p38α MAPK in ventral tegmental (VTA) dopaminergic neurons was required for conditioned place aversion (CPA) in mice. Conditional genetic deletion of floxed KOR or floxed p38α MAPK by Cre recombinase expression in dopaminergic neurons blocked place aversion to the KOR agonist U50,488. Selective viral rescue by wild-type KOR expression in dopaminergic neurons of KOR−/− mice restored U50,488-CPA, whereas expression of a mutated form of KOR that could not initiate p38α MAPK activation did not. Surprisingly, while p38α MAPK inactivation blocked U50,488-CPA, p38α MAPK was not required for KOR inhibition of evoked dopamine release measured by fast scan cyclic voltammetry in the nucleus accumbens. In contrast, KOR activation acutely inhibited VTA dopaminergic neuron firing, and repeated exposure attenuated the opioid response. This adaptation to repeated exposure was blocked by conditional deletion of p38α MAPK, which also blocked KOR-induced tyrosine phosphorylation of the inwardly rectifying potassium channel (GIRK) subunit Kir3.1 in VTA dopaminergic neurons. Consistent with the reduced response, GIRK phosphorylation at this amino terminal tyrosine residue (Y12) enhances channel deactivation. Thus, contrary to prevailing expectations, these results suggest that κ opioid-induced aversion requires regulation of VTA dopaminergic neuron somatic excitability through a p38α MAPK effect on GIRK deactivation kinetics rather than by presynaptically inhibiting dopamine release. SIGNIFICANCE STATEMENT Kappa opioid receptor (KOR) agonists have the potential to be effective, nonaddictive analgesics, but their therapeutic utility is greatly limited by adverse effects on mood

  14. 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

  15. Dopamine release from serotonergic nerve fibers is reduced in L-DOPA-induced dyskinesia

    PubMed Central

    Nevalainen, Nina; af Bjerkén, Sara; Lundblad, Martin; Gerhardt, Greg A.; Strömberg, Ingrid

    2011-01-01

    L-DOPA (3,4-dihydroxyphenyl-L-alanine) is the most commonly used treatment for symptomatic control in patients with Parkinson’s disease. Unfortunately, most patients develop severe side effects, such as dyskinesia, upon chronic L-DOPA treatment. The patophysiology of dyskinesia is unclear, however, involvement of serotonergic nerve fibers in converting L-DOPA to dopamine has been suggested. Therefore, potassium-evoked dopamine release was studied after local application of L-DOPA in the striata of normal, dopamine- and dopamine/serotonin-lesioned L-DOPA naïve, and dopamine-denervated chronically L-DOPA-treated dyskinetic rats using in vivo chronoamperometry. The results revealed that local L-DOPA administration into normal and intact hemisphere of dopamine-lesioned L-DOPA naïve animals significantly increased the potassium-evoked dopamine release. L-DOPA application also increased the dopamine peak amplitude in the dopamine-depleted L-DOPA naïve striatum, although these dopamine levels were several-folds lower than in the normal striatum, while no increased dopamine release was found in the dopamine/serotonin-denervated striatum. In dyskinetic animals, local L-DOPA application did not affect the dopamine release, resulting in significantly attenuated dopamine levels compared to those measured in L-DOPA naïve dopamine-denervated striatum. To conclude, L-DOPA is most likely converted to dopamine in serotonergic nerve fibers in the dopamine-depleted striatum, but the dopamine release is several-fold lower than in normal striatum. Furthermore, L-DOPA loading does not increase the dopamine release in dyskinetic animals as found in L-DOPA naïve animals, despite similar density of serotonergic innervation. Thus, the dopamine overflow produced from the serotonergic nerve fibers appears not to be the major cause of dyskinetic behavior. PMID:21534956

  16. Overexpression of the dopamine D3 receptor in the rat dorsal striatum induces dyskinetic behaviors.

    PubMed

    Cote, Samantha R; Chitravanshi, Vineet C; Bleickardt, Carina; Sapru, Hreday N; Kuzhikandathil, Eldo V

    2014-04-15

    L-DOPA-induced dyskinesias (LID) are motor side effects associated with treatment of Parkinson's disease (PD). The etiology of LID is not clear; however, studies have shown that the dopamine D3 receptor is upregulated in the basal ganglia of mice, rats and non-human primate models of LID. It is not known if the upregulation of D3 receptor is a cause or result of LID. In this paper we tested the hypothesis that overexpression of the dopamine D3 receptor in dorsal striatum, in the absence of dopamine depletion, will elicit LID. Replication-deficient recombinant adeno-associated virus-2 expressing the D3 receptor or enhanced green fluorescent protein (EGFP) were stereotaxically injected, unilaterally, into the dorsal striatum of adult rats. Post-hoc immunohistochemical analysis revealed that ectopic expression of the D3 receptor was limited to neurons near the injection sites in the dorsal striatum. Following a 3-week recovery period, rats were administered saline, 6 mg/kg L-DOPA, 0.1 mg/kg PD128907 or 10 mg/kg ES609, i.p., and motor behaviors scored. Rats overexpressing the D3 receptor specifically exhibited contralateral axial abnormal involuntary movements (AIMs) following administration of L-DOPA and PD128907 but not saline or the novel agonist ES609. Daily injection of 6 mg/kg L-DOPA to the rats overexpressing the D3 receptor also caused increased vacuous chewing behavior. These results suggest that overexpression of the D3 receptor in the dorsal striatum results in the acute expression of agonist-induced axial AIMs and chronic L-DOPA-induced vacuous chewing behavior. Agonists such as ES609 might provide a novel therapeutic approach to treat dyskinesia. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Behavioral pattern analysis and dopamine release in quinpirole-induced repetitive behavior in rats.

    PubMed

    de Haas, Ria; Nijdam, Annelies; Westra, Tjalke A; Kas, Martien J H; Westenberg, Herman G M

    2011-12-01

    Obsessive-compulsive disorder (OCD) is a chronic and disabling psychiatric disease with a lifetime prevalence of 2-3%. People with OCD suffer from intrusive, unwanted and recurrent thoughts (obsessions) and/or repetitive ritualistic behaviors (compulsions). The aim of this study is to quantify the dimensions of ritualistic 'compulsive-like' behavior in quinpirole-induced behavior in rats by using T-pattern behavioral analysis. In addition, we investigated whether the behavioral effects elicited by quinpirole sensitization remained after 2 weeks of cessation of treatment. Finally, to study the neurobiological underpinnings of this 'compulsive-like' behavior, we investigated the effect of quinpirole treatment on the extracellular dopamine levels in the nucleus accumbens. Once established, 'compulsive-like' behavior is dependent upon quinpirole administration, as this behavior rapidly normalized after cessation of treatment. After a single dose of quinpirole the dopamine level decreased more in saline pre-treated animals as compared with animals given quinpirole treatment continuously. Furthermore, T-pattern analysis revealed that quinpirole-induced behavior consists, unlike OCD rituals, of a smaller behavioral repertoire. As seen in patients with OCD, quinpirole-treated animals performed these behaviors with a high rate of repetition. These findings suggest that quinpirole-induced behavior mimics only part of the compulsive behavior as shown in OCD patients.

  18. Role of the basolateral amygdala dopamine receptors in arachidonylcyclopropylamide-induced fear learning deficits.

    PubMed

    Nasehi, Mohammad; Hajian, Maryam; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2016-01-01

    There is much evidence suggesting that the mesoamygdala dopaminergic (DAergic) system plays a crucial role in the formation and expression of fear conditioning, with both D1 and D2 receptors being involved. In addition, cannabinoid CB1 receptor (CB1R) signaling modulates DAergic pathways. The present study sought to determine the involvement of basolateral amygdala (BLA) dopamine receptors in arachidonylcyclopropylamide (ACPA)-induced fear learning deficits. Context- and tone-dependent fear conditioning in adult male NMRI mice was evaluated. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing in context- or tone-dependent fear conditioning, suggesting an acquisition impairment. Pre-training intra-BLA microinjection of a subthreshold dose of SKF38393 (D1-like receptor agonist), SCH23390 (D1-like receptor antagonist), quinpirole (D2-like receptor agonist), or sulpiride (D2-like receptor antagonist) did not alter the context-dependent fear learning deficit induced by ACPA, while SKF38393 or quinpirole restored ACPA effect on tone-dependent fear learning. Moreover, SKF38393 (1 μg/mouse), SCH23390 (0.04 and 0.08 μg/mouse), or quinpirole (0.1 μg/mouse) all impaired context-dependent fear learning. It is concluded that D1 or D2 dopamine (DA) receptor activation restores tone- but not context-dependent fear learning deficit induced by CB1 activation using ACPA.

  19. Impulse radio ultra wideband wireless transmission of dopamine concentration levels recorded by fast-scan cyclic voltammetry.

    PubMed

    Ebrazeh, Ali; Bozorgzadeh, Bardia; Mohseni, Pedram

    2015-01-01

    This paper demonstrates the feasibility of utilizing impulse radio ultra wideband (IR-UWB) signaling technique for reliable, wireless transmission of dopamine concentration levels recorded by fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM) to address the problem of elevated data rates in high-channel-count neurochemical monitoring. Utilizing an FSCV-sensing chip fabricated in AMS 0.35μm 2P/4M CMOS, a 3-5-GHz, IR-UWB transceiver (TRX) chip fabricated in TSMC 90nm 1P/9M RF CMOS, and two off-chip, miniature, UWB antennae, wireless transfer of pseudo-random binary sequence (PRBS) data at 50Mbps over a distance of <;1m is first shown with bit-error rates (BER) <; 10(-3). Further, IR-UWB wireless transmission of dopamine concentration levels prerecorded with FSCV at a CFM during flow injection analysis (FIA) is also demonstrated with transmitter (TX) power dissipation of only ~4.4μW from 1.2V, representing two orders of magnitude reduction in TX power consumption compared to that of a conventional frequency-shift-keyed (FSK) link operating at ~433MHz.

  20. Subchronic apocynin treatment attenuates methamphetamine-induced dopamine release and hyperactivity in rats.

    PubMed

    Miller, Dennis K; Oelrichs, Clark E; Sun, Grace Y; Simonyi, Agnes

    2014-03-07

    The effects of methamphetamine are linked to stimulation of dopaminergic neurons, which can be accompanied by production of reactive oxygen species (ROS). Apocynin (4-hydroxy-3-methoxy-acetophenone) is a nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) inhibitor shown to mitigate oxidative stress in a number of models. The present study aimed at testing whether apocynin suppresses the dopamine-releasing and locomotor-activating properties of methamphetamine. (1) Apocynin (0.01-100μM) was applied to rat striatal slices preloaded with [(3)H]dopamine and its efficacy to evoke [(3)H]overflow and to alter methamphetamine (3μM)-evoked [(3)H]overflow was measured. (2) Groups of rats received apocynin (15 or 50mg/kg/day) or vehicle injection for seven consecutive days, and the efficacy and potency of methamphetamine to evoke [(3)H]overflow were determined. (3) Groups of apocynin-treated rats were administered methamphetamine (0.5 or 1mg/kg) or saline to determine the effect of apocynin on stimulant-induced hyperactivity. (1) Apocynin applied to striatal slices did not evoke [(3)H]overflow or alter methamphetamine-evoked [(3)H]overflow. (2) However, subchronic apocynin treatment significantly and dose-dependently decreased methamphetamine's potency and efficacy to evoke [(3)H]overflow. (3) Subchronic apocynin treatment also decreased the locomotor activity evoked by methamphetamine. Subchronic apocynin treatment diminished methamphetamine induced dopamine-release and its locomotor-activating properties. The pattern of results indicates that apocynin is more effective after repeated, rather than after acute, treatment. The findings also suggest that NOX inhibitors or agents suppressing oxidative stress may constitute a new area for research to understand how methamphetamine produces its deleterious and neurotoxic outcomes in the brain. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Neuroprotective effect of Tinospora cordifolia ethanol extract on 6-hydroxy dopamine induced Parkinsonism

    PubMed Central

    Kosaraju, Jayasankar; Chinni, Santhivardhan; Roy, Partha Deb; Kannan, Elango; Antony, A. Shanish; Kumar, M. N. Satish

    2014-01-01

    Objective: The present study investigates the neuroprotective activity of ethanol extract of Tinospora cordifolia aerial parts against 6-hydroxy dopamine (6-OHDA) lesion rat model of Parkinson's disease (PD). Materials and Methods: T. cordifolia ethanol extract (TCEE) was standardized with high performance thin layer chromatography using berberine. Experimental PD was induced by intracerebral injection of 6-OHDA (8 μg). Animals were divided into five groups: sham operated, negative control, positive control (levodopa 6 mg/kg) and two experimental groups (n = 6/group). Experimental groups received 200 and 400 mg/kg of TCEE once daily for 30 days by oral gavage. Biochemical parameters including dopamine level, oxidative stress, complex I activity and brain iron asymmetry ratio and locomotor activity including skeletal muscle co-ordination and degree of catatonia were assessed. Results: TCEE exhibited significant neuroprotection by increasing the dopamine levels (1.96 ± 0.20 and 2.45 ± 0.40 ng/mg of protein) and complex I activity (77.14 ± 0.89 and 78.50 ± 0.96 nmol/min/mg of protein) at 200 and 400 mg/kg respectively when compared with negative control group. Iron asymmetry ratio was also significantly attenuated by TCEE at 200 (1.57 ± 0.18) and 400 mg/kg (1.11 ± 0.15) when compared with negative control group. Neuroprotection by TCEE was further supported by reduced oxidative stress and restored locomotor activity in treatment groups. Conclusion: Results show that TCEE possess significant neuroprotection in 6-OHDA induced PD by protecting dopaminergic neurons and reducing the iron accumulation. PMID:24741189

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

    PubMed Central

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

    2016-01-01

    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. PMID:26211731

  3. 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

  4. Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma

    SciTech Connect

    Qin, Tian; Wang, Chenlong; Chen, Xuewei; Duan, Chenfan; Zhang, Xiaoyan; Zhang, Jing; Chai, Hongyan; Tang, Tian; Chen, Honglei; Yue, Jiang; Li, Ying; Yang, Jing

    2015-07-15

    Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50 mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia-inducible factor-1α expression in tumor tissues, while increasing the coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling. In summary, DA induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy. - Highlights: • Dopamine induces tumor growth inhibition and vascular normalization in rat C6 glioma. • Dopamine switches macrophage phenotype from M2 to M1. • Dopamine-induced vascular normalization is mediated by macrophage polarization. • Dopamine is a promising agent targeting the microvasculature in tumor

  5. The action of dopamine and vascular dopamine (DA1) receptor agonists on human isolated subcutaneous and omental small arteries.

    PubMed Central

    Hughes, A. D.; Sever, P. S.

    1989-01-01

    1. Human small arteries were obtained from surgical specimens and studied in vitro by use of a myograph technique. Following induction of tone with a potassium depolarizing solution, dopamine in the presence of beta-adrenoceptor and catecholamine uptake blockade relaxed isolated omental and subcutaneous arteries. Preincubation of tissues with phentolamine increased the maximum relaxation in response to dopamine. 2. The selective vascular dopamine receptor agonists, fenoldopam and SKF 38393 also relaxed isolated subcutaneous and omental arteries in a concentration-dependent manner. The order of potency for agonists was dopamine greater than fenoldopam greater than SKF 38393. 3. Dopamine-induced relaxation was competitively antagonized by SCH 23390, (R)- and (S)-sulpiride, and fenoldopam induced relaxation by SCH 23390 and (+)- but not (-)-butaclamol. 4. These results indicate the presence of vascular dopamine receptors (DA1 subtype) on human isolated resistance arteries from omental and subcutaneous sites. PMID:2474354

  6. Association between cerebrospinal fluid dopamine concentrations and catechol-O-methyltransferase gene polymorphisms in forensic autopsy cases of methamphetamine abusers.

    PubMed

    Matsusue, Aya; Ishikawa, Takaki; Michiue, Tomomi; Waters, Brian; Hara, Kenji; Kashiwagi, Masayuki; Takayama, Mio; Ikematsu, Natsuki; Kubo, Shin-Ichi

    2017-01-01

    Methamphetamine (MA) is an illicit psychostimulant that stimulates the release of catecholamines from sympathetic nerve terminals and is widely abused worldwide. Since catechol-O-methyltransferase (COMT) metabolizes catecholamines and mediates adrenergic, noradrenergic, and dopaminergic signaling responses, we investigated the effects of the COMT polymorphisms rs4633 and rs4680 on cerebrospinal fluid (CSF) catecholamine concentrations in autopsies of subjects who died of drug intoxication. 28 MA abusers and 22 fatal psychotropic drug intoxication cases were evaluated. No correlations were identified between rs4633 or rs4680 polymorphisms and CSF concentrations of adrenaline (Adr), noradrenaline (Nad), or dopamine (DA) in fatal psychotropic cases. However, among MA abusers, DA concentrations in the CSF were significantly higher in those with the T allele (CT and TT) of rs4633 than in CC genotype carriers (p=0.004). Moreover, among MA abusers, DA concentrations were significantly higher in those with the A allele (GA and AA) of rs4680 than in GG genotype carriers (p=0.017). In subsequent haplotype analyses of MA abusers, a strong correlation was identified between two COMT haplotypes and CSF DA concentrations (p=0.002). However, the CSF concentrations of Adr and Nad were not associated with COMT genotypes or haplotypes. The present results indicate that rs4633 and rs4680 polymorphisms influence CSF DA concentrations and MA toxicity in MA abusers.

  7. Basal ganglia circuit loops, dopamine and motivation: A review and enquiry.

    PubMed

    Ikemoto, Satoshi; Yang, Chen; Tan, Aaron

    2015-09-01

    Dopamine neurons located in the midbrain play a role in motivation that regulates approach behavior (approach motivation). In addition, activation and inactivation of dopamine neurons regulate mood and induce reward and aversion, respectively. Accumulating evidence suggests that such motivational role of dopamine neurons is not limited to those located in the ventral tegmental area, but also in the substantia nigra. The present paper reviews previous rodent work concerning dopamine's role in approach motivation and the connectivity of dopamine neurons, and proposes two working models: One concerns the relationship between extracellular dopamine concentration and approach motivation. High, moderate and low concentrations of extracellular dopamine induce euphoric, seeking and aversive states, respectively. The other concerns circuit loops involving the cerebral cortex, basal ganglia, thalamus, epithalamus, and midbrain through which dopaminergic activity alters approach motivation. These models should help to generate hypothesis-driven research and provide insights for understanding altered states associated with drugs of abuse and affective disorders.

  8. Decoding the Dopamine Signal in Macaque Prefrontal Cortex: A Simulation Study Using the Cx3Dp Simulator

    PubMed Central

    Spühler, Isabelle Ayumi; Hauri, Andreas

    2013-01-01

    Dopamine transmission in the prefrontal cortex plays an important role in reward based learning, working memory and attention. Dopamine is thought to be released non-synaptically into the extracellular space and to reach distant receptors through diffusion. This simulation study examines how the dopamine signal might be decoded by the recipient neuron. The simulation was based on parameters from the literature and on our own quantified, structural data from macaque prefrontal area 10. The change in extracellular dopamine concentration was estimated at different distances from release sites and related to the affinity of the dopamine receptors. Due to the sparse and random distribution of release sites, a transient heterogeneous pattern of dopamine concentration emerges. Our simulation predicts, however, that at any point in the simulation volume there is sufficient dopamine to bind and activate high-affinity dopamine receptors. We propose that dopamine is broadcast to its distant receptors and any change from the local baseline concentration might be decoded by a transient change in the binding probability of dopamine receptors. Dopamine could thus provide a graduated ‘teaching’ signal to reinforce concurrently active synapses and cell assemblies. In conditions of highly reduced or highly elevated dopamine levels the simulations predict that relative changes in the dopamine signal can no longer be decoded, which might explain why cognitive deficits are observed in patients with Parkinson’s disease, or induced through drugs blocking dopamine reuptake. PMID:23951205

  9. Nifedipine prevents iron accumulation and reverses iron-overload-induced dopamine neuron degeneration in the substantia nigra of rats.

    PubMed

    Ma, ZeGang; Zhou, Yu; Xie, JunXia

    2012-11-01

    The mechanisms of iron accumulation in substantia nigra (SN) of Parkinson's diseases remain unclear. The objective of this study was to investigate effects of nifedipine on iron-overload-induced iron accumulation and neurodegeneration in SN of rats. By high performance liquid chromatography-electrochemical detection, tyrosine hydroxylase (TH) immunohistochemistry, and iron content array, we first quantified iron content and the number of dopamine neurons in SN of experimental rats treated with iron dextran. We further assessed effects of treatment with nifedipine. Our results showed that nifedipine treatment prevents iron dextran-induced dopamine depletion in the striatum. Consistently, we found that nifedipine restores the number of TH-positive neurons reduced by iron dextran overload and prevents increase of iron content in the SN. These results suggested that nifedipine may suppress iron toxicity in dopamine neurons and prevent neurodegeneration.

  10. Molindone: higher doses needed to block pergolide-induced elevation of serum corticosterone than to elevate dopamine metabolites in brain.

    PubMed

    Fuller, R W; Snoddy, H D

    1983-12-05

    Molindone at a dose of 3 mg/kg i.p. in rats prevented pergolide-induced decreases in brain DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid), causing instead significant increases in these dopamine metabolites when given in combination with pergolide. Molindone alone at 3 mg/kg caused two-fold or greater increases in DOPAC and HVA and at doses as low as 0.3 mg/kg caused significant increases in these metabolites. However, molindone at 3 mg/kg and lower doses was without effect on pergolide-induced elevation of serum corticosterone, though a higher dose of molindone, 10 mg/kg, significantly antagonized this increase in corticosterone. These data support earlier findings with molindone, suggesting it has greater affinity for presynaptic dopamine autoreceptors than for postsynaptic dopamine receptors.

  11. Dopamine inhibits ATP-induced responses in the cat petrosal ganglion in vitro.

    PubMed

    Alcayaga, Julio; Retamal, Mauricio; Cerpa, Verónica; Arroyo, Jorge; Zapata, Patricio

    2003-03-21

    The petrosal ganglion (PG) provides sensory innervation to the carotid sinus and carotid body through the carotid (sinus) nerve (CN). Application of either acetylcholine (ACh) or adenosine 5'-triphosphate (ATP) to the PG superfused in vitro activates CN fibers. Dopamine (DA) modulates the effects of ACh. We have previously shown that DA when applied to the PG modulates the effects of ACh on carotid sinus nerve fibers. We currently report the effects of DA on the ATP-induced responses in the isolated PG in vitro. While DA had no effect on the basal activity recorded from the CN, it reduced ATP-induced responses in a dose-dependent manner, when preceding ATP applications by 30 s. Our results suggest that DA-a transmitter present in a group of PG neurons and in carotid body cells-may act as an inhibitory modulator of ATP-evoked responses in PG neurons.

  12. Guanine nucleotide regulation of dopamine receptor agonist affinity states in rat estradiol-induced pituitary tumors

    SciTech Connect

    Di Paolo, T.; Falardeau, P.

    1987-08-31

    The authors have investigated dopamine (DA) receptor agonist high- and low-affinity states in female rate estradiol-induced prolactin (PRL)-secreting pituitary tumors and intact pituitary tissue. Estradiol treatment increased the anterior pituitary weight 9-fold and plasma prolactin levels 74-fold and these measures are correlated (R = 0.745, n = 73, p < 0.001). Competition for (/sup 3/H)-spiperone binding to the DA receptor by apomorphine was compared in normal and adenomatous pituitary tissue. The inhibition constants (Ki) and the proportions of the two apomorphine sites are unchanged in tumors compared to intact pituitary tissue. Guanosine 5'-(..beta..-..gamma..-imino)triphosphate (Gpp(NH)p) causes complete conversion of the high into low affinity dopaminergic agonist site in normal pituitary and in tumors. These results suggest that rats with primary estradiol-induced pituitary tumors have normal and functional DA receptors. 9 references, 2 tables.

  13. Insulin induces long-term depression of VTA dopamine neurons via an endocannabinoid-mediated mechanism

    PubMed Central

    Labouèbe, Gwenaël; Liu, Shuai; Dias, Carine; Zou, Haiyan; Wong, Jovi C.Y.; Karunakaran, Subashini; Clee, Susanne M.; Phillips, Anthony; Boutrel, Benjamin; Borgland, Stephanie L.

    2014-01-01

    The prevalence of obesity has drastically increased over the last few decades. Exploration into how hunger and satiety signals influence the reward system can help us to understand non-homeostatic mechanisms of feeding. Evidence suggests that insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce a long-term depression (LTD) of excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high fat meal, which elevates endogenous insulin levels, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior and conditioned place preference for food. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces salience of food-related cues. PMID:23354329

  14. Is there a role for nitric oxide in methamphetamine-induced dopamine terminal degeneration?

    PubMed

    Friend, Danielle M; Fricks-Gleason, Ashley N; Keefe, Kristen A

    2014-02-01

    Methamphetamine (METH) abuse results in long-term damage to the dopaminergic system, manifesting as decreases in dopamine (DA) tissue content, DA transporter binding, as well as tyrosine hydroxylase and vesicular monoamine transporter immunostaining. However, the exact cascade of events that ultimately result in this damage has not been clearly elucidated. One factor that has been heavily implicated in METH-induced DA terminal degeneration is the production of nitric oxide (NO). Unfortunately, many of the studies attempting to clarify the role of NO in METH-induced neurotoxicity have been confounded by issues such as the disruption of METH-induced hyperthermia, preventing the formation of strong conclusions. As a result, there is a body of work suggesting that NO is sufficient for METH-induced neurotoxicity, while other studies suggest that NO does not play a role in METH-induced degeneration of DA nerve terminals. This review summarizes the existing studies investigating the role of NO in METH-induced neurotoxicity, and argues that while NO may be necessary for METH-induced neurotoxicity, it is not sufficient. Finally, important areas of future investigation are highlighted and discussed.

  15. Is There A Role for Nitric Oxide in Methamphetamine-Induced Dopamine Terminal Degeneration?

    PubMed Central

    Friend, Danielle M.; Fricks-Gleason, Ashley N.; Keefe, Kristen A.

    2013-01-01

    Methamphetamine (METH) abuse results in long-term damage to the dopaminergic system, manifesting as decreases in dopamine (DA) tissue content, DA transporter (DAT) binding, as well as tyrosine hydroxylase (TH) and vesicular monoamine transporter (VMAT) immunostaining. However, the exact cascade of events that ultimately results in this damage has not been clearly elucidated. One factor that has been heavily implicated in METH-induced DA terminal degeneration is the production of nitric oxide (NO). Unfortunately, many of the studies attempting to clarify the role of NO in METH-induced neurotoxicity have been confounded by issues such as the disruption of METH-induced hyperthermia, preventing the formation of strong conclusions. As a result, there is a body of work suggesting that NO is sufficient for METH-induced neurotoxicity, while other studies suggest that NO does not play a role in METH-induced degeneration of DA nerve terminals. This review summarizes the existing studies investigating the role of NO in METH-induced neurotoxicity, and argues that while NO may be necessary for METH-induced neurotoxicity, it is not sufficient. Finally, important areas of future investigation are highlighted and discussed. PMID:23918001

  16. Effects of extracerebral dopamine on salsolinol- or thyrotropin-releasing hormone-induced prolactin (PRL) secretion in goats.

    PubMed

    Inaba, Yuki; Kato, Yuki; Itou, Azumi; Chiba, Aoi; Sawai, Ken; Fülöp, Ferenc; Nagy, György Miklos; Hashizume, Tsutomu

    2016-12-01

    The aim of the present study was to clarify the effect of extracerebral dopamine (DA) on salsolinol (SAL)-induced prolactin (PRL) secretion in goats. An intravenous injection of SAL or thyrotropin-releasing hormone (TRH) was given to female goats before and after treatment with an extracerebral DA receptor antagonist, domperidone (DOM), and the PRL-releasing response to SAL was compared with that to TRH. DOM alone increased plasma PRL concentrations and the PRL-releasing response to DOM alone was greater than that to either SAL alone or TRH alone. The PRL-releasing response to DOM plus SAL was similar to that to DOM alone, and no additive effect of DOM and SAL on the secretion of PRL was observed. In contrast, the PRL-releasing response to DOM plus TRH was greater than that to either TRH alone or DOM alone and DOM synergistically increased TRH-induced PRL secretion. The present results demonstrate that the mechanism involved in PRL secretion by SAL differs from that by TRH, and suggest that the extracerebral DA might be associated in part with the modulation of SAL-induced PRL secretion in goats.

  17. Epigenetic dysregulation of the dopamine system in diet-induced obesity.

    PubMed

    Vucetic, Zivjena; Carlin, Jesse Lea; Totoki, Kathy; Reyes, Teresa M

    2012-03-01

    Chronic intake of high-fat (HF) diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to HF diet have been observed in the hypothalamus, important in the homeostatic control of food intake, as well as within the central reward circuitry [ventral tegmental area (VTA), nucleus accumbens (NAc), and pre-frontal cortex (PFC)], critical for coding the rewarding properties of palatable food and important in hedonically driven feeding behavior. Using a mouse model of diet-induced obesity (DIO), significant alterations in the expression of DA-related genes were documented in adult animals, and the general pattern of gene expression changes was opposite within the hypothalamus versus the reward circuitry (increased vs. decreased, respectively). Differential DNA methylation was identified within the promoter regions of tyrosine hydroxylase (TH) and dopamine transporter (DAT), and the pattern of this response was consistent with the pattern of gene expression. Behaviors consistent with increased hypothalamic DA and decreased reward circuitry DA were observed. These data identify differential DNA methylation as an epigenetic mechanism linking the chronic intake of HF diet with altered DA-related gene expression, and this response varies by brain region and DNA sequence. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

  18. Inhibitory effects of dopamine on spinal synaptic transmission via dopamine D1-like receptors in neonatal rats

    PubMed Central

    Kawamoto, K; Otsuguro, K; Ishizuka, M; Ito, S

    2012-01-01

    BACKGROUND AND PURPOSE Dopamine released from the endings of descending dopaminergic nerve fibres in the spinal cord may be involved in modulating functions such as locomotion and nociception. Here, we examined the effects of dopamine on spinal synaptic transmissions in rats. EXPERIMENTAL APPROACH Spinal reflex potentials, monosynaptic reflex potential (MSR) and slow ventral root potential (sVRP), were measured in the isolated spinal cord of the neonatal rat. Dopamine release was measured by HPLC. KEY RESULTS Dopamine at lower concentrations (<1 µM) depressed sVRP, which is a C fibre-evoked polysynaptic response and believed to reflect nociceptive transmission. At higher concentrations (>1 µM), in addition to a potent sVRP depression, dopamine depolarized baseline potential and slightly depressed MSR. Depression of sVRP by dopamine was partially reversed by dopamine D1-like but not by D2-like receptor antagonists. SKF83959 and SKF81297, D1-like receptor agonists, and methamphetamine, an endogenous dopamine releaser, also caused the inhibition of sVRP. Methamphetamine also depressed MSR, which was inhibited by ketanserin, a 5-HT2A/2C receptor antagonist. Methamphetamine induced the release of dopamine and 5-HT from spinal cords, indicating that the release of endogenous dopamine and 5-HT depresses sVRP and MSR respectively. CONCLUSION AND IMPLICATIONS These results suggested that dopamine at lower concentrations preferentially inhibited sVRP, which is mediated via dopamine D1-like and other unidentified receptors. The dopamine-evoked depression is involved in modulating the spinal functions by the descending dopaminergic pathways. PMID:22168428

  19. Kinetics of polydopamine film deposition as a function of pH and dopamine concentration: insights in the polydopamine deposition mechanism.

    PubMed

    Ball, Vincent; Del Frari, Doriane; Toniazzo, Valérie; Ruch, David

    2012-11-15

    The formation of "polydopamine" thin films becomes a popular method to confer multifunctionality to solid-liquid interfaces through the available catechol groups of such films. The mechanism of film formation is, however, not well elucidated, and most investigators use the protocol developed by Messersmith et al. (H. Lee, S.M. Dellatore, W.M. Miller, P.B. Messersmith, Science 318 (2007) 426.) using a dopamine solution at a constant concentration of 2 g L(-1) in the presence of Tris(hydroxymethyl aminomethane) at pH 8.5. A particular finding of this initial study was that the film thickness reaches a constant value (almost substrate independent) of about 40 nm. Herein, we investigate the change in the polydopamine film thickness, morphology, surface energy and electrochemical properties as a function of the concentration of the dopamine solution put in the presence of silicon substrates. As a surprising finding, we observe a constant increase in the maximal film thickness with an increase in the dopamine solution between 0.1 and 5 g L(-1). The surface morphology is also markedly affected by the concentration of the dopamine solution, whereas the different components of the surface energy stay unaffected by the dopamine solution concentration. In addition, electrochemical impedance spectroscopy shows that the higher the initial dopamine concentration, the more rapidly compact and impermeable films are formed. Finally, we propose a model for the deposition of polydopamine films taking all our findings into account. This model relies on a rate equation taking into account both attractive and repulsive interactions between small polydopamine aggregates on the surface and in solution.

  20. L-DOPA inhibits depolarization-induced [3H]GABA release in the dopamine-denervated globus pallidus of the rat: the effect is dopamine independent and mediated by D2-like receptors.

    PubMed

    Silva, I; Cortes, H; Escartín, E; Rangel, C; Florán, L; Erlij, D; Aceves, J; Florán, B

    2006-12-01

    The effect of L-DOPA on [(3)H]GABA release in slices of globus pallidus from 6-OHDA-lesioned rats was studied. Release was evoked by high (15 mM) K(+). The lesion reduced dopamine content and dopamine synthesized from L-DOPA. The inhibition of DOPA decarboxylase blocked dopamine synthesis. Endogenous dopamine released by high K(+) inhibited [(3)H]GABA release in normal but not in lesioned slices. L-DOPA inhibited (IC(50) = 0.44 microM) evoked [(3)H]GABA release. The inhibition was via D2-like receptors but not mediated by dopamine. The turning behavior induced by L-DOPA methyl ester (25 mg/kg, i.p.) was not abolished by the DOPA decarboxylase inhibitor 3-hydroxybenzylhydrazine but in this condition it was abolished by sulpiride. Results suggest that L-DOPA acting as D2-like agonist inhibits GABA release in the rat globus pallidus and induces turning behavior in rats with unilateral lesions of the dopamine innervation. L-DOPA could control Parkinson's disease symptoms acting not only as dopamine precursor but also by itself.

  1. Intrarenal dopamine D1-like receptor stimulation induces natriuresis via an angiotensin type-2 receptor mechanism.

    PubMed

    Salomone, Leslie J; Howell, Nancy L; McGrath, Helen E; Kemp, Brandon A; Keller, Susanna R; Gildea, John J; Felder, Robin A; Carey, Robert M

    2007-01-01

    We explored the effects of direct renal interstitial stimulation of dopamine D(1)-like receptors with fenoldopam, a selective D(1)-like receptor agonist, on renal sodium excretion and angiotensin type-2 (AT(2)) receptor expression and cellular distribution in rats on a high-sodium intake. In contrast to vehicle-infused rats, sodium excretion increased in fenoldopam-infused rats during each of three 1-hour experimental periods (<0.001). Blood pressure was unaffected by vehicle or fenoldopam. In plasma membranes of renal cortical cells, fenoldopam increased D(1) receptor expression by 38% (P<0.05) and AT(2) receptor expression by 69% (P<0.01). In plasma membranes of renal proximal tubule cells, fenoldopam increased AT(2) receptor expression by 108% (P<0.01). In outer apical membranes of proximal tubule cells, fenoldopam increased AT(2) receptor expression by 59% (P<0.01). No significant change in total AT(2) receptor protein expression was detectable in response to fenoldopam. Fenoldopam-induced natriuresis was abolished when either PD-123319, a specific AT(2) receptor antagonist, or SCH-23390, a potent D(1)-like receptor antagonist, was coinfused with F (P<0.001). In summary, direct renal D(1)-like receptor activation increased urinary sodium excretion and the plasma membrane expression of AT(2) receptors in renal cortical and proximal tubule cells. D(1)-like receptor-induced natriuresis was abolished by intrarenal AT(2) receptor inhibition. These findings suggest that dopaminergic regulation of sodium excretion involves recruitment of AT(2) receptors to the outer plasma membranes of renal proximal tubule cells and that dopamine-induced natriuresis requires AT(2) receptor activation.

  2. Dopamine mediated iron release from ferritin is enhanced at higher temperatures: Possible implications for fever-induced Parkinson's disease

    NASA Astrophysics Data System (ADS)

    Babincová, Melánia; Babinec, Peter

    2005-05-01

    A new molecular mechanism is proposed to explain the pathogenesis of fever-induced Parkinson's disease. This proposal is based on dopamine and 6-hydroxydopamine-mediated free iron release from ferritin magnetic nanoparticles, which is enhanced at higher temperatures, and which may lead to substantial peroxidation and injury of lipid biomembranes of the substantia nigra in the brain.

  3. Dopamine Induces LTP Differentially in Apical and Basal Dendrites through BDNF and Voltage-Dependent Calcium Channels

    ERIC Educational Resources Information Center

    Navakkode, Sheeja; Sajikumar, Sreedharan; Korte, Martin; Soong, Tuck Wah

    2012-01-01

    The dopaminergic modulation of long-term potentiation (LTP) has been studied well, but the mechanism by which dopamine induces LTP (DA-LTP) in CA1 pyramidal neurons is unknown. Here, we report that DA-LTP in basal dendrites is dependent while in apical dendrites it is independent of activation of L-type voltage-gated calcium channels (VDCC).…

  4. Dopamine Induces LTP Differentially in Apical and Basal Dendrites through BDNF and Voltage-Dependent Calcium Channels

    ERIC Educational Resources Information Center

    Navakkode, Sheeja; Sajikumar, Sreedharan; Korte, Martin; Soong, Tuck Wah

    2012-01-01

    The dopaminergic modulation of long-term potentiation (LTP) has been studied well, but the mechanism by which dopamine induces LTP (DA-LTP) in CA1 pyramidal neurons is unknown. Here, we report that DA-LTP in basal dendrites is dependent while in apical dendrites it is independent of activation of L-type voltage-gated calcium channels (VDCC).…

  5. Overexpression of GRK6 rescues L-DOPA-induced signaling abnormalities in the dopamine-depleted striatum of hemiparkinsonian rats.

    PubMed

    Ahmed, M Rafiuddin; Bychkov, Evgeny; Kook, Seunghyi; Zurkovsky, Lilia; Dalby, Kevin N; Gurevich, Eugenia V

    2015-04-01

    l-DOPA therapy in Parkinson's disease often results in side effects such as l-DOPA-induced dyskinesia (LID). Our previous studies demonstrated that defective desensitization of dopamine receptors caused by decreased expression of G protein-coupled receptor kinases (GRKs) plays a role. Overexpression of GRK6, the isoform regulating dopamine receptors, in parkinsonian rats and monkeys alleviated LID and reduced LID-associated changes in gene expression. Here we show that 2-fold lentivirus-mediated overexpression of GRK6 in the dopamine-depleted striatum in rats unilaterally lesioned with 6-hydroxydopamine ameliorated supersensitive ERK response to l-DOPA challenge caused by loss of dopamine. A somewhat stronger effect of GRK6 was observed in drug-naïve than in chronically l-DOPA-treated animals. GRK6 reduced the responsiveness of p38 MAP kinase to l-DOPA challenge rendered supersensitive by dopamine depletion. The JNK MAP kinase was unaffected by loss of dopamine, chronic or acute l-DOPA, or GRK6. Overexpressed GRK6 suppressed enhanced activity of Akt in the lesioned striatum by reducing elevated phosphorylation at its major activating residue Thr(308). Finally, GRK6 reduced accumulation of ΔFosB in the lesioned striatum, the effect that paralleled a decrease in locomotor sensitization to l-DOPA in GRK6-expressing rats. The results suggest that elevated GRK6 facilitate desensitization of DA receptors, thereby normalizing of the activity of multiple signaling pathways implicated in LID. Thus, improving the regulation of dopamine receptor function via the desensitization mechanism could be an effective way of managing LID.

  6. Variations of dopamine, serotonin, and amino acid concentrations in Noda epileptic rat (NER) retina.

    PubMed

    Chanut, Evelyne; Labarthe, Benoît; Lacroix, Brigitte; Noda, Atsuhi; Gasdeblay, Sylvie; Bondier, Jean-Robert; Versaux-Botteri, Claudine

    2006-01-27

    Noda epileptic rats (NER) exhibit frequent spontaneous tonic-clonic convulsions which represent a valuable model of human epilepsy. If implication of brain neurotransmitters was largely reported, little is known about retina. However, it has been reported that human epilepsy syndrome varies not only with the location of seizure foci but also according to rhythmic patterns, for which retina has a major role in the transmission of external light-dark cycle information. The purpose of this work was to evaluate dopamine (DA), DA metabolites, serotonin (5-HT), and amino acid [glutamate, aspartate, glycine, gamma aminobutyric acid (GABA), and taurine] level variations in retina from NER, at two different nycthemeral periods (11 a.m. and 11 p.m.) and at different ages (2, 6, and 12 months). In NER, retinal dopaminergic function was decreased as soon as 2 months, whereas GABA levels were increased, even if no differences among the different ages could be distinguished. These variations were associated to a slight increase in 5-HT. Other amino acids tested were not affected by epilepsy, whereas taurine decreased with aging in NER as well as in control rats. Retinal 5-HT occurs principally as a precursor of melatonin (MEL). A triangular interaction may be hypothesized: MEL could decrease DA synthesis or release by enhancing GABA activity. Taken together, these results suggest that the retinal physiology is affected by the epileptic status and that information transmitted from retina to the brain should be affected by epilepsy in NER.

  7. Does dopamine mediate the psychosis-inducing effects of cannabis? A review and integration of findings across disciplines.

    PubMed

    Kuepper, Rebecca; Morrison, Paul D; van Os, Jim; Murray, Robin M; Kenis, Gunter; Henquet, Cécile

    2010-08-01

    General population epidemiological studies have consistently found that cannabis use increases the risk of developing psychotic disorders in a dose-dependent manner. While the epidemiological signal between cannabis and psychosis has gained considerable attention, the biological mechanism whereby cannabis increases risk for psychosis remains poorly understood. Animal research suggests that delta-9-tetrahydrocannabinol (THC, the main psychoactive component of cannabis) increases dopamine levels in several regions of the brain, including striatal and prefrontal areas. Since dopamine is hypothesized to represent a crucial common final pathway between brain biology and actual experience of psychosis, a focus on dopamine may initially be productive in the examination of the psychotomimetic effects of cannabis. Therefore, this review examines the evidence concerning the interactions between THC, endocannabinoids and dopamine in the cortical as well as subcortical regions implicated in psychosis, and considers possible mechanisms whereby cannabis-induced dopamine dysregulation may give rise to delusions and hallucinations. It is concluded that further study of the mechanisms underlying the link between cannabis and psychosis may be conducted productively from the perspective of progressive developmental sensitization, resulting from gene-environment interactions. Copyright 2010 Elsevier B.V. All rights reserved.

  8. Dopamine improves exploration after expectancy violations and induces psychotic-like experiences in patients with Parkinson's disease.

    PubMed

    Polner, Bertalan; Moustafa, Ahmed A; Nagy, Helga; Takáts, Annamária; Győrfi, Orsolya; Kéri, Szabolcs

    2016-03-11

    Dopamine neurons are sensitive to novel and rewarding events, and dopamine signals can modulate learning in higher-level brain networks. Additionally, dopamine abnormalities appear to be central to the pathophysiology of schizophrenia spectrum disorders. In this study, we investigate the dopaminergic modulation of schizotypal traits and exploration after expectancy violations in Parkinson's disease (PD) patients on dopamine replacement therapy. Exploration after expectancy violations was measured with a latent inhibition and an anomaly categorisation task. Patients with PD had significantly elevated levels of schizotypy and reduced latent inhibition, relative to the controls. Anomaly categorisation was enhanced at trend level among the patients. Dopaminergic antiparkinsonian drugs showed dose-dependent effects: they induced psychotic-like experiences, and at the same time, they disrupted latent inhibition and made categorisation of anomaly more efficient. Most of these findings were replicated in an independent sample of patients with PD. An up-regulated dopamine system in medicated PD patients might tune higher-level brain networks to engage in learning when faced with unexpected information, and therefore hasten the updating of internal models.

  9. Berberine is a dopamine D1- and D2-like receptor antagonist and ameliorates experimentally induced colitis by suppressing innate and adaptive immune responses.

    PubMed

    Kawano, Masaaki; Takagi, Rie; Kaneko, Atsushi; Matsushita, Sho

    2015-12-15

    Berberine is an herbal alkaloid with various biological activities, including anti-inflammatory and antidepressant effects. Here, we examined the effects of berberine on dopamine receptors and the ensuing anti-inflammatory responses. Berberine was found to be an antagonist at both dopamine D1- and D2-like receptors and ameliorates the development of experimentally induced colitis in mice. In lipopolysaccharide-stimulated immune cells, berberine treatment modified cytokine levels, consistent with the effects of the dopamine receptor specific antagonists SCH23390 and L750667. Our findings indicate that dopamine receptor antagonists suppress innate and adaptive immune responses, providing a foundation for their use in combatting inflammatory diseases.

  10. Methamphetamine-induced vascular changes lead to striatal hypoxia and dopamine reduction

    PubMed Central

    Kousik, Sharanya M.; Graves, Steven M.; Napier, T. Celeste; Zhao, Chaohui; Carvey, Paul M.

    2011-01-01

    Methamphetamine (meth) is a potent psychostimulant known to cause neurotoxicity. Clinical reports suggest meth abuse is a risk factor for Parkinson’s disease. We investigated changes in the blood brain barrier and cerebral vasculature as a mechanism underlying this risk in rats treated acutely and trained to self-administer meth. We observed blood brain barrier leakage in rats treated acutely with meth. Hypoperfusion in the striatum was detected with acute and chronic meth treatment and associated with hypoxia. This was correlated with reductions in striatal tyrosine hydroxylase in rats trained to self-administer meth. These findings suggest a new mechanism of meth-induced neurotoxicity involving striatal vasoconstriction resulting in hypoxia and dopamine reductions leading to an increased risk for Parkinson’s disease for meth abusers. PMID:21979424

  11. Dopamine-induced α-synuclein oligomers show self- and cross-propagation properties.

    PubMed

    Planchard, Matthew S; Exley, Sarah E; Morgan, Sarah E; Rangachari, Vijayaraghavan

    2014-10-01

    Amyloid aggregates of α-synuclein (αS) protein are the predominant species present within the intracellular inclusions called Lewy bodies in Parkinson's disease (PD) patients. Among various aggregates, the low-molecular weight ones broadly ranging between 2 and 30 mers are known to be the primary neurotoxic agents responsible for the impairment of neuronal function. Recent research has indicated that the neurotransmitter dopamine (DA) is one of the key physiological agents promoting and augmenting αS aggregation, which is thought to be a significant event in PD pathologenesis. Specifically, DA is known to induce the formation of soluble oligomers of αS, which in turn are responsible for inducing several important cellular changes leading to cellular toxicity. In this report, we present the generation, isolation, and biophysical characterization of five different dopamine-derived αS oligomers (DSOs) ranging between 3 and 15 mers, corroborating previously published reports. More importantly, we establish that these DSOs are also capable of replication by self-propagation, which leads to the replication of DSOs upon interaction with αS monomers, a process similar to that observed in mammilian prions. In addition, DSOs are also able to cross-propagate amyloid-β (Aβ) aggregates involved in Alzheimer's disease (AD). Interestingly, while self-propagation of DSOs occur with no net gain in protein structure, cross-propagation proceeds with an overall gain in β-sheet conformation. These results implicate the involvement of DSOs in the progression of PD, and, in part, provide a molecular basis for the observed co-existence of AD-like pathology among PD patients.

  12. Dopamine-induced α-synuclein oligomers show self- and cross-propagation properties

    PubMed Central

    Planchard, Matthew S; Exley, Sarah E; Morgan, Sarah E; Rangachari, Vijayaraghavan

    2014-01-01

    Amyloid aggregates of α-synuclein (αS) protein are the predominant species present within the intracellular inclusions called Lewy bodies in Parkinson’s disease (PD) patients. Among various aggregates, the low-molecular weight ones broadly ranging between 2 and 30 mers are known to be the primary neurotoxic agents responsible for the impairment of neuronal function. Recent research has indicated that the neurotransmitter dopamine (DA) is one of the key physiological agents promoting and augmenting αS aggregation, which is thought to be a significant event in PD pathologenesis. Specifically, DA is known to induce the formation of soluble oligomers of αS, which in turn are responsible for inducing several important cellular changes leading to cellular toxicity. In this report, we present the generation, isolation, and biophysical characterization of five different dopamine-derived αS oligomers (DSOs) ranging between 3 and 15 mers, corroborating previously published reports. More importantly, we establish that these DSOs are also capable of replication by self-propagation, which leads to the replication of DSOs upon interaction with αS monomers, a process similar to that observed in mammilian prions. In addition, DSOs are also able to cross-propagate amyloid-β (Aβ) aggregates involved in Alzheimer’s disease (AD). Interestingly, while self-propagation of DSOs occur with no net gain in protein structure, cross-propagation proceeds with an overall gain in β-sheet conformation. These results implicate the involvement of DSOs in the progression of PD, and, in part, provide a molecular basis for the observed co-existence of AD-like pathology among PD patients. PMID:25044276

  13. Prefrontocortical dopamine depletion induces antidepressant-like effects in rats and alters the profile of desipramine during Porsolt's test.

    PubMed

    Espejo, E F; Miñano, F J

    1999-01-01

    The objective of this study was to investigate whether bilateral dopamine depletion within the medial prefrontal cortex affects depression state, as well as the antidepressant efficacy of desipramine, in the forced swimming test. The rat's behaviour was evaluated by quantifying duration of immobility, climbing, swimming and diving. Immobility latency was also quantified and proved to be a suitable novel parameter. Monoamine levels within the medial prefrontal cortex were measured by high-performance liquid chromatography during Porsolt's test, as well as one week after it. While Porsolt's test was followed by a typical depression-like profile in sham rats, depletion of prefrontocortical dopamine (86% vs sham controls) reduced immobility and enhanced swimming, which is consistent with a diminished depression tonus. The observed enhancement of swimming was correlated with a high prefrontocortical serotonergic neurotransmission. On the other hand, desipramine induced antidepression-like effects in sham rats by increasing prefrontocortical noradrenaline and serotonin neurotransmisson, but also by blocking the normal increase in dopamine activity during the swimming test. Interestingly, desipramine behaved in a quite different manner in lesioned rats. Thus, immobility duration was not further reduced and only climbing, but not swimming, was enhanced. These effects were correlated with a preferential enhancement of noradrenaline neurotransmission. In conclusion, the results indicate that: (i) dopamine neurotransmission within the medial prefrontal cortex is a factor involved in depression, since dopamine reduction led to a low depression tonus; (ii) desipramine induces antidepression not only by enhancing prefrontocortical noradrenaline and serotonin neurotransmission, but also by blocking the normal increase in dopamine neurotransmission during a depressant situation; (iii) a selective enhancement of prefrontocortical serotonin neurotransmission mediates swimming; and

  14. Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

    PubMed Central

    Gaskill, Peter J.; Yano, Hideaki H.; Kalpana, Ganjam V.; Javitch, Jonathan A.; Berman, Joan W.

    2014-01-01

    Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

  15. Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors.

    PubMed

    Mikhailova, Maria A; Bass, Caroline E; Grinevich, Valentina P; Chappell, Ann M; Deal, Alex L; Bonin, Keith D; Weiner, Jeff L; Gainetdinov, Raul R; Budygin, Evgeny A

    2016-10-01

    Recent optogenetic studies demonstrated that phasic dopamine release in the nucleus accumbens may play a causal role in multiple aspects of natural and drug reward-related behaviors. The role of tonic dopamine release in reward consummatory behavior remains unclear. The current study used a combinatorial viral-mediated gene delivery approach to express ChR2 on mesolimbic dopamine neurons in rats. We used optical activation of this dopamine circuit to mimic tonic dopamine release in the nucleus accumbens and to explore the causal relationship between this form of dopamine signaling within the ventral tegmental area (VTA)-nucleus accumbens projection and consumption of a natural reward. Using a two bottle choice paradigm (sucrose vs. water), the experiments revealed that tonic optogenetic stimulation of mesolimbic dopamine transmission significantly decreased reward consummatory behaviors. Specifically, there was a significant decrease in the number of bouts, licks and amount of sucrose obtained during the drinking session. Notably, activation of VTA dopamine cell bodies or dopamine terminals in the nucleus accumbens resulted in identical behavioral consequences. No changes in water intake were evident under the same experimental conditions. Collectively, these data demonstrate that tonic optogenetic stimulation of VTA-nucleus accumbens dopamine release is sufficient to inhibit reward consummatory behavior, possibly by preventing this circuit from engaging in phasic activity that is thought to be essential for reward-based behaviors. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  16. G-protein coupled receptor 6 deficiency alters striatal dopamine and cAMP concentrations and reduces dyskinesia in a mouse model of Parkinson's disease.

    PubMed

    Oeckl, Patrick; Hengerer, Bastian; Ferger, Boris

    2014-07-01

    The orphan G-protein coupled receptor 6 (GPR6) is a constitutively active receptor which is positively coupled to the formation of cyclic adenosine-3',5'-monophosphate (cAMP). GPR6 is predominantly expressed in striatopallidal neurons. Here, we investigated neurochemical and behavioural effects of Gpr6 deficiency in mice. Gpr6 depletion decreased in vivo cAMP tissue concentrations (20%) in the striatum. An increase of striatal tissue dopamine concentrations (10%) was found in Gpr6(-/-) mice, whereas basal extracellular dopamine levels were not changed compared with Gpr6(+/+) mice, as shown by in vivo microdialysis. Western blot analyses revealed no alteration in the expression and subcellular localisation of the dopamine D2 receptor in the striatum of Gpr6(-/-) mice, and the number of tyrosine hydroxylase positive neurons in the substantia nigra was unchanged. DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32kDa) expression in the striatum of Gpr6(-/-) mice was not altered, however, a twofold increase in the phosphorylation of DARPP-32 at Thr34 was detected in Gpr6(-/-) compared with Gpr6(+/+) mice. Gpr6(-/-) mice showed higher locomotor activity in the open field, which persisted after treatment with the dopamine D2 receptor antagonist haloperidol. They also displayed reduced abnormal involuntary movements after apomorphine and quinpirole treatment in the mouse dyskinesia model of Parkinson's disease. In conclusion, the depletion of Gpr6 reduces cAMP concentrations in the striatum and alters the striatal dopaminergic system. Gpr6 deficiency causes an interesting behavioural phenotype in the form of enhanced motor activity combined with reduced abnormal involuntary movements. These findings could offer an opportunity for the treatment of Parkinson's disease beyond dopamine replacement.

  17. Dopamine is not essential for the development of methamphetamine-induced neurotoxicity

    PubMed Central

    Yuan, Jie; Darvas, Martin; Sotak, Bethany; Hatzidimitriou, George; McCann, Una D; Palmiter, Richard D; Ricaurte, George A

    2010-01-01

    It is widely believed that dopamine (DA) mediates methamphetamine (METH)-induced toxicity to brain dopaminergic neurons, because drugs that interfere with DA neurotransmission decrease toxicity, whereas drugs that increase DA neurotransmission enhance toxicity. However, temperature effects of drugs that have been used to manipulate brain DA neurotransmission confound interpretation of the data. Here we show that the recently reported ability of l-dihydroxyphenylalanine to reverse the protective effect of alpha-methyl-para-tyrosine on METH-induced DA neurotoxicity is also confounded by drug effects on body temperature. Further, we show that mice genetically engineered to be deficient in brain DA develop METH neurotoxicity, as long as the thermic effects of METH are preserved. In addition, we demonstrate that mice genetically engineered to have unilateral brain DA deficits develop METH-induced dopaminergic deficits that are of comparable magnitude on both sides of the brain. Taken together, these findings demonstrate that DA is not essential for the development of METH-induced dopaminergic neurotoxicity and suggest that mechanisms independent of DA warrant more intense investigation. PMID:20533999

  18. Dopamine induces lipid accumulation, NADPH oxidase-related oxidative stress, and a proinflammatory status of the plasma membrane in H9c2 cells.

    PubMed

    Begieneman, Mark P V; Ter Horst, Ellis N; Rijvers, Liza; Meinster, Elisa; Leen, René; Pankras, Jeannette E; Fritz, Jan; Kubat, Bela; Musters, René J P; van Kuilenburg, André B P; Stap, Jan; Niessen, Hans W M; Krijnen, Paul A J

    2016-11-01

    Excess catecholamine levels are suggested to be cardiotoxic and to underlie stress-induced heart failure. The cardiotoxic effects of norepinephrine and epinephrine are well recognized. However, although cardiac and circulating dopamine levels are also increased in stress cardiomyopathy patients, knowledge regarding putative toxic effects of excess dopamine levels on cardiomyocytes is scarce. We now studied the effects of elevated dopamine levels in H9c2 cardiomyoblasts. H9c2 cells were cultured and treated with dopamine (200 μM) for 6, 24, and 48 h. Subsequently, the effects on lipid accumulation, cell viability, flippase activity, reactive oxygen species (ROS) production, subcellular NADPH oxidase (NOX) protein expression, and ATP/ADP and GTP/GDP levels were analyzed. Dopamine did not result in cytotoxic effects after 6 h. However, after 24 and 48 h dopamine treatment induced a significant increase in lipid accumulation, nitrotyrosine levels, indicative of ROS production, and cell death. In addition, dopamine significantly reduced flippase activity and ATP/GTP levels, coinciding with phosphatidylserine exposure on the outer plasma membrane. Furthermore, dopamine induced a transient increase in cytoplasmic and (peri)nucleus NOX1 and NOX4 expression after 24 h that subsided after 48 h. Moreover, while dopamine induced a similar transient increase in cytoplasmic NOX2 and p47(phox) expression, in the (peri)nucleus this increased expression persisted for 48 h where it colocalized with ROS. Exposure of H9c2 cells to elevated dopamine levels induced lipid accumulation, oxidative stress, and a proinflammatory status of the plasma membrane. This can, in part, explain the inflammatory response in patients with stress-induced heart failure.

  19. The Role of Dopamine in Reinforcement: Changes in Reinforcement Sensitivity Induced by D[subscript 1]-Type, D[subscript 2]-Type, and Nonselective Dopamine Receptor Agonists

    ERIC Educational Resources Information Center

    Bratcher, Natalie A.; Farmer-Dougan, Valeri; Dougan, James D.; Heidenreich, Byron A.; Garris, Paul A.

    2005-01-01

    Dose-dependent changes in sensitivity to reinforcement were found when rats were treated with low, moderate, and high doses of the partial dopamine D[subscript 1]-type receptor agonist SKF38393 and with the nonselective dopamine agonist apomorphine, but did not change when rats were treated with similar doses of the selective dopamine D[subscript…

  20. The Role of Dopamine in Reinforcement: Changes in Reinforcement Sensitivity Induced by D[subscript 1]-Type, D[subscript 2]-Type, and Nonselective Dopamine Receptor Agonists

    ERIC Educational Resources Information Center

    Bratcher, Natalie A.; Farmer-Dougan, Valeri; Dougan, James D.; Heidenreich, Byron A.; Garris, Paul A.

    2005-01-01

    Dose-dependent changes in sensitivity to reinforcement were found when rats were treated with low, moderate, and high doses of the partial dopamine D[subscript 1]-type receptor agonist SKF38393 and with the nonselective dopamine agonist apomorphine, but did not change when rats were treated with similar doses of the selective dopamine D[subscript…

  1. Extent of pre-operative L-DOPA-induced dyskinesia predicts the severity of graft-induced dyskinesia after fetal dopamine cell transplantation.

    PubMed

    García, Joanna; Carlsson, Thomas; Döbrössy, Máté; Nikkhah, Guido; Winkler, Christian

    2011-12-01

    Graft-induced dyskinesia has emerged as a problematic side effect after transplantation of fetal dopamine cells into the striatum of patients with Parkinson's disease. These adverse effects of dystonic and choreatiform hyperkinesias that persisted even after withdrawal of L-DOPA medication are not yet fully understood, which poses a main obstacle for the re-initiation of neural transplantation in Parkinson's disease. The severity of pre-operative L-DOPA-induced dyskinesia has been proposed as one of several parameters influencing the development of graft-induced dyskinesia. We have therefore characterized graft-induced dyskinesia in the rat model of Parkinson's disease in animals with either mild or severe pre-operative L-DOPA-induced dyskinesia. We show that animals with intrastriatal grafts of fetal dopamine cells and severe pre-operative L-DOPA-induced dyskinesia will reduce their L-DOPA-induced dyskinesia scores by more than 75% but at the same time develop graft-induced dyskinesia of intermediate to strong severity. In contrast, animals with dopamine grafts of similar size but only mild pre-operative L-DOPA-induced dyskinesia also developed graft-induced dyskinesia but this was very mild and of intermediate severity only in a single animal. Severity of pre-operative L-DOPA-induced dyskinesia was correlated with the severity of graft-induced dyskinesia. Our data suggest that patients with no or only mild L-DOPA-induced dyskinesia may carry a lower risk for the development of graft-induced dyskinesia and therefore are better candidates to receive intracerebral grafts of fetal dopamine cells as compared to patients with more pronounced L-DOPA-induced dyskinesia.

  2. Endogenous glutamate increases extracellular concentrations of dopamine, GABA, and taurine through NMDA and AMPA/kainate receptors in striatum of the freely moving rat: a microdialysis study.

    PubMed

    Segovia, G; Del Arco, A; Mora, F

    1997-10-01

    Interactions between glutamate (Glu), dopamine (DA), GABA, and taurine (Tau) were investigated in striatum of the freely moving rat by using microdialysis. Intrastriatal infusions of the selective Glu uptake inhibitor L-trans-pyrrolidine-3,4-dicarboxylic acid (PDC) were used to increase the endogenous extracellular [Glu]. Correlations between extracellular [Glu] and extracellular [DA], [GABA], and [Tau], and the effects of a selective blockade of ionotropic Glu receptors, were studied. PDC (1, 2, and 4 mM) produced a dose-related increase in extracellular [Glu]. At the highest dose of PDC, [Glu] increased from 1.55 +/- 0.35 to 6.11 +/- 0.88 microM. PDC also increased extracellular [DA], [GABA], and [Tau]. The increasing [Glu] was correlated significantly with increasing [DA], [GABA], and [Tau]. PDC also decreased extracellular concentrations of DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA). Perfusion with the NMDA-receptor antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (1 mM) or the AMPA/kainate-receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) (1 mM) attenuated the increases produced by PDC (4 mM) on [DA], [GABA], and [Tau], and decreases in [DOPAC] and [HVA]. DNQX also attenuated the increases in [Glu] induced by PDC. These data show that endogenous Glu plays a role in modulating the extracellular concentrations of DA, GABA, and Tau in striatum of the freely moving rat.

  3. Pre-Existing Differences and Diet-Induced Alterations in Striatal Dopamine Systems of Obesity-Prone Rats

    PubMed Central

    Vollbrecht, Peter J.; Mabrouk, Omar S.; Nelson, Andrew D.; Kennedy, Robert T.; Ferrario, Carrie R.

    2016-01-01

    Objective Interactions between pre-existing differences in mesolimbic function and neuroadaptations induced by consumption of fatty, sugary foods are thought to contribute to human obesity. This study examined basal and cocaine-induced changes in striatal neurotransmitter levels without diet manipulation and D2/D3 dopamine receptor-mediated transmission prior to and after consumption of “junk-foods” in obesity-prone and obesity-resistant rats. Methods Microdialysis and liquid chromatography-mass spectrometry were used to determine basal and cocaine-induced changes in neurotransmitter levels in real time with cocaine-induced locomotor activity. Sensitivity to the D2/D3 dopamine receptor agonist quinpirole was examined before and after restricted junk-food exposure. Selectively bred obesity-prone and obesity-resistant rats were used. Results Cocaine-induced locomotion was greater in obesity-prone rats versus obesity-resistant rats prior to diet manipulation. Basal and cocaine-induced increases in dopamine and serotonin levels did not differ. Obesity-prone rats were more sensitive to the D2 receptor-mediated effects of quinpirole, and junk-food produced modest alterations in quinpirole sensitivity in obesity-resistant rats. Conclusions These data show that mesolimbic systems differ prior to diet manipulation in susceptible versus resistant rats, and that consumption of fatty, sugary foods produce different neuroadaptations in these populations. These differences may contribute to enhanced food craving and an inability to limit food intake in susceptible individuals. PMID:26847484

  4. Pre-existing differences and diet-induced alterations in striatal dopamine systems of obesity-prone rats.

    PubMed

    Vollbrecht, Peter J; Mabrouk, Omar S; Nelson, Andrew D; Kennedy, Robert T; Ferrario, Carrie R

    2016-03-01

    Interactions between pre-existing differences in mesolimbic function and neuroadaptations induced by consumption of fatty, sugary foods are thought to contribute to human obesity. This study examined basal and cocaine-induced changes in striatal neurotransmitter levels without diet manipulation and D2 /D3 dopamine receptor-mediated transmission prior to and after consumption of "junk-foods" in obesity-prone and obesity-resistant rats. Microdialysis and liquid chromatography-mass spectrometry were used to determine basal and cocaine-induced changes in neurotransmitter levels in real time with cocaine-induced locomotor activity. Sensitivity to the D2 /D3 dopamine receptor agonist quinpirole was examined before and after restricted junk-food exposure. Selectively bred obesity-prone and obesity-resistant rats were used. Cocaine-induced locomotion was greater in obesity-prone rats versus obesity-resistant rats prior to diet manipulation. Basal and cocaine-induced increases in dopamine and serotonin levels did not differ. Obesity-prone rats were more sensitive to the D2 receptor-mediated effects of quinpirole, and junk-food produced modest alterations in quinpirole sensitivity in obesity-resistant rats. These data show that mesolimbic systems differ prior to diet manipulation in susceptible versus resistant rats, and that consumption of fatty, sugary foods produce different neuroadaptations in these populations. These differences may contribute to enhanced food craving and an inability to limit food intake in susceptible individuals. © 2016 The Obesity Society.

  5. Inhibition of titanium-particle-induced inflammatory osteolysis after local administration of dopamine and suppression of osteoclastogenesis via D2-like receptor signaling pathway.

    PubMed

    Yang, Huilin; Xu, Yaozeng; Zhu, Mo; Gu, Ye; Zhang, Wen; Shao, Hongguo; Wang, Yijun; Ping, Zichuan; Hu, Xuanyang; Wang, Liangliang; Geng, Dechun

    2016-02-01

    Chronic inflammation and extensive osteoclast formation play critical roles in wear-debris-induced peri-implant osteolysis. We investigated the potential impact of dopamine on titanium-particle-induced inflammatory osteolysis in vivo and in vitro. Twenty-eight C57BL/6J mice were randomly assigned to four groups: sham control (PBS treatment), titanium (titanium/PBS treatment), low- (titanium/2 μg kg(-1) day(-1) dopamine) and high-dopamine (titanium/10 μg kg(-1) day(-1) dopamine). After 2 weeks, mouse calvariae were collected for micro-computed tomography (micro-CT) and histomorphometry analysis. Bone-marrow-derived macrophages (BMMs) were isolated to assess osteoclast differentiation. Dopamine significantly reduced titanium-particle-induced osteolysis compared with the titanium group as confirmed by micro-CT and histomorphometric data. Osteoclast numbers were 34.9% and 59.7% (both p < 0.01) lower in the low- and high-dopamine-treatment groups, respectively, than in the titanium group. Additionally, low RANKL, tumor necrosis factor-α, interleukin-1β and interleukin-6 immunochemistry staining were noted in dopamine-treatment groups. Dopamine markedly inhibited osteoclast formation, osteoclastogenesis-related gene expression and pro-inflammatory cytokine expression in BMMs in a dose-dependent manner. Moreover, the resorption area was decreased with 10(-9) M and 10(-8) M dopamine to 40.0% and 14.5% (both p < 0.01), respectively. Furthermore, the inhibitory effect of dopamine was reversed by the D2-like-receptor antagonist haloperidol but not by the D1-like-receptor antagonist SCH23390. These results suggest that dopamine therapy could be developed into an effective and safe method for osteolysis-related disease caused by chronic inflammation and excessive osteoclast formation.

  6. Association of amphetamine-induced striatal dopamine release and cortisol responses to psychological stress.

    PubMed

    Wand, Gary S; Oswald, Lynn M; McCaul, Mary E; Wong, Dean F; Johnson, Elizabeth; Zhou, Yun; Kuwabara, Hiroto; Kumar, Anil

    2007-11-01

    Preclinical studies have shown that stress and glucocorticoids increase mesolimbic dopamine (DA) and thereby facilitate psychostimulant self-administration. The relationship between stress-induced cortisol and mesolimbic DA responses to psychostimulants has not been studied in humans. To test the hypotheses that glucocorticoid responses to psychological stress are correlated with DA and subjective responses to psychostimulants in humans, 25 healthy adults (18-29 years) completed the Trier Social Stress Test (TSST) and two positron emission tomography (PET) scans with high-specific [11C]raclopride. The first scan was preceded by intravenous saline and the second by amphetamine (AMPH). Findings showed that stress-induced cortisol levels were positively associated with AMPH-induced DA release in the ventral striatum and other striatal regions. Subjects with higher cortisol responses to stress also reported more positive subjective drug effects with AMPH than subjects with lower responses. The results are consistent with preclinical findings showing an interrelationship between glucocorticoids and mesolimbic DA dynamics, which may influence psychostimulant self-administration in humans.

  7. Dopamine receptors and the persistent neurovascular dysregulation induced by methamphetamine self-administration in rats.

    PubMed

    Kousik, Sharanya M; Napier, T Celeste; Ross, Ryan D; Sumner, D Rick; Carvey, Paul M

    2014-11-01

    Recently abstinent methamphetamine (Meth) abusers showed neurovascular dysregulation within the striatum. The factors that contribute to this dysregulation and the persistence of these effects are unclear. The current study addressed these knowledge gaps. First, we evaluated the brains of rats with a history of Meth self-administration following various periods of forced abstinence. Micro-computed tomography revealed a marked reduction in vessel diameter and vascular volume uniquely within the striatum between 1 and 28 days after Meth self-administration. Microvessels showed a greater impairment than larger vessels. Subsequently, we determined that dopamine (DA) D2 receptors regulated Meth-induced striatal vasoconstriction via acute noncontingent administration of Meth. These receptors likely regulated the response to striatal hypoxia, as hypoxia inducible factor 1α was elevated. Acute Meth exposure also increased striatal levels of endothelin receptor A and decreased neuronal nitric oxide synthase. Collectively, the data provide novel evidence that Meth-induced striatal neurovascular dysregulation involves DA receptor signaling that results in vasoconstriction via endothelin receptor A and nitric oxide signaling. As these effects can lead to hypoxia and trigger neuronal damage, these findings provide a mechanistic explanation for the selective striatal toxicity observed in the brains of Meth-abusing humans. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  8. The Unique Dopamine/Ecdysteroid Receptor Modulates Ethanol-Induced Sedation in Drosophila

    PubMed Central

    Petruccelli, Emily; Li, Qi; Rao, Yi

    2016-01-01

    Steroids profoundly influence behavioral responses to alcohol by activating canonical nuclear hormone receptors and exerting allosteric effects on ion channels. Accumulating evidence has demonstrated that steroids can also trigger biological effects by directly binding G-protein-coupled receptors (GPCRs), yet physiological roles of such unconventional steroid signaling in controlling alcohol-induced behaviors remain unclear. The dopamine/ecdysteroid receptor (DopEcR) is a GPCR that mediates nongenomic actions of ecdysteroids, the major steroid hormones in insects. Here, we report that Drosophila DopEcR plays a critical role in ethanol-induced sedation. DopEcR mutants took longer than control flies to become sedated during exposure to ethanol, despite having normal ethanol absorption or metabolism. RNAi-mediated knockdown of DopEcR expression revealed that this receptor is necessary after eclosion, and is required in particular neuronal subsets, including cholinergic and peptidergic neurons, to mediate this behavior. Additionally, flies ubiquitously overexpressing DopEcR cDNA had a tendency to become sedated quickly upon ethanol exposure. These results indicate that neuronal subset-specific expression of DopEcR in adults is required for normal sedation upon exposure to ethanol. We also obtained evidence indicating that DopEcR may promote ethanol sedation by suppressing epidermal growth factor receptor/extracellular signal-regulated kinase signaling. Last, genetic and pharmacological analyses suggested that in adult flies ecdysone may serve as an inverse agonist of DopEcR and suppress the sedation-promoting activity of DopEcR in the context of ethanol exposure. Our findings provide the first evidence for the involvement of nongenomic G-protein-coupled steroid receptors in the response to alcohol, and shed new light on the potential roles of steroids in alcohol-use disorders. SIGNIFICANCE STATEMENT Alcohol abuse is an alarming personal and societal burden. The

  9. The novel nonapeptide acein targets angiotensin converting enzyme in the brain and induces dopamine release

    PubMed Central

    Neasta, Jérémie; Valmalle, Charlène; Coyne, Anne‐Claire; Carnazzi, Eric; Subra, Gilles; Galleyrand, Jean‐Claude; Gagne, Didier; M'Kadmi, Céline; Bernad, Nicole; Bergé, Gilbert; Cantel, Sonia; Marin, Philippe; Marie, Jacky; Banères, Jean‐Louis; Kemel, Marie‐Lou; Daugé, Valérie; Puget, Karine

    2016-01-01

    Background and Purpose Using an in‐house bioinformatics programme, we identified and synthesized a novel nonapeptide, H‐Pro‐Pro‐Thr‐Thr‐Thr‐Lys‐Phe‐Ala‐Ala‐OH. Here, we have studied its biological activity, in vitro and in vivo, and have identified its target in the brain. Experimental Approach The affinity of the peptide was characterized using purified whole brain and striatal membranes from guinea pigs and rats . Its effect on behaviour in rats following intra‐striatal injection of the peptide was investigated. A photoaffinity UV cross‐linking approach combined with subsequent affinity purification of the ligand covalently bound to its receptor allowed identification of its target. Key Results The peptide bound with high affinity to a single class of binding sites, specifically localized in the striatum and substantia nigra of brains from guinea pigs and rats. When injected within the striatum of rats, the peptide stimulated in vitro and in vivo dopamine release and induced dopamine‐like motor effects. We purified the target of the peptide, a ~151 kDa protein that was identified by MS/MS as angiotensin converting enzyme (ACE I). Therefore, we decided to name the peptide acein. Conclusion and Implications The synthetic nonapeptide acein interacted with high affinity with brain membrane‐bound ACE. This interaction occurs at a different site from the active site involved in the well‐known peptidase activity, without modifying the peptidase activity. Acein, in vitro and in vivo, significantly increased stimulated release of dopamine from the brain. These results suggest a more important role for brain ACE than initially suspected. PMID:27027724

  10. Pergolide inhibition of calcium-induced /sup 3/H-dopamine release from striatal synaptosomes

    SciTech Connect

    Bowyer, J.F.; Weiner, N.

    1986-03-05

    Several investigators have reported that dopamine agonists or antagonists are unable to modulate the K/sup +/-evoked release of /sup 3/H-dopamine (/sup 3/H-DA) from striatal synaptosomes. To further assess the role of DA in regulating its release, they have examined the effects of pergolide on Ca/sup + +/ (1.25 mM)-evoked release of /sup 3/H-DA from partially K/sup +/-depolarized striatal synaptosomes. Synaptosomes (P2 pellet) were isolated from rat striatum and incubated for 5 min at 37/sup 0/C in a Ca/sup + +/-free Krebs-Ringer buffer containing 25 nM /sup 3/H-DA. After radiolabeling, the synaptosomes were superfused for 12 min with Ca/sup + +/-free 6 mM Krebs-Ringer buffer to determine basal release of /sup 3/H-DA. Synaptosomes were then exposed to test drugs for 8 min prior to Ca/sup + +/ challenge. Ca/sup + +/ addition resulted in a 3-fold increase in /sup 3/H-DA release within 2-4 min. Pergolide inhibited the release of /sup 3/H-DA in a concentration-dependent manner. Release was inhibited to 56% of control by 10 nM pergolide. This was largely reversed by 0.1 ..mu..M S-sulpiride. Ca/sup + +/-evoked release was inhibited over 70% by 1 ..mu..M tetrodotoxin (TTX), indicating that voltage-dependent Na/sup +/ channels may play a role in the release process. The combination of pergolide and TTX inhibited release to a degree similar to TTX alone. These results suggest that pergolide may inhibit /sup 3/H-DA release by a TTX-sensitive mechanism and that the dopaminergic autoreceptors may be linked to voltage-sensitive Na/sup +/ channels.

  11. The antipsychotic aripiprazole induces antinociceptive effects: Possible role of peripheral dopamine D2 and serotonin 5-HT1A receptors.

    PubMed

    Almeida-Santos, Ana F; Ferreira, Renata C M; Duarte, Igor D; Aguiar, Daniele C; Romero, Thiago R L; Moreira, Fabricio A

    2015-10-15

    Aripiprazole is an antipsychotic that acts by multiple mechanisms, including partial agonism at dopamine D2 and serotonin 5-HT1A receptors. Since these neurotransmitters also modulate pain and analgesia, we tested the hypothesis that systemic or local administration of aripiprazole induces antinociceptive responses. Systemic aripiprazole (0.1-10 mg/kg; i.p.) injection in mice inhibited formalin-induced paw licking and PGE2-induced hyperalgesia in the paw pressure test. This effect was mimicked by intra-plantar administration (12.5-100 µg/paw) in the ipsi, but not contralateral, paw. The peripheral action of aripiprazole (100 µg/paw) was reversed by haloperidol (0.1-10 µg/paw), suggesting the activation of dopamine receptors as a possible mechanism. Accordingly, quinpirole (25-100 µg/paw), a full agonist at D2/D3 receptors, also reduced nociceptive responses.. In line with the partial agoniztic activity of aripiprazole, low dose of this compound inhibited the effect of quinpirole (both at 25 µg/paw). Finally, peripheral administration of NAN-190 (0.1-10 μg/paw), a 5-HT1A antagonist, also prevented aripiprazole-induced antinociception. In conclusion, systemic or local administration of aripiprazole induces antinociceptive effects. Similar to its antipsychotic activity, the possible peripheral mechanism involves dopamine D2 and serotoninergic 5-HT1A receptors. Aripiprazole and other dopaminergic modulators should be further investigated as new treatments for certain types of pain.

  12. The effects of lobeline and naltrexone on methamphetamine-induced place preference and striatal dopamine and serotonin levels in adolescent rats with a history of maternal separation.

    PubMed

    Dimatelis, J J; Russell, V A; Stein, D J; Daniels, W M

    2012-09-01

    Exposure to early life stress has been suggested to increase an individual's vulnerability to methamphetamine (MA) dependence. Although there is no cure for drug dependence, the opioid and vesicular monoamine transporter 2 (VMAT2) systems may be useful targets for treatment insofar as they play pivotal roles in the neurochemistry of addiction. Here we investigated the effects of naltrexone (opioid antagonist) and lobeline (VMAT2 inhibitor) on MA-induced place preference in adolescent rodents subjected to early life trauma (maternal separation, MS) and controls, as well as the effects on dopamine and serotonin levels in the striatum. We found: (1) maternal separation attenuated methamphetamine-induced place preference; (2) lobeline and naltrexone treatment had differential effects on serotonin and dopamine concentrations in the striatum, naltrexone increased serotonin levels in the maternally separated animals. The hypothesized effect of early adversity increasing MA-induced place preference may not be apparent in adolescence. However the data are consistent with the hypothesis that early life stress influences neurochemical pathways that predispose an individual to drug dependence.

  13. Methamphetamine-induced dopamine terminal deficits in the nucleus accumbens are exacerbated by reward-associated cues and attenuated by CB1 receptor antagonism.

    PubMed

    Loewinger, Gabriel C; Beckert, Michael V; Tejeda, Hugo A; Cheer, Joseph F

    2012-06-01

    Methamphetamine (METH) exposure is primarily associated with deleterious effects to dopaminergic neurons. While several studies have implicated the endocannabinoid system in METH's locomotor, rewarding and neurochemical effects, a role for this signaling system in METH's effects on dopamine terminal dynamics has not been elucidated. Given that CB1 receptor blockade reduces the acute potentiation of phasic extracellular dopamine release from other psychomotor stimulant drugs and that the degree of acute METH-induced increases in extracellular dopamine levels is related to the severity of dopamine depletion, we predicted that pretreatment with the CB1 receptor antagonist rimonabant would reduce METH-induced alterations at dopamine terminals. Furthermore, we hypothesized that administration of METH in environments where reward associated-cues were present would potentiate METH's acute effects on dopamine release in the nucleus accumbens and exacerbate changes in dopamine terminal activity. Fast-scan cyclic voltammetry was used to measure electrically-evoked dopamine release in the nucleus accumbens and revealed markers of compromised dopamine terminal integrity nine days after a single dose of METH. These were exacerbated in animals that received METH in the presence of reward-associated cues, and attenuated in rimonabant-pretreated animals. While these deficits in dopamine dynamics were associated with reduced operant responding on days following METH administration in animals treated with only METH, rimonabant-pretreated animals exhibited levels of operant responding comparable to control. Moreover, dopamine release correlated significantly with changes in lever pressing behavior that occurred on days following METH administration. Together these data suggest that the endocannabinoid system is involved in the subsecond dopaminergic response to METH.

  14. METHAMPHETAMINE-INDUCED DOPAMINE TERMINAL DEFICITS IN THE NUCLEUS ACCUMBENS ARE EXACERBATED BY REWARD-ASSOCIATED CUES AND ATTENUATED BY CB1 RECEPTOR ANTAGONISM

    PubMed Central

    Loewinger, Gabriel C.; Beckert, Michael V.; Tejeda, Hugo A.; Cheer, Joseph F.

    2012-01-01

    Methamphetamine (METH) exposure is primarily associated with deleterious effects to dopaminergic neurons. While several studies have implicated the endocannabinoid system in METH’s locomotor, rewarding and neurochemical effects, a role for this signaling system in METH’s effects on dopamine terminal dynamics has not been elucidated. Given that CB1 receptor blockade reduces the acute potentiation of phasic extracellular dopamine release from other psychomotor stimulant drugs and that the degree of acute METH-induced increases in extracellular dopamine levels is related to the severity of dopamine depletion, we predicted that pretreatment with the CB1 receptor antagonist rimonabant would reduce METH-induced alterations at dopamine terminals. Furthermore, we hypothesized that administration of METH in environments where reward associated-cues were present would potentiate METH’s acute effects on dopamine release in the nucleus accumbens and exacerbate changes in dopamine terminal activity. Fast-scan cyclic voltammetry was used to measure electrically-evoked dopamine release in the nucleus accumbens and revealed markers of compromised dopamine terminal integrity nine days after a single dose of METH. These were exacerbated in animals that received METH in the presence of reward-associated cues, and attenuated in rimonabant-pretreated animals. While these deficits in dopamine dynamics were associated with reduced operant responding on days following METH administration in animals treated with only METH, rimonabant-pretreated animals exhibited levels of operant responding comparable to control. Moreover, dopamine release correlated significantly with changes in lever pressing behavior that occurred on days following METH administration. Together these data suggest that the endocannabinoid system is involved in the subsecond dopaminergic response to METH. PMID:22306525

  15. Greater Ethanol-Induced Locomotor Activation in DBA/2J versus C57BL/6J Mice Is Not Predicted by Presynaptic Striatal Dopamine Dynamics

    PubMed Central

    Rose, Jamie H.; Calipari, Erin S.; Mathews, Tiffany A.; Jones, Sara R.

    2013-01-01

    A large body of research has aimed to determine the neurochemical factors driving differential sensitivity to ethanol between individuals in an attempt to find predictors of ethanol abuse vulnerability. Here we find that the locomotor activating effects of ethanol are markedly greater in DBA/2J compared to C57BL/6J mice, although it is unclear as to what neurochemical differences between strains mediate this behavior. Dopamine elevations in the nucleus accumbens and caudate-putamen regulate locomotor behavior for most drugs, including ethanol; thus, we aimed to determine if differences in these regions predict strain differences in ethanol-induced locomotor activity. Previous studies suggest that ethanol interacts with the dopamine transporter, potentially mediating its locomotor activating effects; however, we found that ethanol had no effects on dopamine uptake in either strain. Ex vivo voltammetry allows for the determination of ethanol effects on presynaptic dopamine terminals, independent of drug-induced changes in firing rates of afferent inputs from either dopamine neurons or other neurotransmitter systems. However, differences in striatal dopamine dynamics did not predict the locomotor-activating effects of ethanol, since the inhibitory effects of ethanol on dopamine release were similar between strains. There were differences in presynaptic dopamine function between strains, with faster dopamine clearance in the caudate-putamen of DBA/2J mice; however, it is unclear how this difference relates to locomotor behavior. Because of the role of the dopamine system in reinforcement and reward learning, differences in dopamine signaling between the strains could have implications for addiction-related behaviors that extend beyond ethanol effects in the striatum. PMID:24349553

  16. L-DOPA Reverses the Increased Free Amino Acids Tissue Levels Induced by Dopamine Depletion and Rises GABA and Tyrosine in the Striatum.

    PubMed

    Solís, Oscar; García-Sanz, Patricia; Herranz, Antonio S; Asensio, María-José; Moratalla, Rosario

    2016-07-01

    Perturbations in the cerebral levels of various amino acids are associated with neurological disorders, and previous studies have suggested that such alterations have a role in the motor and non-motor symptoms of Parkinson's disease. However, the direct effects of chronic L-DOPA treatment, that produces dyskinesia, on neural tissue amino acid concentrations have not been explored in detail. To evaluate whether striatal amino acid concentrations are altered in peak dose dyskinesia, 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian mice were treated chronically with L-DOPA and tissue amino acid concentrations were assessed by HPLC analysis. These experiments revealed that neither 6-OHDA nor L-DOPA treatment are able to alter glutamate in the striatum. However, glutamine increases after 6-OHDA and returns back to normal levels with L-DOPA treatment, suggesting increased striatal glutamatergic transmission with lack of dopamine. In addition, glycine and taurine levels are increased following dopamine denervation and restored to normal levels by L-DOPA. Interestingly, dyskinetic animals showed increased levels of GABA and tyrosine, while aspartate striatal tissue levels are not altered. Overall, our results indicate that chronic L-DOPA treatment, besides normalizing the altered levels of some amino acids after 6-OHDA, robustly increases striatal GABA and tyrosine levels which may in turn contribute to the development of L-DOPA-induced dyskinesia.

  17. The newly synthesized pool of dopamine determines the severity of methamphetamine-induced neurotoxicity

    PubMed Central

    Thomas, David M.; Francescutti-Verbeem, Dina M.; Kuhn, Donald M.

    2009-01-01

    The neurotransmitter dopamine (DA) has long been implicated as a participant in the neurotoxicity caused by methamphetamine (METH), yet, its mechanism of action in this regard is not fully understood. Treatment of mice with the tyrosine hydroxylase (TH) inhibitor α-methyl-p-tyrosine (AMPT) lowers striatal cytoplasmic DA content by 55% and completely protects against METH-induced damage to DA nerve terminals. Reserpine, by disrupting vesicle amine storage, depletes striatal DA by more than 95% and accentuates METH-induced neurotoxicity. L-DOPA reverses the protective effect of AMPT against METH and enhances neurotoxicity in animals with intact TH. Inhibition of MAO-A by clorgyline increases pre-synaptic DA content and enhances METH striatal neurotoxicity. In all conditions of altered pre-synaptic DA homeostasis, increases or decreases in METH neurotoxicity paralleled changes in striatal microglial activation. Mice treated with AMPT, L-DOPA, or clorgyline + METH developed hyperthermia to the same extent as animals treated with METH alone, whereas mice treated with reserpine + METH were hypothermic, suggesting that the effects of alterations in cytoplasmic DA on METH neurotoxicity were not strictly mediated by changes in core body temperature. Taken together, the present data reinforce the notion that METH-induced release of DA from the newly synthesized pool of transmitter into the extracellular space plays an essential role in drug-induced striatal neurotoxicity and microglial activation. Subtle alterations in intracellular DA content can lead to significant enhancement of METH neurotoxicity. Our results also suggest that reactants derived from METH-induced oxidation of released DA may serve as neuronal signals that lead to microglial activation early in the neurotoxic process associated with METH. PMID:18088364

  18. The newly synthesized pool of dopamine determines the severity of methamphetamine-induced neurotoxicity.

    PubMed

    Thomas, David M; Francescutti-Verbeem, Dina M; Kuhn, Donald M

    2008-05-01

    The neurotransmitter dopamine (DA) has long been implicated as a participant in the neurotoxicity caused by methamphetamine (METH), yet, its mechanism of action in this regard is not fully understood. Treatment of mice with the tyrosine hydroxylase (TH) inhibitor alpha-methyl-p-tyrosine (AMPT) lowers striatal cytoplasmic DA content by 55% and completely protects against METH-induced damage to DA nerve terminals. Reserpine, by disrupting vesicle amine storage, depletes striatal DA by more than 95% and accentuates METH-induced neurotoxicity. l-DOPA reverses the protective effect of AMPT against METH and enhances neurotoxicity in animals with intact TH. Inhibition of MAO-A by clorgyline increases pre-synaptic DA content and enhances METH striatal neurotoxicity. In all conditions of altered pre-synaptic DA homeostasis, increases or decreases in METH neurotoxicity paralleled changes in striatal microglial activation. Mice treated with AMPT, l-DOPA, or clorgyline + METH developed hyperthermia to the same extent as animals treated with METH alone, whereas mice treated with reserpine + METH were hypothermic, suggesting that the effects of alterations in cytoplasmic DA on METH neurotoxicity were not strictly mediated by changes in core body temperature. Taken together, the present data reinforce the notion that METH-induced release of DA from the newly synthesized pool of transmitter into the extracellular space plays an essential role in drug-induced striatal neurotoxicity and microglial activation. Subtle alterations in intracellular DA content can lead to significant enhancement of METH neurotoxicity. Our results also suggest that reactants derived from METH-induced oxidation of released DA may serve as neuronal signals that lead to microglial activation early in the neurotoxic process associated with METH.

  19. Basal ganglia circuit loops, dopamine and motivation: A review and enquiry

    PubMed Central

    Ikemoto, Satoshi; Yang, Chen; Tan, Aaron

    2015-01-01

    Dopamine neurons located in the midbrain play a role in motivation that regulates approach behavior (approach motivation). In addition, activation and inactivation of dopamine neurons regulate mood and induce reward and aversion, respectively. Accumulating evidence suggests that such motivational role of dopamine neurons is not limited to those located in the ventral tegmental area, but also in the substantia nigra. The present paper reviews previous rodent work concerning dopamine’s role in approach motivation and the connectivity of dopamine neurons, and proposes two working models: One concerns the relationship between extracellular dopamine concentration and approach motivation. High, moderate and low concentrations of extracellular dopamine induce euphoric, seeking and aversive states, respectively. The other concerns circuit loops involving the cerebral cortex, basal ganglia, thalamus, epithalamus, and midbrain through which dopaminergic activity alters approach motivation. These models should help to generate hypothesis-driven research and provide insights for understanding altered states associated with drugs of abuse and affective disorders. PMID:25907747

  20. Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson’s disease model

    PubMed Central

    Choi, Won-Seok; Palmiter, Richard D.

    2011-01-01

    Mitochondrial complex I dysfunction is regarded as underlying dopamine neuron death in Parkinson’s disease models. However, inactivation of the Ndufs4 gene, which compromises complex I activity, does not affect the survival of dopamine neurons in culture or in the substantia nigra pars compacta of 5-wk-old mice. Treatment with piericidin A, a complex I inhibitor, does not induce selective dopamine neuron death in either Ndufs4+/+ or Ndufs4−/− mesencephalic cultures. In contrast, rotenone, another complex I inhibitor, causes selective toxicity to dopamine neurons, and Ndufs4 inactivation potentiates this toxicity. We identify microtubule depolymerization and the accumulation of cytosolic dopamine and reactive oxygen species as alternative mechanisms underlying rotenone-induced dopamine neuron death. Enhanced rotenone toxicity to dopamine neurons from Ndufs4 knockout mice may involve enhanced dopamine synthesis caused by the accumulation of nicotinamide adenine dinucleotide reduced. Our results suggest that the combination of disrupting microtubule dynamics and inhibiting complex I, either by mutations or exposure to toxicants, may be a risk factor for Parkinson’s disease. PMID:21383081

  1. Gamma-vinyl GABA inhibits methamphetamine, heroin, or ethanol-induced increases in nucleus accumbens dopamine.

    PubMed

    Gerasimov, M R; Ashby, C R; Gardner, E L; Mills, M J; Brodie, J D; Dewey, S L

    1999-10-01

    We examined the acute effect of the irreversible GABA-transaminase inhibitor, gamma-vinyl GABA (GVG, Sabril((R)), Vigabatrin((R))) on increases in nucleus accumbens (NAc) dopamine (DA) following acute administration of methamphetamine, heroin, or ethanol. Methamphetamine (2.5 mg/kg) produced a dose-dependent increase (2, 700%) in NAc DA. GVG preadministration (300 or 600 mg/kg), however, inhibited this response by approximately 39 and 61%, respectively. The lower dose of methamphetamine (1.25 mg/kg), increased DA by 1, 700%. This response was inhibited to a similar extent (44%) regardless of the GVG dose preadministered (300 or 600 mg/kg). In addition, heroin-induced increases in NAc DA (0.5 mg/kg, 170%) were inhibited or completely abolished by GVG (150 or 300 mg/kg, 65 and 100%, respectively). Finally, at half the dose necessary for heroin, GVG (150 mg/kg) also completely abolished ethanol-induced increases in NAc DA following a 0.25 g/kg challenge dose (140%). Taken with our previous findings using nicotine or cocaine as the challenge drug, these results indicate that GVG attenuates increases in NAc DA by a mechanism common to many drugs of abuse. However, it appears unlikely that an acute dose of GVG can completely inhibit increases in NAc DA following challenges with a drug whose mechanism of action is mediated primarily through the DA reuptake site.

  2. Organophosphates dysregulate dopamine signaling, glutamatergic neurotransmission, and induce neuronal injury markers in striatum

    PubMed Central

    Torres-Altoro, Melissa I.; Mathur, Brian N.; Drerup, Justin M.; Thomas, Rachel; Lovinger, David; O’Callaghan, James P.; Bibb, James A.

    2011-01-01

    The neurological effects of organophosphate pesticides, commonly used on foods and in households, are an important public health concern. Furthermore, subclinical exposure to combinations of organophosphates is implicated in Gulf War illness. Here we characterized the effects of the broadly-used insecticide chlorpyrifos on dopamine and glutamatergic neurotransmission effectors in corticostriatal motor/reward circuitry. Chlorpyrifos potentiated PKA-dependent phosphorylation of the striatal protein DARPP-32 and the GluR1 subunit of AMPA receptors in mouse brain slices. It also increased GluR1 phosphorylation by PKA when administered systemically. This correlated with enhanced glutamate release from cortical projections in rat striatum. Similar effects were induced by the sarin congener, diisopropyl fluorophosphate, alone or in combination with the putative neuroprotectant, pyridostigmine bromide and the pesticide DEET. This combination, meant to mimic the neurotoxicant exposure encountered by veterans of the 1991 Persian Gulf War, also induced hyperphosphorylation of the neurofibrillary tangle-associated protein tau. Diisopropyl fluorophosphate and pyrodostigmine bromide, alone or in combination, also increased the aberrant activity of the protein kinase, Cdk5, as indicated by conversion of its activating cofactor p35 to p25. Thus consistent with recent findings in humans and animals, organophosphate exposure causes dysregulation in the motor/reward circuitry and invokes mechanisms associated with neurological disorders and neurodegeneration. PMID:21848865

  3. Vitamin D3: A Role in Dopamine Circuit Regulation, Diet-Induced Obesity, and Drug Consumption123

    PubMed Central

    Land, Benjamin B.; Wickham, Robert J.; Maldonado-Aviles, Jaime; de Araujo, Ivan E.; Addy, Nii A.

    2016-01-01

    Abstract The influence of micronutrients on dopamine systems is not well defined. Using mice, we show a potential role for reduced dietary vitamin D3 (cholecalciferol) in promoting diet-induced obesity (DIO), food intake, and drug consumption while on a high fat diet. To complement these deficiency studies, treatments with exogenous fully active vitamin D3 (calcitriol, 10 µg/kg, i.p.) were performed. Nondeficient mice that were made leptin resistant with a high fat diet displayed reduced food intake and body weight after an acute treatment with exogenous calcitriol. Dopamine neurons in the midbrain and their target neurons in the striatum were found to express vitamin D3 receptor protein. Acute calcitriol treatment led to transcriptional changes of dopamine-related genes in these regions in naive mice, enhanced amphetamine-induced dopamine release in both naive mice and rats, and increased locomotor activity after acute amphetamine treatment (2.5 mg/kg, i.p.). Alternatively, mice that were chronically fed either the reduced D3 high fat or chow diets displayed less activity after acute amphetamine treatment compared with their respective controls. Finally, high fat deficient mice that were trained to orally consume liquid amphetamine (90 mg/L) displayed increased consumption, while nondeficient mice treated with calcitriol showed reduced consumption. Our findings suggest that reduced dietary D3 may be a contributing environmental factor enhancing DIO as well as drug intake while eating a high fat diet. Moreover, these data demonstrate that dopamine circuits are modulated by D3 signaling, and may serve as direct or indirect targets for exogenous calcitriol. PMID:27257625

  4. Dopamine agonist-induced substance addiction: the next piece of the puzzle.

    PubMed

    Evans, Andrew

    2011-02-01

    Traditional antiparkinson treatment strategies strive to balance the antiparkinson effects of dopaminergic drugs with the avoidance of motor response complications. Dopamine agonists have an established role in delaying the emergence of motor response complications or reducing motor "off" periods. The recent recognition of a range of "behavioural addictions" that are linked to dopamine agonist use has highlighted the role of dopamine in brain reward function and addiction disorders in general. Dopamine agonists have now even been linked occasionally to new substance addictions. The challenge now for the Parkinsonologist is to also balance the net benefits of using dopamine agonists for their motor effects with avoiding the harm from behavioural compulsions. Copyright © 2010 Elsevier Ltd. All rights reserved.

  5. Impact of dopamine versus serotonin cell transplantation for the development of graft-induced dyskinesia in a rat Parkinson model.

    PubMed

    García, Joanna; Carlsson, Thomas; Döbrössy, Máté; Nikkhah, Guido; Winkler, Christian

    2012-08-27

    Graft-induced dyskinesia (GID), covering a range of dystonic and choreiform involuntary movements, has been observed in some patients with Parkinson's disease (PD) after intracerebral cell transplantation. These dyskinesias have been severe in a number of patients and represent one of the main obstacles for further development of the cell therapy in PD. Serotonin neurons, included into the dopaminergic cell suspension due to the nature of the dissection process, have been suggested as a key factor for the development of GID, since the administration of the serotonin (5-HT)(1A)-receptor agonist buspirone reduced dyskinesia in transplanted PD patients. In the present study, we characterized GID in the rat PD model after transplantation of dopaminergic grafts containing different amounts of serotonin neurons. The severity of GID was significantly correlated with the amount of grafted dopamine and serotonin neurons, but the r-values were low. However, neither the innervation density of dopamine and serotonin fibers in the grafted striatum nor the dopamine-to-serotonin cell ratio correlated significantly with the severity of GID. The results extend prior knowledge of the role of dopaminergic grafts in the development of GID and show that, in the animal model, serotonin neurons within the graft suspension might be involved, but given sufficient dopamine cells, their impact on GID may be minor.

  6. Evidence against an essential role of endogenous brain dopamine in methamphetamine-induced dopaminergic neurotoxicity.

    PubMed

    Yuan, J; Callahan, B T; McCann, U D; Ricaurte, G A

    2001-06-01

    The present studies examined the role of endogenous dopamine (DA) in methamphetamine (METH)-induced dopaminergic neurotoxicity while controlling for temperature-related neuroprotective effects of the test compounds, reserpine and alpha-methyl-p-tyrosine (AMPT). To determine if the vesicular pool of DA was essential for the expression of METH-induced DA neurotoxicity, reserpine (3 mg/kg, given iintraperitoneally 24-26 h prior to METH) was given prior to a toxic dose regimen of METH. Despite severe striatal DA deficits during the period of METH exposure, mice treated with reserpine prior to METH developed long-term reductions in striatal DA axonal markers, suggesting that vesicular DA stores were not crucial for the development of METH neurotoxicity, but leaving open the possibility that cytoplasmic DA might be involved. To evaluate this possibility, cytoplasmic DA stores were depleted with AMPT prior to METH administration. When this study was carried out at 28 degrees C, complete neuroprotection was observed, likely due to lingering effects on core temperature because when the same study was repeated at 33 degrees C (to eliminate AMPT's hypothermic effect in METH-treated animals), the previously observed neuroprotection was no longer evident. In the third and final set of experiments, mice were pretreated with a combination of reserpine and AMPT, to deplete both vesicular and cytoplasmic DA pools, and to reduce striatal DA levels to negligible values during the period of METH administration (< 0.05%). When core temperature differences were eliminated by raising ambient temperature, METH-induced DA neurotoxic changes were evident in mice pretreated with reserpine and AMPT. Collectively, these findings bring into question the view that endogenous DA plays an essential role in METH-induced DA neurotoxicity.

  7. Protective effects of glutathione and cysteine on the methylmercury-induced striatal dopamine release in vivo.

    PubMed

    Faro, L R F; do Nascimento, J L M; Campos, F; Vidal, L; Alfonso, M; Durán, R

    2005-06-10

    The possible protective effects of glutathione (GSH), cysteine (CYS) and methionine (MET) on the Methylmercury (MeHg)-induced dopamine (DA) release from rat striatum were investigated using in vivo microdialysis coupled to HPLC with electrochemical detection. Intrastriatal infusion of MeHg 400 microM increased extracellular DA levels to 1941 +/- 199% in terms of basal levels. Infusion of MeHg 400 microM in GSH 400 microM pretreated animals, only increased striatal DA levels to 465 +/- 104%, in terms of basal levels, this increase being 76% lower than induced by MeHg alone. Conversely, the infusion of MeHg 400 microM after infusion of GSH 400 microM increased DA levels to 1019 +/- 96% in terms of basal levels, this increase being 47.5% lower than that observed in MeHg non-pretreated animals. The infusion of MeHg 400 microM in CYS 400 microM -pretreated animals, increased striatal DA levels to 740 +/- 149%, in terms of basal levels, this increase being 62% lower than that induced by MeHg in non-pretreated animals. The infusion of MeHg 400 microM in MET 400 microM pretreated animals increased striatal DA levels to 2011 +/- 230% in terms of basal, an increase that was not significantly different from that produced by MeHg 400 muM alone. In summary, the administration of compounds containing free -SH groups prevented the MeHg-induced DA release from rat striatum, probably due to the binding of MeHg to -SH groups. This would result in a lower metal availability to interact with -SH membrane proteins groups, which would decrease MeHg ability to interact with DA transporter.

  8. 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

    2016-12-08

    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.

  9. Blockade of the dorsal hippocampal dopamine D1 receptors inhibits the scopolamine-induced state-dependent learning in rats.

    PubMed

    Piri, M; Rostampour, M; Nasehi, M; Zarrindast, M R

    2013-11-12

    In the present study, we investigated the possible role of the dorsal hippocampal (CA1) dopamine D1 receptors on scopolamine-induced amnesia as well as scopolamine state-dependent memory in adult male Wistar rats. Animals were bilaterally implanted with chronic cannulae in the CA1 regions of the dorsal hippocampus, trained in a step-through type inhibitory avoidance task, and tested 24h after training for their step-through latency. Results indicated that pre-training or pre-test intra-CA1 administration of scopolamine (1.5 and 3 μg/rat) dose-dependently reduced the step-through latency, showing an amnestic response. The pre-training scopolamine-induced amnesia (3 μg/rat) was reversed by the pre-test administration of scopolamine, indicating a state-dependent effect. Similarly, the pre-test administration of dopamine D1 receptor agonist, 1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF38393; 1, 2 and 4 μg/rat, intra-CA1), could significantly reverse the scopolamine-induced amnesia. Interestingly, administration of an ineffective dose of scopolamine (0.25 μg/rat, intra-CA1) before different doses of SKF38393, blocked the reversal effect of SKF38393 on the pre-training scopolamine-induced amnesia. Moreover, while the pre-test intra-CA1 injection of the dopamine D1 receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.1 and 0.5 μg/rat, intra-CA1), resulted in apparent memory impairment, microinjection of the same doses of this agent inhibited the scopolamine-induced state-dependent memory. These results indicate that the CA1 dopamine D1 receptors may potentially play an important role in scopolamine-induced amnesia as well as the scopolamine state-dependent memory. Furthermore, our results propose that dopamine D1 receptor agonist, SKF38393 reverses the scopolamine-induced amnesia via acetylcholine release and possibly through the activation of muscarinic

  10. A dopamine receptor contributes to paraquat-induced neurotoxicity in Drosophila

    PubMed Central

    Cassar, Marlène; Issa, Abdul-Raouf; Riemensperger, Thomas; Petitgas, Céline; Rival, Thomas; Coulom, Hélène; Iché-Torres, Magali; Han, Kyung-An; Birman, Serge

    2015-01-01

    Long-term exposure to environmental oxidative stressors, like the herbicide paraquat (PQ), has been linked to the development of Parkinson's disease (PD), the most frequent neurodegenerative movement disorder. Paraquat is thus frequently used in the fruit fly Drosophila melanogaster and other animal models to study PD and the degeneration of dopaminergic neurons (DNs) that characterizes this disease. Here, we show that a D1-like dopamine (DA) receptor, DAMB, actively contributes to the fast central nervous system (CNS) failure induced by PQ in the fly. First, we found that a long-term increase in neuronal DA synthesis reduced DAMB expression and protected against PQ neurotoxicity. Secondly, a striking age-related decrease in PQ resistance in young adult flies correlated with an augmentation of DAMB expression. This aging-associated increase in oxidative stress vulnerability was not observed in a DAMB-deficient mutant. Thirdly, targeted inactivation of this receptor in glutamatergic neurons (GNs) markedly enhanced the survival of Drosophila exposed to either PQ or neurotoxic levels of DA, whereas, conversely, DAMB overexpression in these cells made the flies more vulnerable to both compounds. Fourthly, a mutation in the Drosophila ryanodine receptor (RyR), which inhibits activity-induced increase in cytosolic Ca2+, also strongly enhanced PQ resistance. Finally, we found that DAMB overexpression in specific neuronal populations arrested development of the fly and that in vivo stimulation of either DNs or GNs increased PQ susceptibility. This suggests a model for DA receptor-mediated potentiation of PQ-induced neurotoxicity. Further studies of DAMB signaling in Drosophila could have implications for better understanding DA-related neurodegenerative disorders in humans. PMID:25158689

  11. A dopamine receptor contributes to paraquat-induced neurotoxicity in Drosophila.

    PubMed

    Cassar, Marlène; Issa, Abdul-Raouf; Riemensperger, Thomas; Petitgas, Céline; Rival, Thomas; Coulom, Hélène; Iché-Torres, Magali; Han, Kyung-An; Birman, Serge

    2015-01-01

    Long-term exposure to environmental oxidative stressors, like the herbicide paraquat (PQ), has been linked to the development of Parkinson's disease (PD), the most frequent neurodegenerative movement disorder. Paraquat is thus frequently used in the fruit fly Drosophila melanogaster and other animal models to study PD and the degeneration of dopaminergic neurons (DNs) that characterizes this disease. Here, we show that a D1-like dopamine (DA) receptor, DAMB, actively contributes to the fast central nervous system (CNS) failure induced by PQ in the fly. First, we found that a long-term increase in neuronal DA synthesis reduced DAMB expression and protected against PQ neurotoxicity. Secondly, a striking age-related decrease in PQ resistance in young adult flies correlated with an augmentation of DAMB expression. This aging-associated increase in oxidative stress vulnerability was not observed in a DAMB-deficient mutant. Thirdly, targeted inactivation of this receptor in glutamatergic neurons (GNs) markedly enhanced the survival of Drosophila exposed to either PQ or neurotoxic levels of DA, whereas, conversely, DAMB overexpression in these cells made the flies more vulnerable to both compounds. Fourthly, a mutation in the Drosophila ryanodine receptor (RyR), which inhibits activity-induced increase in cytosolic Ca(2+), also strongly enhanced PQ resistance. Finally, we found that DAMB overexpression in specific neuronal populations arrested development of the fly and that in vivo stimulation of either DNs or GNs increased PQ susceptibility. This suggests a model for DA receptor-mediated potentiation of PQ-induced neurotoxicity. Further studies of DAMB signaling in Drosophila could have implications for better understanding DA-related neurodegenerative disorders in humans. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Cesarean plus anoxia at birth induces hyperresponsiveness to locomotor activity by dopamine D2 agonist.

    PubMed

    Juárez, Ismael; De La Cruz, Fidel; Zamudio, Sergio; Flores, Gonzalo

    2005-12-15

    Transient global anoxia after Cesarean birth in rats may produce alterations in the subcortical DA function and related behaviors. The reports only tested the behavioral changes induced by a general DA agonist, such as amphetamine or apomorphine, in adult rats. Here we investigated the role of perinatal anoxia on the locomotion induced by a specific dopamine (DA) agonist and its relation to the DA D1-like and D2-like receptors, measured by autoradiography at two different ages, prepubertal (35 days old, P35) and postpubertal (60 days old, P60). Cesarean birth with or without (C-only) an additional period of 10 min of the anoxia was done in Sprague-Dawley rats, and the effects of the DA D1-like and D2-like agonist and their receptors were studied at P35 and P60. In addition, a third group of animals born vaginally served as the control. The quantitative autoradiography study of the DA D1-like and D2-like receptors revealed an enhancement of the DA D1-like receptor levels in the nucleus accumbens (NAcc) and dorsolateral part of the caudate-putamen in the prepubertal C-only animals. The postpubertal C-only rats showed a decrease in the levels of DA D2-like receptors in the NAcc. However, quinpirole, a DA D2 agonist (0.125 and 0.25 mg/kg, s.c.), induced a dose-dependent increase of the locomotor activity in the animals born by Cesarean with anoxia at birth at both ages. Our results suggest that Cesarean with or without anoxia at birth may mediate differently the neurodevelopmental aspects of the dopaminergic system before and after puberty. Copyright 2005 Wiley-Liss, Inc.

  13. Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia.

    PubMed

    Taylor, Norman E; Van Dort, Christa J; Kenny, Jonathan D; Pei, JunZhu; Guidera, Jennifer A; Vlasov, Ksenia Y; Lee, Justin T; Boyden, Edward S; Brown, Emery N; Solt, Ken

    2016-10-24

    Dopamine (DA) promotes wakefulness, and DA transporter inhibitors such as dextroamphetamine and methylphenidate are effective for increasing arousal and inducing reanimation, or active emergence from general anesthesia. DA neurons in the ventral tegmental area (VTA) are involved in reward processing, motivation, emotion, reinforcement, and cognition, but their role in regulating wakefulness is less clear. The current study was performed to test the hypothesis that selective optogenetic activation of VTA DA neurons is sufficient to induce arousal from an unconscious, anesthetized state. Floxed-inverse (FLEX)-Channelrhodopsin2 (ChR2) expression was targeted to VTA DA neurons in DA transporter (DAT)-cre mice (ChR2+ group; n = 6). Optical VTA stimulation in ChR2+ mice during continuous, steady-state general anesthesia (CSSGA) with isoflurane produced behavioral and EEG evidence of arousal and restored the righting reflex in 6/6 mice. Pretreatment with the D1 receptor antagonist SCH-23390 before optical VTA stimulation inhibited the arousal responses and restoration of righting in 6/6 ChR2+ mice. In control DAT-cre mice, the VTA was targeted with a viral vector lacking the ChR2 gene (ChR2- group; n = 5). VTA optical stimulation in ChR2- mice did not restore righting or produce EEG changes during isoflurane CSSGA in 5/5 mice. These results provide compelling evidence that selective stimulation of VTA DA neurons is sufficient to induce the transition from an anesthetized, unconscious state to an awake state, suggesting critical involvement in behavioral arousal.

  14. Intrarenal Dopamine Attenuates DOCA/HS-Induced Blood Pressure Elevation in Part through Activation of a Medullary COX-2 Pathway

    PubMed Central

    Yao, Bing; Harris, Raymond C.; Zhang, Ming-Zhi

    2009-01-01

    Locally produced dopamine in the renal proximal tubule inhibits salt and fluid reabsorption, and a dysfunctional intrarenal dopaminergic system has been reported in essential hypertension and experimental hypertension models. Using catechol-O-methyl-transferase knockout (COMT−/−) mice, which have increased renal dopamine due to deletion of the major renal dopamine metabolizing enzyme, we investigated the effect of intrarenal dopamine on the development of hypertension in the deoxycorticosterone acetate/high salt (DOCA/HS) model. DOCA/HS led to significant increases in systolic blood pressure (SBP) in wild type mice (from 115 ± 2 to 153 ± 4 mmHg), which was significantly attenuated in COMT−/− mice (from 114 ± 2 to 135 ± 3 mmHg). In DOCA/HS COMT−/− mice, the D1-like receptor antagonist SCH-23390 increased SBP (156 ± 2 mmHg). DOCA/HS COMT−/− mice also exhibited more urinary sodium excretion (COMT−/− vs. wild type: 3038 ± 430 vs. 659 ± 102 μM/24 h, P < 0.01). Furthermore, DOCA/HS-induced renal oxidative stress was significantly attenuated in COMT−/− mice. COX-2-derived prostaglandins in the renal medulla promote sodium excretion, and dopamine stimulates medullary prostaglandin production. Renal medullary COX-2 expression and urinary PGE2 excretion were significantly higher in COMT−/− than wild type mice after DOCA/HS treatment. In DOCA/HS treated COMT−/− mice, the COX-2 inhibitor SC-58236 reduced urinary sodium and PGE2 excretion and increased SBP (153 ± 2 mmHg). These studies indicate that an activated renal dopaminergic system attenuates the development of hypertension, at least in large part through activating medullary COX-2 expression/activity and also decreases oxidative stress resulting from DOCA/HS. PMID:19770404

  15. A dopamine-secreting pheochromocytoma.

    PubMed

    Yasunari, K; Kohno, M; Minami, M; Kano, H; Ohhira, M; Nakamura, K; Yoshikawa, J

    2000-01-01

    We describe a patient with pheochromocytoma, which secretes dopamine. He was admitted to hospital because of chronic diarrhea. After surgical resection of the tumor, dramatic cessation of the diarrhea and blood pressure elevation were observed. Decreased expression of dopamine beta-hydroxylase in the tumor was considered a possible mechanism of producing a pathophysiological concentration of dopamine. This case shows that excessive excretion of dopamine, a vasodilative hormone, may affect blood pressure.

  16. Dopamine Disposition in the Presynaptic Process Regulates the Severity of Methamphetamine-induced Neurotoxicity

    PubMed Central

    KUHN, DONALD M.; FRANCESCUTTI-VERBEEM, DINA M.; THOMAS, DAVID M.

    2008-01-01

    Methamphetamine (METH) is well-known for its ability to cause damage to dopamine (DA) nerve endings of the striatum. The mechanisms by which METH causes neurotoxicity are not fully understood but likely candidates are increased oxidative and nitrosative stress and mitochondrial dysfunction. Microglial activation is also emerging as an important element of the METH neurotoxic cascade and it appears that extensive crosstalk between these cells and DA nerve endings is an early event in this process. It may seem paradoxical, but DA itself is also thought to be an essential factor in the neuronal damaging effects of METH, but issues relating to its precise role in this regard remain unanswered. We present in this overview a summary of studies that tested how alterations in the disposition of presynaptic DA (injections of reserpine, L-DOPA, or clorgyline) modulate METH neurotoxicity. In all cases, these drugs significantly increased the magnitude of microglial activation as well as the severity of damage to striatal DA nerve endings caused by METH. The enhancement of METH effects in striatum by reserpine, L-DOPA, and clorgyline persisted for 14 days and showed no evidence of recovery. These data establish that subtle shifts in the newly-synthesized pool of DA can cause substantial changes in the severity of METH-induced neurotoxicity. DA released into the synapse by METH is very likely the source of downstream reactants that provoke microglial activation and the ensuing damage to DA nerve endings. PMID:18991856

  17. Persistent Drug-Induced Parkinsonism in Patients with Normal Dopamine Transporter Imaging

    PubMed Central

    Sunwoo, Mun Kyung; Oh, Jungsu S.; Kim, Jae Seung; Sohn, Young H.; Lee, Phil Hyu

    2016-01-01

    Functional neuroimaging for the dopamine transporter (DAT) is used to distinguish drug-induced parkinsonism (DIP) from subclinical Parkinson’s disease (PD). Although DIP patients who show a normal DAT image are expected to recover completely, some do not. We investigated whether these patients showed changes in striatal DAT activity using semi-quantitative analysis of 18F-FP-CIT PET data. DIP patients with visually normal DAT images were selected from medical records. The subjects were classified as patients who recovered partially (PR) or completely within 12 months (CR). The 18F-FP-CIT uptake in each striatal subregion was compared between the CR and the PR groups. In total, 41 and 9 patients of the CR and PR groups were assessed, respectively. The two patient groups were comparable in terms of clinical characteristics including age, sex, and severity of parkinsonism. From semi-quantitative analysis of the PET image, the PR patients showed a relatively lower ligand uptake in the ventral striatum, the anterior putamen and the posterior putamen compared with the CR patients. This result suggests that persistent DIP in patients with visually normal DAT imaging may be associated with subtle decrement of DAT activity. PMID:27294367

  18. Dopamine disposition in the presynaptic process regulates the severity of methamphetamine-induced neurotoxicity.

    PubMed

    Kuhn, Donald M; Francescutti-Verbeem, Dina M; Thomas, David M

    2008-10-01

    Methamphetamine (METH) is well known for its ability to cause damage to dopamine (DA) nerve endings of the striatum. The mechanisms by which METH causes neurotoxicity are not fully understood, but likely candidates are increased oxidative and nitrosative stress and mitochondrial dysfunction. Microglial activation is also emerging as an important element of the METH neurotoxic cascade, and it appears that extensive cross-talk between these cells and DA nerve endings is an early event in this process. It may seem paradoxical, but DA itself is also thought to be an essential factor in the neuronal damaging effects of METH, but issues relating to its precise role in this regard remain unanswered. We present in this overview a summary of studies that tested how alterations in the disposition of presynaptic DA (injections of reserpine, L-DOPA, or clorgyline) modulate METH neurotoxicity. In all cases, these drugs significantly increased the magnitude of microglial activation as well as the severity of damage to striatal DA nerve endings caused by METH. The enhancement of METH effects in striatum by reserpine, L-DOPA, and clorgyline persisted for 14 days and showed no evidence of recovery. These data establish that subtle shifts in the newly synthesized pool of DA can cause substantial changes in the severity of METH-induced neurotoxicity. DA released into the synapse by METH is very likely the source of downstream reactants that provoke microglial activation and the ensuing damage to DA nerve endings.

  19. Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

    SciTech Connect

    Ferretti, C.; Blengio, M.; Ghi, P.; Racca, S.; Genazzani, E.; Portaleone, P.

    1988-01-01

    We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modification induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17..beta..-estradiol (E/sub 2/) at both low (0.1 ..mu..g/kg) and high (20 ..mu..g/kg) doses confirmed its ability to increase the number of striatal /sup 3/H-Spiperone (/sup 3/H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E/sub 2/, to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophy-seal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusions: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of it antiestrogenic activity.

  20. Heterogeneous effects of dopamine on highly localized, voltage-induced Ca2+ accumulation in identified motoneurons.

    PubMed

    Kloppenburg, Peter; Zipfel, Warren R; Webb, Watt W; Harris-Warrick, Ronald M

    2007-11-01

    Modulation of synaptic transmission is a major mechanism for the functional reconfiguration of neuronal circuits. Neurotransmitter release and, consequently, synaptic strength are regulated by intracellular Ca(2+) levels in presynaptic terminals. In identified neurons of the lobster pyloric network, we studied localized, voltage-induced Ca(2+) accumulation and its modulation in varicosities on distal neuritic arborizations, which have previously been shown to be sites of synaptic contacts. We previously demonstrated that dopamine (DA) weakens synaptic output from the pyloric dilator (PD) neuron and strengthens synaptic output from the lateral pyloric (LP) and pyloric constrictor (PY) neurons. Here we show that DA modifies voltage-activated Ca(2+) accumulation in many varicosities in ways that are consistent with DA's effects on synaptic transmission: DA elevates Ca(2+) accumulation in LP and PY varicosities and reduces Ca(2+) accumulation in PD varicosities. However, in all three neuron types, we also found varicosities that were unaffected by DA. In the PY neurons, we found that DA can simultaneously increase and decrease voltage-evoked Ca(2+) accumulation at different varicosities, even within the same neuron. These results suggest that regulation of Ca(2+) entry is a common mechanism to regulate synaptic strength in the pyloric network. However, voltage-evoked local Ca(2+) accumulation can be differentially modulated to control Ca(2+)-dependent processes in functionally separate varicosities of a single neuron.

  1. Synergistic elevations in nucleus accumbens extracellular dopamine concentrations during self-administration of cocaine/heroin combinations (Speedball) in rats.

    PubMed

    Hemby, S E; Co, C; Dworkin, S I; Smith, J E

    1999-01-01

    The abuse of cocaine/opiate combinations (speedball) represents a growing trend in illicit drug use. Delineation of neurobiological substrates mediating the reinforcing effects of the combination may increase our knowledge of reinforcement mechanisms and provide useful new information for the development of pharmacotherapies. Several studies suggest dopaminergic innervations of the nucleus accumbens (NAc) have a central role in the brain processes underlying drug reinforcement. The present study was undertaken to determine the relationship between the self-administration of cocaine/heroin combinations and NAc extracellular dopamine concentrations ([DA]e) using in vivo microdialysis and microbore high-pressure liquid chromatography. Rats were assigned randomly to one of three groups to self-administer i.v. cocaine (125, 250, and 500 micrograms/infusion; n = 5), heroin (4.5, 9, and 18 micrograms/infusion; n = 5), or cocaine/heroin combinations (125/4.5; 250/9, and 500/18 micrograms/infusion; n = 4) under a fixed ratio (FR) 10: 20-s time-out schedule of reinforcement/multicomponent dosing session. After stable rates of responding were engendered and maintained, microdialysis samples were collected in 10-min intervals during the self-administration session. Self-administration of cocaine/heroin combinations produced synergisitic elevations in NAc [DA]e (1000% baseline) compared with cocaine (400% baseline) and heroin (not significantly different from baseline levels). Neither the number of infusions nor the interinfusion intervals was significantly different between the groups across the self-administration session. Moreover, cocaine concentrations were not significantly different between the cocaine and cocaine/heroin groups. These results demonstrate that heroin interacts with cocaine to produce synergistic elevations in [DA]e, providing a neurochemical basis for understanding the abuse liability of cocaine/opiate combinations.

  2. Modulation of Bleomycin-Induced Lung Fibrosis by Pegylated Hyaluronidase and Dopamine Receptor Antagonist in Mice

    PubMed Central

    Pershina, Olga Victorovna; Reztsova, Alena Mikhaylovna; Ermakova, Natalia Nikolaevna; Khmelevskaya, Ekaterina Sergeevna; Krupin, Vycheslav Andreevich; Stepanova, Inna Ernestovna; Artamonov, Andrew Vladimirovich; Bekarev, Andrew Alexandrovich; Madonov, Pavel Gennadjevich

    2015-01-01

    Hyaluronidases are groups of enzymes that degrade hyaluronic acid (HA). To stop enzymatic hydrolysis we modified testicular hyaluronidase (HYAL) by activated polyethylene oxide with the help of electron-beam synthesis. As a result we received pegylated hyaluronidase (pegHYAL). Spiperone is a selective D2 dopamine receptor antagonist. It was demonstrated on the model of a single bleomycin damage of alveolar epithelium that during the inflammatory phase monotherapy by pegHYAL or spiperone reduced the populations of hematopoietic stem /progenitor cells in the lung parenchyma. PegHYAL also reduced the levels of transforming growth factor (TGF)-β, interleukin (IL)-1β, tumor necrosis factor (TNF)-α in the serum and lungs, while spiperone reduced the level of the serum IL-1β. Polytherapy by spiperone and pegHYAL caused the increase of the quantity of hematopoietic stem/ progenitor cells in the lungs. Such an influx of blood cell precursors was observed on the background of considerable fall level of TGF-β and the increase level of TNF-α in the serum and lungs. These results show pegHYAL reduced the bleomycin-induced fibrosis reaction (production and accumulation of collagen) in the lung parenchyma. This effect was observed at a single and repetitive bleomycin damage of alveolar epithelium, the antifibrotic activity of pegHYAL surpassing the activity of testicular HYAL. The antifibrotic effect of pegHYAL is enhanced by an additional instillation of spiperone. Therapy by pegHYAL causes the flow of CD31‒CD34‒CD45‒CD44+CD73+CD90+CD106+-cells into the fibrous lungs. These cells are incapable of differentiating into fibroblast cells. Spiperone instillation separately or together with pegHYAL reduced the MSC-like cells considerably. These data enable us to assume, that pegHYAL is a new and promising instrument both for preventive and therapy of toxic pneumofibrosis. The blockage of D2 dopamine receptors with the following change of hyaluronan matrix can be considered

  3. Caloric Restriction Protects against Lactacystin-Induced Degeneration of Dopamine Neurons Independent of the Ghrelin Receptor.

    PubMed

    Coppens, Jessica; Bentea, Eduard; Bayliss, Jacqueline A; Demuyser, Thomas; Walrave, Laura; Albertini, Giulia; Van Liefferinge, Joeri; Deneyer, Lauren; Aourz, Najat; Van Eeckhaut, Ann; Portelli, Jeanelle; Andrews, Zane B; Massie, Ann; De Bundel, Dimitri; Smolders, Ilse

    2017-03-04

    Parkinson's disease (PD) is a neurodegenerative disorder, characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Caloric restriction (CR) has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-based animal model for PD. We here investigated whether CR is neuroprotective in the lactacystin (LAC) mouse model for PD, in which proteasome disruption leads to the destruction of the DA neurons of the SNc, and whether this effect is mediated via the ghrelin receptor. Adult male ghrelin receptor wildtype (WT) and knockout (KO) mice were maintained on an ad libitum (AL) diet or on a 30% CR regimen. After 3 weeks, LAC was injected unilaterally into the SNc, and the degree of DA neuron degeneration was evaluated 1 week later. In AL mice, LAC injection significanty reduced the number of DA neurons and striatal DA concentrations. CR protected against DA neuron degeneration following LAC injection. However, no differences were observed between ghrelin receptor WT and KO mice. These results indicate that CR can protect the nigral DA neurons from toxicity related to proteasome disruption; however, the ghrelin receptor is not involved in this effect.

  4. Autonomic failure mimicing dopamine agonist induced vertigo in a patient with macroprolactinoma.

    PubMed

    Seiler, L; Braune, S; Borm, K; Magerkurth, C; Talazko, J; Peters, T; Reincke, M

    2002-10-01

    A 68-year-old man presented with general fatigue, increasing adynamia, weakness, vertigo and recurrent syncope. Six weeks earlier the diagnosis of a macroprolactinoma had been established based on a greatly elevated prolactin concentration (161 170 micro U/l) and MR-evidence of a 3.5 cm measuring pituitary mass. The patient had been started on cabergoline (1.5 mg weekly). Orthostatic hypotension due to the dopamine agonist was considered very likely and carbergoline therapy was stopped. However, there was no relief of the symptoms and further syncopes followed. Testing of blood pressure and heart rate regulation, selective testing of postganglionic cardiac neurons with [ 123 J] metaiodobenzylguanidine scintigraphy provided evidence of grossly impaired neurogenic cardiovascular regulation due to failure of postganglionic efferent sympathetic activity. This is characteristic for pure autonomic failure. The patient was treated symptomatically with high fluid intake, compression stockings, fludrohydrocortisone (0.1 mg o.d.s.), piroxicam (20 mg o.d.s.) and etilephrin (10 mg q.d.s.), which enabled him to cope with daily activities without syncope. This case shows that vertigo in a patient with macroprolactinoma is not always related to drug therapy but may be related to other causes.

  5. Caloric Restriction Protects against Lactacystin-Induced Degeneration of Dopamine Neurons Independent of the Ghrelin Receptor

    PubMed Central

    Coppens, Jessica; Bentea, Eduard; Bayliss, Jacqueline A.; Demuyser, Thomas; Walrave, Laura; Albertini, Giulia; Van Liefferinge, Joeri; Deneyer, Lauren; Aourz, Najat; Van Eeckhaut, Ann; Portelli, Jeanelle; Andrews, Zane B.; Massie, Ann; De Bundel, Dimitri; Smolders, Ilse

    2017-01-01

    Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Caloric restriction (CR) has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-based animal model for PD. We here investigated whether CR is neuroprotective in the lactacystin (LAC) mouse model for PD, in which proteasome disruption leads to the destruction of the DA neurons of the SNc, and whether this effect is mediated via the ghrelin receptor. Adult male ghrelin receptor wildtype (WT) and knockout (KO) mice were maintained on an ad libitum (AL) diet or on a 30% CR regimen. After 3 weeks, LAC was injected unilaterally into the SNc, and the degree of DA neuron degeneration was evaluated 1 week later. In AL mice, LAC injection significanty reduced the number of DA neurons and striatal DA concentrations. CR protected against DA neuron degeneration following LAC injection. However, no differences were observed between ghrelin receptor WT and KO mice. These results indicate that CR can protect the nigral DA neurons from toxicity related to proteasome disruption; however, the ghrelin receptor is not involved in this effect. PMID:28273852

  6. Activation, internalization, and recycling of the serotonin 2A receptor by dopamine

    PubMed Central

    Bhattacharyya, Samarjit; Raote, Ishier; Bhattacharya, Aditi; Miledi, Ricardo; Panicker, Mitradas M.

    2006-01-01

    Serotonergic and dopaminergic systems, and their functional interactions, have been implicated in the pathophysiology of various CNS disorders. Here, we use recombinant serotonin (5-HT) 2A (5-HT2A) receptors to further investigate direct interactions between dopamine and 5-HT receptors. Previous studies in Xenopus oocytes showed that dopamine, although not the cognate ligand for the 5-HT2A receptor, acts as a partial-efficacy agonist. At micromolar concentrations, dopamine also acts as a partial-efficacy agonist on 5-HT2A receptors in HEK293 cells. Like 5-HT, dopamine also induces receptor-internalization in these cells, although at significantly higher concentrations than 5-HT. Interestingly, if the receptors are first sensitized or “primed” by subthreshold concentrations of 5-HT, then dopamine-induced internalization occurs at concentrations ≈10-fold lower than when dopamine is used alone. Furthermore, unlike 5-HT-mediated internalization, dopamine-mediated receptor internalization, alone, or after sensitization by 5-HT, does not depend on PKC. Dopamine-internalized receptors recycle to the surface at rates similar to those of 5-HT-internalized receptors. Our results suggest a previously uncharacterized role for dopamine in the direct activation and internalization of 5-HT2A receptors that may have clinical relevance to the function of serotonergic systems in anxiety, depression, and schizophrenia and also to the treatment of these disorders. PMID:17005723

  7. Dopamine D2 receptors mediate the increase in reinstatement of the conditioned rewarding effects of cocaine induced by acute social defeat.

    PubMed

    Reguilón, Marina Daiana; Montagud-Romero, Sandra; Ferrer-Pérez, Carmen; Roger-Sánchez, Concepción; Aguilar, María Asunción; Miñarro, José; Rodríguez-Arias, Marta

    2017-03-15

    Social stress modifies the activity of brain areas involved in the rewarding effects of psychostimulants, inducing neuroadaptations in the dopaminergic mesolimbic system and modifying the sensitivity of dopamine receptors. In the present study we evaluated the effect of the dopamine D1- and D2-like receptor antagonists (SCH23390 and raclopride, respectively) on the short-time effects of acute social defeat (ASD). Male OF1 mice were socially defeated before each conditioning session of the conditioned place preference (CPP) induced by 1mg/kg or 25mg/kg of cocaine plus the corresponding dopamine antagonist. A final experiment was designed to evaluate the effect of the dopamine antagonists on the CPP induced by 3mg/kg of cocaine with or without a stress experience. Mice exposed to ASD showed an increase in reinstatement of the conditioned reinforcing effects of cocaine that was blocked by all of the dopamine receptor antagonists. Blockade of dopamine D2-like receptors with raclopride specifically prevented the effects of stress without affecting the rewarding properties of cocaine. However, SCH23390 inhibited cocaine-induced preference in the control groups and even induced aversion in defeated mice conditioned with the lower dose of cocaine. Moreover, the lowest dose of SCH23390 blocked the rewarding effects of 3mg/kg of cocaine-induced CPP. Our results confirm that the dopamine D2 receptor is involved in the short-term effects of ASD on the rewarding effects of cocaine. The dopamine D1 receptor is clearly involved in the rewarding effects of cocaine, but its role in the effects of ASD remains to be demonstrated.

  8. Stimulation of metabotropic but not ionotropic glutamatergic receptors in the nucleus accumbens is required for the D-amphetamine-induced release of functional dopamine.

    PubMed

    Darracq, L; Drouin, C; Blanc, G; Glowinski, J; Tassin, J P

    2001-01-01

    We have previously shown that a large part of the D-amphetamine-induced release of dopamine in the nucleus accumbens is not associated with an increase in locomotor activity, and that "functional" dopamine release (i.e. release of dopamine associated with locomotor activity) requires the distal facilitation of noradrenergic transmission through alpha1-adrenergic receptors in the prefrontal cortex. To determine the role of monosynaptic or polysynaptic projections from the prefrontal cortex to the nucleus accumbens in these amphetamine responses, either AMPA/kainate (6-cyano-7-nitroquinoxaline-2,3-dione, CNQX, 300microM), N-methyl-D-aspartate (D(-)-2-amino-5-phosphono-pentanoic acid, APV, 500microM) or metabotropic [(+)-alpha-methyl-4-carboxy-phenylglycine, MCPG, 10mM] glutamate receptor antagonists were infused through a dialysis probe in the rat nucleus accumbens. CNQX and MCPG but not APV reduced the "non-functional" release of dopamine evoked by local (3microM) and systemic D-amphetamine (2mg/kg i.p.) treatments. However, the locomotor hyperactivity and functional dopamine release induced by systemic D-amphetamine were abolished by MCPG, but neither by CNQX nor by APV. MCPG treatment also abolished the hyperlocomotor activity and functional dopamine release evoked by bilateral morphine injection into the ventral tegmental area. The dopamine release evoked by this morphine treatment was 16-fold lower than that induced by the systemic D-amphetamine injection, although similar behavioral activations were observed. Altogether, our results further aid the discrimination of functional and non-functional release of dopamine. We suggest that the activation of metabotropic glutamate receptors in the nucleus accumbens is required for functional dopamine release following systemic D-amphetamine injection.

  9. Carrier-dependent and Ca2+-dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4-methylendioxy-methamphetamine, p-chloroamphetamine and (+)-fenfluramine

    PubMed Central

    Crespi, Daniela; Mennini, Tiziana; Gobbi, Marco

    1997-01-01

    The mechanism underlying 5-hydroxytryptamine (5-HT) and/or dopamine release induced by (+)-amphetamine ((+)-Amph), 3,4-methylendioxymethamphetamine (MDMA), p-chloroamphetamine (pCA) and (+)-fenfluramine ((+)-Fen) was investigated in rat brain superfused synaptosomes preloaded with the 3H neurotransmitters. Their rank order of potency for [3H]-5-HT-releasing activity was the same as for inhibition of 5-HT uptake (pCA⩾MDMA⩾(+)-Fen>>(+)-Amph). Similarly, their rank order as [3H]-dopamine releasers and dopamine uptake inhibitors was the same ((+)-Amph>>pCA=MDMA>>(+)-Fen). We also confirmed that the release induced by these compounds was prevented by selective transporter inhibitors (indalpine or nomifensine). [3H]-5-HT and/or [3H]-dopamine release induced by all these compounds was partially (31–80%), but significantly Ca2+-dependent. Lack of extracellular Ca2+ did not alter uptake mechanisms nor did it modify the carrier-dependent dopamine-induced [3H]-dopamine release. (+)-Amph-induced [3H]-dopamine release and pCA- and MDMA-induced [3H]-5-HT release were significantly inhibited by ω-agatoxin-IVA, a specific blocker of P-type voltage-operated Ca2+-channels, similar to the previous results on (+)-Fen-induced [3H]-5-HT release. Methiothepin inhibited the Ca2+-dependent component of (+)-Amph-induced [3H]-dopamine release with high potency (70 nM), as previously found with (+)-Fen-induced [3H]-5-HT release. The inhibitory effect of methiothepin was not due to its effects as a transporter inhibitor or Ca2+-channel blocker and is unlikely to be due to its antagonist properties on 5-HT1/2, dopamine or any other extracellular receptor. These results indicate that the release induced by these compounds is both ‘carrier-mediated' and Ca2+-dependent (possibly exocytotic-like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca2+-dependent release is mediated by Ca2+-influx (mainly through P-type Ca2+-channels), possibly triggered by

  10. Modulation of cue-induced firing of ventral tegmental area dopamine neurons by leptin and ghrelin

    PubMed Central

    van der Plasse, G; van Zessen, R; Luijendijk, M C M; Erkan, H; Stuber, G D; Ramakers, G M J; Adan, R A H

    2015-01-01

    Background/objectives: The rewarding value of palatable foods contributes to overconsumption, even in satiated subjects. Midbrain dopaminergic activity in response to reward-predicting environmental stimuli drives reward-seeking and motivated behavior for food rewards. This mesolimbic dopamine (DA) system is sensitive to changes in energy balance, yet it has thus far not been established whether reward signaling of DA neurons in vivo is under control of hormones that signal appetite and energy balance such as ghrelin and leptin. Subjects/methods: We trained rats (n=11) on an operant task in which they could earn two different food rewards. We then implanted recording electrodes in the ventral tegmental area (VTA), and recorded from DA neurons during behavior. Subsequently, we assessed the effects of mild food restriction and pretreatment with the adipose tissue-derived anorexigenic hormone leptin or the orexigenic hormone ghrelin on VTA DA reward signaling. Results: Animals showed an increase in performance following mild food restriction (P=0.002). Importantly, food-cue induced DA firing increased when animals were food restricted (P=0.02), but was significantly attenuated after leptin pretreatment (P=0.00). While ghrelin did affect baseline DA activity (P=0.025), it did not affect cue-induced firing (P⩾0.353). Conclusions: Metabolic signals, such as leptin, affect food seeking, a process that is dependent on the formation of cue-reward outcomes and involves midbrain DA signaling. These data show that food restriction engages the encoding of food cues by VTA DA neurons at a millisecond level and leptin suppresses this activity. This suggests that leptin is a key in linking metabolic information to reward signaling. PMID:26183405

  11. Human brain dopamine metabolism in levodopa-induced dyskinesia and wearing-off.

    PubMed

    Rajput, Ali H; Fenton, Mark E; Di Paolo, Thérèse; Sitte, Harold; Pifl, Christian; Hornykiewicz, Oleh

    2004-06-01

    The objective of this study was to identify dopamine (DA) metabolism pattern in Lewy body Parkinson's disease (PD) patients with dyskinesia (Dysk) only, with wearing-off (WO) only, or no motor complications (NMC) induced by levodopa (LD). DA, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 3-methoxytyramine (3-MT) were measured individual basal ganglia nuclei of nine PD patients who received LD for 6-18 years. Three patients had only Dysk, three only WO, and three had neither Dysk nor WO. Biochemical measurements in PD brains were compared with four non-neurological control brains from individuals matched for age and post-mortem retrieval time. DA levels in the PD were reduced in the caudate by 87% and putamen by 99%. In the caudates, the HVA/DA molar ratio as an index of DA metabolism was similar in the WO and the Dysk patients. However, in the putamen, the ratio of HVA/DA was significantly higher in the WO compared with the Dysk (p = 0.03)and the NMC (p = 0.04) groups of patients. In the putamen, the DOPAC levels were higher in the WO cases while in the Dysk cases, 3-MT levels were higher. The results suggest that in the WO only cases, the putaminal DA was in large measure metabolized intraneuronally while the DA metabolism in our Dysk only patients was mainly extraneuronal. We conclude that the magnitude and the site (intra vs. extraneuronal) of the synaptic DA metabolism in the putamen plays a significant role in LD-induced Dysk and WO.

  12. CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects

    PubMed Central

    Bilbao, Ainhoa; Rieker, Claus; Cannella, Nazzareno; Parlato, Rosanna; Golda, Slawomir; Piechota, Marcin; Korostynski, Michal; Engblom, David; Przewlocki, Ryszard; Schütz, Günther; Spanagel, Rainer; Parkitna, Jan R.

    2014-01-01

    It is suggested that striatal cAMP responsive element binding protein (CREB) regulates sensitivity to psychostimulants. To test the cell-specificity of this hypothesis we examined the effects of a dominant-negative CREB protein variant expressed in dopamine receptor D1 (D1R) neurons on cocaine-induced behaviors. A transgenic mouse strain was generated by pronuclear injection of a BAC-derived transgene harboring the A-CREB sequence under the control of the D1R gene promoter. Compared to wild-type, drug-naïve mutants showed moderate alterations in gene expression, especially a reduction in basal levels of activity-regulated transcripts such as Arc and Egr2. The behavioral responses to cocaine were elevated in mutant mice. Locomotor activity after acute treatment, psychomotor sensitization after intermittent drug injections and the conditioned locomotion after saline treatment were increased compared to wild-type littermates. Transgenic mice had significantly higher cocaine conditioned place preference, displayed normal extinction of the conditioned preference, but showed an augmented cocaine-seeking response following priming-induced reinstatement. This enhanced cocaine-seeking response was associated with increased levels of activity-regulated transcripts and prodynorphin. The primary reinforcing effects of cocaine were not altered in the mutant mice as they did not differ from wild-type in cocaine self-administration under a fixed ratio schedule at the training dose. Collectively, our data indicate that expression of a dominant-negative CREB variant exclusively in neurons expressing D1R is sufficient to recapitulate the previously reported behavioral phenotypes associated with virally expressed dominant-negative CREB. PMID:24966820

  13. Cocaine cue–induced dopamine release in the human prefrontal cortex

    PubMed Central

    Milella, Michele S.; Fotros, Aryandokht; Gravel, Paul; Casey, Kevin F.; Larcher, Kevin; Verhaeghe, Jeroen A.J.; Cox, Sylvia M.L.; Reader, Andrew J.; Dagher, Alain; Benkelfat, Chawki; Leyton, Marco

    2016-01-01

    Background Accumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown. Methods We used high-resolution positron emission tomography with [18F]fallypride to measure cortical and striatal DA D2/3 receptor availability in the presence versus absence of drug-related cues in volunteers with current cocaine dependence. Results Twelve individuals participated in our study. Among participants reporting a craving response (9 of 12), exposure to the cocaine cues significantly decreased [18F]fallypride binding potential (BPND) values in the medial orbitofrontal cortex and striatum. In all 12 participants, individual differences in the magnitude of craving correlated with BPND changes in the medial orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, and striatum. Consistent with the presence of autoreceptors on mesostriatal but not mesocortical DA cell bodies, midbrain BPND values were significantly correlated with changes in BPND within the striatum but not the cortex. The lower the midbrain D2 receptor levels, the greater the striatal change in BPND and self-reported craving. Limitations Limitations of this study include its modest sample size, with only 2 female participants. Newer tracers might have greater sensitivity to cortical DA release. Conclusion In people with cocaine use disorders, the presentation of drug-related cues induces DA release within cortical and striatal regions. Both effects are associated with craving, but only the latter is regulated by midbrain autoreceptors. Together, the results suggest that cortical and subcortical DA responses might both influence drug-focused incentive motivational states, but with separate regulatory mechanisms. PMID:26900792

  14. RAPID DOPAMINE TRANSMISSION WITHIN THE NUCLEUS ACCUMBENS DRAMATICALLY DIFFERS FOLLOWING MORPHINE AND OXYCODONE DELIVERY

    PubMed Central

    Mabrouk, Omar S.; Lovic, Vedran; Singer, Bryan F.; Kennedy, Robert T.; Aragona, Brandon J.

    2014-01-01

    While most drugs of abuse increase dopamine neurotransmission, rapid neurochemical measurements show that different drugs evoke distinct dopamine release patterns within the nucleus accumbens. Rapid changes in dopamine concentration following psychostimulant administration have been well studied; however, such changes have never been examined following opioid delivery. Here, we provide novel measures of rapid dopamine release following intravenous infusion of two opioids, morphine and oxycodone, in drug naïve rats using fast-scan cyclic voltammetry and rapid (1 min) microdialysis coupled with mass spectrometry. In addition to measuring rapid dopamine transmission, microdialysis HPLC-MS measures changes in GABA, glutamate, monoamines, monoamine metabolites, and several other neurotransmitters. Although both opioids increased dopamine release in the nucleus accumbens, their patterns of drug-evoked dopamine transmission differed dramatically. Oxycodone evoked a robust and stable increase in dopamine concentration and a robust increase in the frequency and amplitude of phasic dopamine release events. Conversely, morphine evoked a brief (~ 1 min) increase in dopamine that was coincident with a surge in GABA concentration and then both transmitters returned to baseline levels. Thus, by providing rapid measures of neurotransmission, this study reveals previously unknown differences in opioid-induced neurotransmitter signaling. Investigating these differences may be essential for understanding how these two drugs of abuse could differentially usurp motivational circuitry and powerfully influence behavior. PMID:25208732

  15. Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats

    PubMed Central

    Brioni, Jorge D.; Moreland, Robert B.; Cowart, Marlon; Hsieh, Gin C.; Stewart, Andrew O.; Hedlund, Petter; Donnelly-Roberts, Diana L.; Nakane, Masaki; Lynch, James J.; Kolasa, Teodozyi; Polakowski, James S.; Osinski, Mark A.; Marsh, Kennan; Andersson, Karl-Erik; Sullivan, James P.

    2004-01-01

    Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D4 receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D4 receptor agonist that activates human dopamine D4 receptors with an EC50 of 12.4 nM and 61% efficacy, with no effect on dopamine D1, D2, D3, or D5 receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction. PMID:15087502

  16. Activation-Induced Conformational Changes of Dopamine D3 Receptor Promote the Formation of the Internal Water Channel.

    PubMed

    Weng, Wei-Hsiang; Li, Ya-Tzu; Hsu, Hao-Jen

    2017-10-06

    The atomic-level dopamine activation mechanism for transmitting extracellular ligand binding events through transmembrane helices to the cytoplasmic G protein remains unclear. In the present study, the complete dopamine D3 receptor (D3R), with a homology-modeled N-terminus, was constructed to dock different ligands to simulate conformational alterations in the receptor's active and inactive forms during microsecond-timescale molecular dynamic simulations. In agonist-bound systems, the D3R N-terminus formed a "lid-like" structure and lay flat on the binding site opening, whereas in antagonist and inverse agonist-bound systems, the N-terminus exposed the binding cavity. Receptor activation was characterized using the different molecular switch residue distances, and G protein-binding site volumes. A continuous water pathway was observed only in the dopamine-Gαi-bound system. In the inactive D3Rs, water entry was hindered by the hydrophobic layers. Finally, a complete activation mechanism of D3R was proposed. Upon agonist binding, the "lid-like" conformation of the N-terminus induces a series of molecular switches to increase the volume of the D3R cytoplasmic binding part for G protein association. Meanwhile, water enters the transmembrane region inducing molecular switches to assist in opening the hydrophobic layers to form a continuous water channel, which is crucial for maintaining a fully active conformation for signal transduction.

  17. L-theanine inhibits nicotine-induced dependence via regulation of the nicotine acetylcholine receptor-dopamine reward pathway.

    PubMed

    Di, Xiaojing; Yan, Jingqi; Zhao, Yan; Chang, Yanzhong; Zhao, Baolu

    2012-12-01

    In this study, the inhibitory effect of L-theanine, an amino acid derivative of tea, on the rewarding effects of nicotine and its underlying mechanisms of action were studied. We found that L-theanine inhibited the rewarding effects of nicotine in a conditioned place preference (CPP) model of the mouse and reduced the excitatory status induced by nicotine in SH-SY5Y cells to the same extent as the nicotine receptor inhibitor dihydro-beta-erythroidine (DHβE). Further studies using high performance liquid chromatography, western blotting and immunofluorescence staining analyses showed that L-theanine significantly inhibited nicotine-induced tyrosine hydroxylase (TH) expression and dopamine production in the midbrain of mice. L-theanine treatment also reduced the upregulation of the α(4), β(2) and α(7) nicotine acetylcholine receptor (nAChR) subunits induced by nicotine in mouse brain regions that related to the dopamine reward pathway, thus decreasing the number of cells that could react to nicotine. In addition, L-theanine treatment inhibited nicotine-induced c-Fos expression in the reward circuit related areas of the mouse brain. Knockdown of c-Fos by siRNA inhibited the excitatory status of cells but not the upregulation of TH induced by nicotine in SH-SY5Y cells. Overall, the present study showed that L-theanine reduced the nicotine-induced reward effects via inhibition of the nAChR-dopamine reward pathway. These results may offer new therapeutic strategies for treatment of tobacco addiction.

  18. Habenula-Induced Inhibition of Midbrain Dopamine Neurons Is Diminished by Lesions of the Rostromedial Tegmental Nucleus.

    PubMed

    Brown, P Leon; Palacorolla, Heather; Brady, Dana; Riegger, Katelyn; Elmer, Greg I; Shepard, Paul D

    2017-01-04

    Neurons in the lateral habenula (LHb) are transiently activated by aversive events and have been implicated in associative learning. Functional changes associated with tonic and phasic activation of the LHb are often attributed to a corresponding inhibition of midbrain dopamine (DA) neurons. Activation of GABAergic neurons in the rostromedial tegmental nucleus (RMTg), a region that receives dense projections from the LHb and projects strongly to midbrain monoaminergic nuclei, is believed to underlie the transient inhibition of DA neurons attributed to activation of the LHb. To test this premise, the effects of axon-sparing lesions of the RMTg were assessed on LHb-induced inhibition of midbrain DA cell firing in anesthetized rats. Quinolinic acid lesions decreased the number of NeuN-positive neurons in the RMTg significantly while largely sparing cells in neighboring regions. Lesions of the RMTg reduced both the number of DA neurons inhibited by, and the duration of inhibition resulting from, LHb stimulation. Although the firing rate was not altered, the regularity of DA cell firing was increased in RMTg-lesioned rats. Locomotor activity in an open field was also elevated. These results are the first to show that RMTg neurons contribute directly to LHb-induced inhibition of DA cell activity and support the widely held proposition that GABAergic neurons in the mesopontine tegmentum are an important component of a pathway that enables midbrain DA neurons to encode the negative valence associated with failed expectations and aversive stimuli. Phasic changes in the activity of midbrain dopamine cells motivate and guide future behavior. Activation of the lateral habenula by aversive events inhibits dopamine neurons transiently, providing a neurobiological representation of learning models that incorporate negative reward prediction errors. Anatomical evidence suggests that this inhibition occurs via the rostromedial tegmental nucleus, but this hypothesis has yet to be

  19. Pharmacological characterization of renal vascular dopamine receptors.

    PubMed

    Schmidt, M; Imbs, J L

    1980-01-01

    We present an in vitro method for studying the renal effects of dopamine in the isolated rat kidney. The organ is perfused in an open circuit and can be maintained satisfactorily for up to 180 min. The responses to dopamine were studied in the presence of phenoxybenzamine (10(-5) M) and sotalol (10(-5) M) while stable renal vasoconstriction was maintained by perfusion with prostaglandine F2 alpha. Dopamine induced dose-dependent renal vasodilation with an ED50 of 2.53 X 10(-6) moles/liter, which was not modified by reserpine pretreatment. (+) Butaclamol but not (-) butaclamol shifted the dopamine dose-response curve to the right in a parallel fashion, indicating competitive antagonism. Haloperidol and sulpiride at concentrations without intrinsic effect on vascular resistance also acted as competitive inhibitors for dopamine. Calculation of empirical pA2 values yielded the following relative potencies for these antagonists: (+) butaclamol greater than haloperidol greater than sulpiride. The renal vascular dopamine receptors are tentatively classified as being of the D1 type.

  20. Gastric mucosal lesions induced by complete dopamine system failure in rats. The effects of dopamine agents, ranitidine, atropine, omeprazole and pentadecapeptide BPC 157.

    PubMed

    Sikiric, P; Separovic, J; Buljat, G; Anic, T; Stancic-Rokotov, D; Mikus, D; Duplancic, B; Marovic, A; Zoricic, I; Prkacin, I; Lovric-Bencic, M; Aralica, G; Ziger, T; Perovic, D; Jelovac, N; Dodig, G; Rotkvic, I; Mise, S; Seiwerth, S; Turkovic, B; Grabarevic, Z; Petek, M; Rucman, R

    2000-01-01

    Up to now, for gastric lesions potentiation or induction, as well as determination of endogenous dopamine significance, dopamine antagonist or dopamine vesicle depletor were given separately. Therefore, without combination studies, the evidence for dopamine significance remains split on either blockade of dopamine post-synaptic receptor or inhibition of dopamine storage, essentially contrasting with endogenous circumstances, where both functions could be simultaneously disturbed. For this purpose, a co-administration of reserpine and haloperidol, a dopamine granule depletor combined with a dopamine antagonist with pronounced ulcerogenic effect, was tested, and the rats were sacrificed 24 h after injurious agent(s) administration. Haloperidol (5 mg x kg(-1) b.w. i.p.), given alone, produced the lesions in all rats. Reserpine (5 mg x kg(-1) b.w. i.p.), given separately, also produced lesions. When these agents were given together, the lesions were apparently larger than in the groups injured with separate administration of either haloperidol or reserpine alone. Along with our previous results, when beneficial agents were co-administered, all dopaminomimetics (bromocriptine 10 mg, apomophine 1 mg, amphetamine 20 mg x kg(-1) i.p.) apparently attenuated the otherwise consistent haloperidol-gastric lesions. Likewise, an apparent inhibition of the reserpine-lesions was noted as well. However, if they were given in rats injured with combination of haloperidol and reserpine, their otherwise prominent beneficial effects were absent. Ranitidine (10 mg), omeprazole (10 mg), atropine (10 mg), pentadecapeptide BPC 157 (Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) (10 microg or 10 ng x kg(-1) i.p.) evidently prevented both haloperidol-gastric lesions and reserpine-gastric lesions. Confronted with potentiated lesions following a combination of haloperidol and reserpine, these agents maintained their beneficial effects, noted in the rats treated with either

  1. The sigma receptor ligand (+/-)-BMY 14802 prevents methamphetamine-induced dopaminergic neurotoxicity via interactions at dopamine receptors.

    PubMed

    Terleckyj, I; Sonsalla, P K

    1994-04-01

    The possibility that compounds which interact with the putative sigma receptor might influence the dopaminergic neuropathology produced by the administration of methamphetamine (METH) to mice was investigated. (+/-)-BMY 14802 [alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride] attenuated METH-induced dopaminergic neuropathology whereas several other sigma-acting compounds such as R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, 1,3-di-o-tolyl-guanidine, rimcazole, clorgyline or (-)-butaclamol did not alter neurotoxicity produced by this central nervous system stimulant. (-)-BMY 14802, which has a lower affinity for the sigma site than (+)-BMY 14802, was more potent than (+)-BMY 14802 in antagonizing METH-induced neuropathology. In addition, the ketone metabolite (BMY 14786; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanone hydrochloride), which is a major metabolite formed from (-)-BMY 14802, also attenuated the METH-induced effects. (+/-)-BMY 14802 pretreatment of mice prevented the reduction in D1 and D2 dopamine receptor number produced by the systemic administration of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and demonstrates that (+/-)-BMY 14802 and/or its metabolites interact with the dopamine receptor subtypes. Taken together, these findings suggest that the protective effect of (+/-)-BMY 14802 against METH-induced neuropathology is mediated, at least in part, through dopamine receptor antagonism. Furthermore, the failure of other sigma-acting compounds to alter METH-induced neurotoxicity indicates that the putative sigma receptor is unlikely to be an important mediator in this type of neuropathology.

  2. Computational modeling of extracellular dopamine kinetics suggests low probability of neurotransmitter release.

    PubMed

    Rooney, Katherine E; Wallace, Lane J

    2015-11-01

    Dopamine in the striatum signals the saliency of current environmental input and is involved in learned formation of appropriate responses. The regular baseline-firing rate of dopaminergic neurons suggests that baseline dopamine is essential for proper brain function. The first goal of the study was to estimate the likelihood of full exocytotic dopamine release associated with each firing event under baseline conditions. A computer model of extracellular space associated with a single varicosity was developed using the program MCell to estimate kinetics of extracellular dopamine. Because the literature provides multiple kinetic values for dopamine uptake depending on the system tested, simulations were run using different kinetic parameters. With all sets of kinetic parameters evaluated, at most, 25% of a single vesicle per varicosity would need to be released per firing event to maintain a 5-10 nM extracellular dopamine concentration, the level reported by multiple microdialysis experiments. The second goal was to estimate the fraction of total amount of stored dopamine released during a highly stimulated condition. This was done using the same model system to simulate published measurements of extracellular dopamine following electrical stimulation of striatal slices in vitro. The results suggest the amount of dopamine release induced by a single electrical stimulation may be as large as the contents of two vesicles per varicosity. We conclude that dopamine release probability at any particular varicosity is low. This suggests that factors capable of increasing release probability could have a powerful effect on sculpting dopamine signals.

  3. Effects of hypothalamic dopamine on growth hormone-releasing hormone-induced growth hormone secretion and thyrotropin-releasing hormone-induced prolactin secretion in goats.

    PubMed

    Jin, Jin; Hashizume, Tsutomu

    2015-06-01

    The aim of the present study was to clarify the effects of hypothalamic dopamine (DA) on the secretion of growth hormone (GH) in goats. The GH-releasing response to an intravenous (i.v.) injection of GH-releasing hormone (GHRH, 0.25 μg/kg body weight (BW)) was examined after treatments to augment central DA using carbidopa (carbi, 1 mg/kg BW) and L-dopa (1 mg/kg BW) in male and female goats under a 16-h photoperiod (16 h light, 8 h dark) condition. GHRH significantly and rapidly stimulated the release of GH after its i.v. administration to goats (P < 0.05). The carbi and L-dopa treatments completely suppressed GH-releasing responses to GHRH in both male and female goats (P < 0.05). The prolactin (PRL)-releasing response to an i.v. injection of thyrotropin-releasing hormone (TRH, 1 μg/kg BW) was additionally examined in male goats in this study to confirm modifications to central DA concentrations. The treatments with carbi and L-dopa significantly reduced TRH-induced PRL release in goats (P < 0.05). These results demonstrated that hypothalamic DA was involved in the regulatory mechanisms of GH, as well as PRL secretion in goats.

  4. The membrane-raft protein Flotillin-1 is essential in dopamine neurons for amphetamine-induced behavior in Drosophila

    PubMed Central

    Pizzo, Andrea B.; Karam, Caline S.; Zhang, Yuchao; Yano, Hideaki; Freyberg, Robin J.; Karam, David S.; Freyberg, Zachary; Yamamoto, Ai; McCabe, Brian D.; Javitch, Jonathan A.

    2012-01-01

    The dopamine transporter (DAT) is the primary molecular target responsible for the rewarding properties of the psychostimulants amphetamine (AMPH) and cocaine. AMPH increases extracellular dopamine (DA) by promoting its nonexocytotic release via DAT-mediated efflux. Previous studies in heterologous cells have shown that phosphorylation of the amino terminus of DAT is required for AMPH-induced DA efflux but not for DA uptake. However, the identity of many of the modulatory proteins and the molecular mechanisms that coordinate efflux and the ensuing behavioral effects remain poorly defined. Here we establish a robust assay for AMPH-induced hyperlocomotion in Drosophila melanogaster larvae. Using a variety of genetic and pharmacological approaches we demonstrate that this behavioral response is dependent on DA and on DAT and its phosphorylation. We also show that methylphenidate (MPH), which competitively inhibits DA uptake but does not induce DAT-mediated DA efflux, also leads to DAT-dependent hyperlocomotion, but this response is independent of DAT phosphorylation. Moreover, we demonstrate that the membrane raft protein Flotillin1 is required for AMPH-induced but not MPH-induced hyperlocomotion. These results are the first evidence of a role for a raft protein in an AMPH-mediated behavior. Thus, using our assay we are able to translate molecular and cellular findings to a behavioral level and to differentiate in vivo the distinct mechanisms of two psychostimulants. PMID:22710269

  5. From the Cover: Manganese and Rotenone-Induced Oxidative Stress Signatures Differ in iPSC-Derived Human Dopamine Neurons.

    PubMed

    Neely, M Diana; Davison, Carrie Ann; Aschner, Michael; Bowman, Aaron B

    2017-10-01

    Parkinson's disease (PD) is the result of complex interactions between genetic and environmental factors. Two chemically distinct environmental stressors relevant to PD are the metal manganese and the pesticide rotenone. Both are thought to exert neurotoxicity at least in part via oxidative stress resulting from impaired mitochondrial activity. Identifying shared mechanism of action may reveal clues towards an understanding of the mechanisms underlying PD pathogenesis. Here we compare the effects of manganese and rotenone in human-induced pluripotent stem cells-derived postmitotic mesencephalic dopamine neurons by assessing several different oxidative stress endpoints. Manganese, but not rotenone caused a concentration and time-dependent increase in intracellular reactive oxygen/nitrogen species measured by quantifying the fluorescence of oxidized chloromethyl 2',7'-dichlorodihydrofluorescein diacetate (DCF) assay. In contrast, rotenone but not manganese caused an increase in cellular isoprostane levels, an indicator of lipid peroxidation. Manganese and rotenone both caused an initial decrease in cellular reduced glutathione; however, glutathione levels remained low in neurons treated with rotenone for 24 h but recovered in manganese-exposed cells. Neurite length, a sensitive indicator of overall neuronal health was adversely affected by rotenone, but not manganese. Thus, our observations suggest that the cellular oxidative stress evoked by these 2 agents is distinct yielding unique oxidative stress signatures across outcome measures. The protective effect of rasagiline, a compound used in the clinic for PD, had negligible impact on any of oxidative stress outcome measures except a subtle significant decrease in manganese-dependent production of reactive oxygen/nitrogen species detected by the DCF assay. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. The metal transporter SMF-3/DMT-1 mediates aluminum-induced dopamine neuron degeneration.

    PubMed

    VanDuyn, Natalia; Settivari, Raja; LeVora, Jennifer; Zhou, Shaoyu; Unrine, Jason; Nass, Richard

    2013-01-01

    Aluminum (Al(3+)) is the most prevalent metal in the earth's crust and is a known human neurotoxicant. Al(3+) has been shown to accumulate in the substantia nigra of patients with Parkinson's disease (PD), and epidemiological studies suggest correlations between Al(3+) exposure and the propensity to develop both PD and the amyloid plaque-associated disorder Alzheimer's disease (AD). Although Al(3+) exposures have been associated with the development of the most common neurodegenerative disorders, the molecular mechanism involved in Al(3+) transport in neurons and subsequent cellular death has remained elusive. In this study, we show that a brief exposure to Al(3+) decreases mitochondrial membrane potential and cellular ATP levels, and confers dopamine (DA) neuron degeneration in the genetically tractable nematode Caenorhabditis elegans (C. elegans). Al(3+) exposure also exacerbates DA neuronal death conferred by the human PD-associated protein α-synuclein. DA neurodegeneration is dependent on SMF-3, a homologue to the human divalent metal transporter (DMT-1), as a functional null mutation partially inhibits the cell death. We also show that SMF-3 is expressed in DA neurons, Al(3+) exposure results in a significant decrease in protein levels, and the neurodegeneration is partially dependent on the PD-associated transcription factor Nrf2/SKN-1 and caspase Apaf1/CED-4. Furthermore, we provide evidence that the deletion of SMF-3 confers Al(3+) resistance due to sequestration of Al(3+) into an intracellular compartment. This study describes a novel model for Al(3+)-induced DA neurodegeneration and provides the first molecular evidence of an animal Al(3+) transporter. © 2012 International Society for Neurochemistry.

  7. Gastrin and D1 dopamine receptor interact to induce natriuresis and diuresis.

    PubMed

    Chen, Yue; Asico, Laureano D; Zheng, Shuo; Villar, Van Anthony M; He, Duofen; Zhou, Lin; Zeng, Chunyu; Jose, Pedro A

    2013-11-01

    Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl. Gastrin is the major gastrointestinal hormone taken up by renal proximal tubule (RPT) cells. We hypothesized that renal gastrin and dopamine receptors interact to synergistically increase sodium excretion, an impaired interaction of which may be involved in the pathogenesis of hypertension. In Wistar-Kyoto rats, infusion of gastrin induced natriuresis and diuresis, which was abrogated in the presence of a gastrin (cholecystokinin B receptor [CCKBR]; CI-988) or a D1-like receptor antagonist (SCH23390). Similarly, the natriuretic and diuretic effects of fenoldopam, a D1-like receptor agonist, were blocked by SCH23390, as well as by CI-988. However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats. The gastrin/D1-like receptor interaction was also confirmed in RPT cells. In RPT cells from Wistar-Kyoto but not spontaneously hypertensive rats, stimulation of either D1-like receptor or gastrin receptor inhibited Na(+)-K(+)-ATPase activity, an effect that was blocked in the presence of SCH23390 or CI-988. In RPT cells from Wistar-Kyoto and spontaneously hypertensive rats, CCKBR and D1 receptor coimmunoprecipitated, which was increased after stimulation of either D1 receptor or CCKBR in RPT cells from Wistar-Kyoto rats; stimulation of one receptor increased the RPT cell membrane expression of the other receptor, effects that were not observed in spontaneously hypertensive rats. These data suggest that there is a synergism between CCKBR and D1-like receptors to increase sodium excretion. An aberrant interaction between the renal CCK BR and D1-like receptors (eg, D1 receptor) may play a role in the pathogenesis of hypertension.

  8. Behavioral sensitization to different dopamine agonists in a parkinsonian rodent model of drug-induced dyskinesias.

    PubMed

    Delfino, M A; Stefano, A V; Ferrario, J E; Taravini, I R E; Murer, M G; Gershanik, O S

    2004-07-09

    Repeated treatment with dopamine (DA) receptor agonists strongly potentiates contralateral turning behavior due to selective stimulation of D1 or D2-class receptors in 6-hydroxydopamine (6-OHDA)-lesioned rats. This phenomenon, referred to as sensitization, is believed to be related to the motor response complications (dyskinesias, on-off states) that occur during chronic administration of levodopa in Parkinson's disease patients. In recent years a new method for the evaluation of abnormal involuntary movements (AIMs) secondary to dopaminergic stimulation in 6-OHDA-lesioned rats was described. These AIMs resemble dyskinesias as seen in parkinsonian patients under levodopa therapy. Our objective was to evaluate the effects of repeated treatment with different regimes of DA agonists on turning behavior and on an AIMs scale in 6-OHDA lesioned rats, with the aim of discriminating between drugs with different dyskinesia-inducing potential. In addition, we explored the effects of a previous exposure to a DA agonist (priming) on the behavioral response to the subsequent administration of a DA agonist with the same or different pharmacologic profile. Our results show that in apomorphine-treated rats, rotational behavior and AIMs run a parallel course of enhancement, while in those receiving quinpirole there is a dissociation, suggesting that they could be mediated by different mechanisms. The finding of a significant priming effect on subsequent testing of 6-OHDA lesioned rats should be borne in mind as the use of these pharmacological tests in the screening of well lesioned animals could lead to an erroneous interpretation of further results on dyskinesias and rotational behavior. Copyright 2003 Elsevier B.V.

  9. 5-HT1A and 5-HT7 receptors contribute to lurasidone-induced dopamine efflux.

    PubMed

    Huang, Mei; Horiguchi, Masakuni; Felix, Anna R; Meltzer, Herbert Y

    2012-05-09

    Lurasidone is a novel, atypical antipsychotic drug with serotonin [5-hydroxytryptamine (5-HT)]2A, 5-HT7, dopamine (DA) D2 antagonist, and 5-HT1A receptor partial agonist properties. The ability of lurasidone to reverse the effects of subchronic administration phencyclidine, to impair novel object recognition in rats, an animal model of cognitive impairment in schizophrenia, is dependent, in part, on its 5-HT1A agonist and 5-HT7 receptor antagonist properties. We tested whether 5-HT1A partial agonism or 5-HT7 antagonism, or both, contributed to the ability of lurasidone to enhance cortical and hippocampal DA efflux, which may be related to its ability to improve cognition. Here, we report that lurasidone, 0.25 and 0.5, but not 0.1 mg/kg, subcutaneously, significantly increased DA efflux in the prefrontal cortex and hippocampus in a dose-dependent manner. Lurasidone, 0.5 mg/kg, also produced a smaller increase in DA efflux in the nucleus accumbens. Pretreatment with the 5-HT1A receptor antagonist, WAY100635 (0.2 mg/kg, subcutaneously), partially blocked the lurasidone-induced cortical and hippocampal DA efflux. Further, subeffective doses of the 5-HT1A receptor agonist, tandospirone (0.2 mg/kg), or the 5-HT7 antagonist, SB269970 (0.3 mg/kg), potentiated the ability of a subeffective dose of lurasidone (0.1 mg/kg) to increase DA efflux in the prefrontal cortex. These findings suggest that the effects of lurasidone on the prefrontal cortex and hippocampus, DA efflux are dependent, at least partially, on its 5-HT1A agonist and 5-HT7 antagonist properties and may contribute to its efficacy to reverse the effects of subchronic phencyclidine treatment and improve schizophrenia.

  10. Effect of in vitro inorganic lead on dopamine release from superfused rat striatal synaptosomes.

    PubMed

    Minnema, D J; Greenland, R D; Michaelson, I A

    1986-06-30

    The effect of inorganic lead in vitro in several aspects of [3H]dopamine release from superfused rat striatal synaptosomes was examined. Under conditions of spontaneous release, lead (1-30 microM) induced dopamine release in a concentration-dependent manner. The onset of the lead-induced release was delayed by approximately 15-30 sec. The magnitude of dopamine release induced by lead was increased when calcium was removed from the superfusing buffer. Lead-induced release was unaffected in the presence of putative calcium, sodium, and/or potassium channel blockers (nickel, tetrodotoxin, tetraethylammonium, respectively). Depolarization-evoked dopamine release, produced by a 1-sec exposure to 61 mM potassium, was diminished at calcium concentrations below 0.254 mM. The onset of depolarization-evoked release was essentially immediate following exposure of the synaptosomes to high potassium. The combination of lead (3 or 10 microM) with high potassium reduced the magnitude of depolarization-evoked dopamine release. This depression of depolarization-evoked release by lead was greater in the presence of 0.25 mM than 2.54 mM calcium in the superfusing buffer. These findings demonstrate multiple actions of lead on synaptosomal dopamine release. Lead can induce dopamine release by yet unidentified neuronal mechanisms independent of external calcium. Lead can also reduce depolarization-evoked dopamine release by apparent competition with calcium influx at the neuronal membrane calcium channel.

  11. Effect of in vitro inorganic lead on dopamine release from superfused rat striatal synaptosomes

    SciTech Connect

    Minnema, D.J.; Greenland, R.D.; Michaelson, I.A.

    1986-06-30

    The effect of inorganic lead in vitro in several aspects of (/sup 3/H)dopamine release from superfused rat striatal synaptosomes was examined. Under conditions of spontaneous release, lead (1-30 microM) induced dopamine release in a concentration-dependent manner. The onset of the lead-induced release was delayed by approximately 15-30 sec. The magnitude of dopamine release induced by lead was increased when calcium was removed from the superfusing buffer. Lead-induced release was unaffected in the presence of putative calcium, sodium, and/or potassium channel blockers (nickel, tetrodotoxin, tetraethylammonium, respectively). Depolarization-evoked dopamine release, produced by a 1-sec exposure to 61 mM potassium, was diminished at calcium concentrations below 0.254 mM. The onset of depolarization-evoked release was essentially immediate following exposure of the synaptosomes to high potassium. The combination of lead (3 or 10 microM) with high potassium reduced the magnitude of depolarization-evoked dopamine release. This depression of depolarization-evoked release by lead was greater in the presence of 0.25 mM than 2.54 mM calcium in the superfusing buffer. These findings demonstrate multiple actions of lead on synaptosomal dopamine release. Lead can induce dopamine release by yet unidentified neuronal mechanisms independent of external calcium. Lead can also reduce depolarization-evoked dopamine release by apparent competition with calcium influx at the neuronal membrane calcium channel.

  12. Extracellular dopamine and alterations on dopamine transporter are related to reserpine toxicity in Caenorhabditis elegans.

    PubMed

    Reckziegel, Patrícia; Chen, Pan; Caito, Sam; Gubert, Priscila; Soares, Félix Alexandre Antunes; Fachinetto, Roselei; Aschner, Michael

    2016-03-01

    Reserpine is used as an animal model of parkinsonism. We hypothesized that the involuntary movements induced by reserpine in rodents are induced by dopaminergic toxicity caused by extracellular dopamine accumulation. The present study tested the effects of reserpine on the dopaminergic system in Caenorhabditis elegans. Reserpine was toxic to worms (decreased the survival, food intake, development and changed egg laying and defecation cycles). In addition, reserpine increased the worms' locomotor rate on food and decreased dopamine levels. Morphological evaluations of dopaminergic CEP neurons confirmed neurodegeneration characterized by decreased fluorescence intensity and the number of worms with intact CEP neurons, and increased number of shrunken somas per worm. These effects were unrelated to reserpine's effect on decreased expression of the dopamine transporter, dat-1. Interestingly, the locomotor rate on food and the neurodegenerative parameters fully recovered to basal conditions upon reserpine withdrawal. Furthermore, reserpine decreased survival in vesicular monoamine transporter and dat-1 loss-of-function mutant worms. In addition, worms pre-exposed to dopamine followed by exposure to reserpine had decreased survival. Reserpine activated gst-4, which controls a phase II detoxification enzymes downstream of nuclear factor (erythroid-derived-2)-like 2. Our findings establish that the dopamine transporter, dat-1, plays an important role in reserpine toxicity, likely by increasing extracellular dopamine concentrations.

  13. Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons.

    PubMed Central

    Sklair-Tavron, L; Shi, W X; Lane, S B; Harris, H W; Bunney, B S; Nestler, E J

    1996-01-01

    The mesolimbic dopamine system, which arises in the ventral tegmental area (VTA), is an important neural substrate for opiate reinforcement and addiction. Chronic exposure to opiates is known to produce biochemical adaptations in this brain region. We now show that these adaptations are associated with structural changes in VTA dopamine neurons. Individual VTA neurons in paraformaldehyde-fixed brain sections from control or morphine-treated rats were injected with the fluorescent dye Lucifer yellow. The identity of the injected cells as dopaminergic or nondopaminergic was determined by immunohistochemical labeling of the sections for tyrosine hydroxylase. Chronic morphine treatment resulted in a mean approximately 25% reduction in the area and perimeter of VTA dopamine neurons. This reduction in cell size was prevented by concomitant treatment of rats with naltrexone, an opioid receptor antagonist, as well as by intra-VTA infusion of brain-derived neurotrophic factor. In contrast, chronic morphine treatment did not alter the size of nondopaminergic neurons in the VTA, nor did it affect the total number of dopaminergic neurons in this brain region. The results of these studies provide direct evidence for structural alterations in VTA dopamine neurons as a consequence of chronic opiate exposure, which could contribute to changes in mesolimbic dopamine function associated with addiction. Images Fig. 2 Fig. 4 PMID:8855333

  14. CD200 attenuates methamphetamine-induced microglial activation and dopamine depletion.

    PubMed

    Yue, Xia; Qiao, Dongfang; Wang, Aifeng; Tan, Xiaohui; Li, Yanhong; Liu, Chao; Wang, Huijun

    2012-06-01

    This study examined the neuroprotective effect of cluster of differentiation molecule 200 (CD200) against methamphetamine (METH)-induced neurotoxicity. In the in vitro experiment, neuron-microglia cultures were treated with METH (20 μmol/L), METH (20 μmol/L)+CD200-Fc (10 μg/mL) or CD200-Fc (10 μg/mL). Those untreated served as control. Microglia activation expressed as the ratio of MHC-II/CD11b was assessed by flow cytometry. The cytokines (IL-1β, TNF-α) secreted by activated microglia were detected by enzyme-linked immunosorbent assay (ELISA). In the in vivo experiment, 40 SD rats were divided into control, METH, METH+CD200-Fc and CD200-Fc groups at random. Rats were intraperitoneally injected with METH (15 mg/kg 8 times at 12 h interval) in METH group, with METH (administered as the same dose and time as the METH group) and CD200-Fc (1 mg/kg at day 0, 2, 4 after METH injection) in METH+CD200-Fc group, with CD200-Fc (1 mg/kg injected as the same time as the METH+CD200-Fc group) or with physiological saline solution in the control group. The level of striatal dopamine (DA) in rats was measured by high-performance liquid chromatography (HPLC). The microglial cells were immunohistochemically detected for the expression of Iba-1, a marker for microglial activation. The results showed that METH could increase the microglia activation in the neuron-microglia cultures and elevate the secretion of IL-1β and TNF-α, which could be attenuated by CD200-Fc. Moreover, CD200-Fc could partially reverse the striatal DA depletion induced by METH and reduce the number of activated microglia, i.e. Iba-1-positive cells. It was concluded that CD200 may have neuroprotective effects against METH-induced neurotoxicity by inhibiting microglial activation and reversing DA depletion in striatum.

  15. Speech-induced striatal dopamine release is left lateralized and coupled to functional striatal circuits in healthy humans: A combined PET, fMRI and DTI study

    PubMed Central

    Simonyan, Kristina; Herscovitch, Peter; Horwitz, Barry

    2013-01-01

    Considerable progress has been recently made in understanding the brain mechanisms underlying speech and language control. However, the neurochemical underpinnings of normal speech production remain largely unknown. We investigated the extent of striatal endogenous dopamine release and its influences on the organization of functional striatal speech networks during production of meaningful English sentences using a combination of positron emission tomography (PET) with the dopamine D2/D3 receptor radioligand [11C]raclopride and functional MRI (fMRI). In addition, we used diffusion tensor tractography (DTI) to examine the extent of dopaminergic modulatory influences on striatal structural network organization. We found that, during sentence production, endogenous dopamine was released in the ventromedial portion of the dorsal striatum, in its both associative and sensorimotor functional divisions. In the associative striatum, speech-induced dopamine release established a significant relationship with neural activity and influenced the left-hemispheric lateralization of striatal functional networks. In contrast, there were no significant effects of endogenous dopamine release on the lateralization of striatal structural networks. Our data provide the first evidence for endogenous dopamine release in the dorsal striatum during normal speaking and point to the possible mechanisms behind the modulatory influences of dopamine on the organization of functional brain circuits controlling normal human speech. PMID:23277111

  16. Dopamine quinones activate microglia and induce a neurotoxic gene expression profile: relationship to methamphetamine-induced nerve ending damage.

    PubMed

    Kuhn, Donald M; Francescutti-Verbeem, Dina M; Thomas, David M

    2006-08-01

    Methamphetamine (METH) intoxication leads to persistent damage of dopamine (DA) nerve endings of the striatum. Recently, we and others have suggested that the neurotoxicity associated with METH is mediated by extensive microglial activation. DA itself has been shown to play an obligatory role in METH neurotoxicity, possibly through the formation of quinone species. We show presently that DA-quinones (DAQ) cause a time-dependent activation of cultured microglial cells. Microarray analysis of the effects of DAQ on microglial gene expression revealed that 101 genes were significantly changed in expression, with 73 genes increasing and 28 genes decreasing in expression. Among those genes differentially regulated by DAQ were those often associated with neurotoxic conditions including inflammation, cytokines, chemokines, and prostaglandins. In addition, microglial genes associated with a neuronally protective phenotype were among those that were downregulated by DAQ. These results implicate DAQ as one species that could cause early activation of microglial cells in METH intoxication, manifested as an alteration in the expression of a broad biomarker panel of genes. These results also link oxidative stress, chemical alterations in DA to its quinone, and microglial activation as part of a cascade of glial-neuronal crosstalk that can amplify METH-induced neurotoxicity.

  17. Adrenergic hyperactivity and metanephrine excess in the nucleus accumbens after prefrontocortical dopamine depletion.

    PubMed

    Espejo, E F; Miñano, J

    2001-03-01

    Selective dopamine depletion within the medial prefrontal cortex in rats is known to enhance dopamine and norepinephrine levels in the nucleus accumbens and to induce characteristic behavioral disturbances. The present study was designed to determine levels of adrenaline, apart from dopamine and norepinephrine, and metabolites in the nucleus accumbens after prefrontocortical dopamine depletion. Prefrontocortical dopamine depletion was carried out by injecting 6-hydroxydopamine, and it was validated through: the emergence of behavioral disturbances such as amphetamine-induced stereotypies, spontaneous motor hyperactivity, and enhanced "anxiety-like" responses and through postmortem quantification of catecholamine levels by using high-performance liquid chromatography. The findings indicated that lesioned rats exhibited more oral stereotypies after amphetamine, were hyperlocomotive, and showed more pronounced anxiety-like behaviors than controls. Following prefrontocortical dopamine depletion, postmortem concentrations of dopamine and norepinephrine, along with the metabolites 3,4-dihydroxyphenylacetic acid and vanillylmandelic acid, were reliably enhanced in the nucleus accumbens as expected, and dopamine turnover was decreased. Furthermore the nucleus accumbens contained higher levels of adrenaline and its transmethylated metabolite metanephrine. To sum up, prefrontocortical dopamine depletion induces motor and emotional disturbances in rats and alters the neurochemical profile of the nucleus accumbens, not only inducing dopaminergic and noradrenergic hyperactivity but also leading to adrenaline and metanephrine excess.

  18. Reboxetine enhances the olanzapine-induced antipsychotic-like effect, cortical dopamine outflow and NMDA receptor-mediated transmission.

    PubMed

    Marcus, Monica M; Jardemark, Kent; Malmerfelt, Anna; Björkholm, Carl; Svensson, Torgny H

    2010-08-01

    Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D(2/3) antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain.

  19. Pathogen-Mimicking Polymeric Nanoparticles based on Dopamine Polymerization as Vaccines Adjuvants Induce Robust Humoral and Cellular Immune Responses.

    PubMed

    Liu, Qi; Jia, Jilei; Yang, Tingyuan; Fan, Qingze; Wang, Lianyan; Ma, Guanghui

    2016-04-06

    Aiming to enhance the immunogenicity of subunit vaccines, a novel antigen delivery and adjuvant system based on dopamine polymerization on the surface of poly(D,L-lactic-glycolic-acid) nanoparticles (NPs) with multiple mechanisms of immunity enhancement is developed. The mussel-inspired biomimetic polydopamine (pD) not only serves as a coating to NPs but also functionalizes NP surfaces. The method is facile and mild including simple incubation of the preformed NPs in the weak alkaline dopamine solution, and incorporation of hepatitis B surface antigen and TLR9 agonist unmethylated cytosine-guanine (CpG) motif with the pD surface. The as-constructed NPs possess pathogen-mimicking manners owing to their size, shape, and surface molecular immune-activating properties given by CpG. The biocompatibility and biosafety of these pathogen-mimicking NPs are confirmed using bone marrow-derived dendritic cells. Pathogen-mimicking NPs hold great potential as vaccine delivery and adjuvant system due to their ability to: 1) enhance cytokine secretion and immune cell recruitment at the injection site; 2) significantly activate and maturate dendritic cells; 3) induce stronger humoral and cellular immune responses in vivo. Furthermore, this simple and versatile dopamine polymerization method can be applicable to endow NPs with characteristics to mimic pathogen structure and function, and manipulate NPs for the generation of efficacious vaccine adjuvants. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. 3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: β-ketoamphetamine modulation of neurotoxicity by the dopamine transporter

    PubMed Central

    Anneken, John H.; Angoa-Pérez, Mariana; Kuhn, Donald M.

    2016-01-01

    Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of ‘bath salts’ and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity. PMID:25626880

  1. Protection of malonate-induced GABA but not dopamine loss by GABA transporter blockade in rat striatum.

    PubMed

    Zeevalk, Gail D; Manzino, Lawrence; Sonsalla, Patricia K

    2002-07-01

    Previous work has shown that overstimulation of GABA(A) receptors can potentiate neuronal cell damage during excitotoxic or metabolic stress in vitro and that GABA(A) antagonists or GABA transport blockers are neuroprotective under these situations. Malonate, a reversible succinate dehydrogenase/mitochondrial complex II inhibitor, is frequently used in animals to model cell loss in neurodegenerative diseases such as Parkinson's and Huntington's diseases. To determine if GABA transporter blockade during mitochondrial impairment can protect neurons in vivo as compared with in vitro studies, rats received a stereotaxic infusion of malonate (2 micromol) into the left striatum to induce a metabolic stress. The nonsubstrate GABA transport blocker, NO711 (20 nmol) was infused in some rats 30 min before and 3 h following malonate infusion. After 1 week, dopamine and GABA levels in the striata were measured. Malonate caused a significant loss of striatal dopamine and GABA. Blockade of the GABA transporter significantly attenuated GABA, but not dopamine loss. In contrast with several in vitro reports, GABA(A) receptors were not a downstream mediator of protection by NO711. Intrastriatal infusion of malonate (2 micromol) plus or minus the GABA(A) receptor agonist muscimol (1 micromol), the GABA(A) Cl- binding site antagonist picrotoxin (50 nmol) or the GABA(B) receptor antagonist saclofen (33 nmol) did not modify loss of striatal dopamine or GABA when examined 1 week following infusion. These data show that GABA transporter blockade during mitochondrial impairment in the striatum provides protection to GABAergic neurons. GABA transporter blockade, which is currently a pharmacological strategy for the treatment of epilepsy, may thus also be beneficial in the treatment of acute and chronic conditions involving energy inhibition such as stroke/ischemia or Huntington's disease. These findings also point to fundamental differences between immature and adult neurons in the

  2. Mesolimbic dopamine and its neuromodulators in obesity and binge eating.

    PubMed

    Naef, Lindsay; Pitman, Kimberley A; Borgland, Stephanie L

    2015-12-01

    Obesity has reached epidemic prevalence, and much research has focused on homeostatic and nonhomeostatic mechanisms underlying overconsumption of food. Mesocorticolimbic circuitry, including dopamine neurons of the ventral tegmental area (VTA), is a key substrate for nonhomeostatic feeding. The goal of the present review is to compare changes in mesolimbic dopamine function in human obesity with diet-induced obesity in rodents. Additionally, we will review the literature to determine if dopamine signaling is altered with binge eating disorder in humans or binge eating modeled in rodents. Finally, we assess modulation of dopamine neurons by neuropeptides and peripheral peptidergic signals that occur with obesity or binge eating. We find that while decreased dopamine concentration is observed with obesity, there is inconsistency outside the human literature on the relationship between striatal D2 receptor expression and obesity. Finally, few studies have explored how orexigenic or anorexigenic peptides modulate dopamine neuronal activity or striatal dopamine in obese models. However, ghrelin modulation of dopamine neurons may be an important factor for driving binge feeding in rodents.

  3. Acute treatment with doxorubicin induced neurochemical impairment of the function of dopamine system in rat brain structures.

    PubMed

    Antkiewicz-Michaluk, Lucyna; Krzemieniecki, Krzysztof; Romanska, Irena; Michaluk, Jerzy; Krygowska-Wajs, Anna

    2016-06-01

    The clinical studies have shown that chemotherapy may impair cognitive functions especially in the patients treated for breast cancer. It should be mention that only few studies have made use of animals to investigate the effects of chemotherapy on the brain function. Doxorubicin (Adriamycin) is an anthracycline antibiotic commonly used for chemotherapy of breast cancer. This study examined the effect of doxorubicin (1.5 and 3.0mg/kg ip) after acute administration on the levels of dopamine, noradrenaline, serotonin and their metabolites in the rat brain structures connected with cognition and psychiatric disorders. The data indicate that doxorubicin produced a significant and specific for the dopamine system inhibition of its activity in the investigated structures connected with the fall of dopamine concentration (decrease from 25 to 30% in the frontal cortex; from 30 to 60% in the hippocampus and about 20% of the control in the striatum, p<0.05) and its extraneuronal metabolite, 3-MT (from 35% in the frontal cortex to 60% in the hippocampus of the control level, p<0.01). However, doxorubicin did not affect others monoaminergic transmitters in the brain: noradrenaline and serotonin. Summing up, these data indicate that a single injection of doxorubicin produced a clear and significant inhibition of dopamine system activity in all investigated structures with the strongest effect in the hippocampus what may lead to the disturbances of the cognitive functions at the patients treated for cancer. Moreover, such treatment did not significantly affect others monoaminergic transmitters such as noradrenaline and serotonin. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  4. High-Fat-Diet-Induced Deficits in Dopamine Terminal Function Are Reversed by Restoring Insulin Signaling.

    PubMed

    Fordahl, Steve C; Jones, Sara R

    2017-02-15

    Systemically released insulin crosses the blood-brain barrier and binds to insulin receptors on several neural cell types, including dopaminergic neurons. Insulin has been shown to decrease dopamine neuron firing in the ventral tegmental area (VTA), but potentiate release and reuptake at dopamine terminals in the nucleus accumbens (NAc). Here we show that prolonged consumption of a high fat diet blocks insulin's effects in the NAc, but insulin's effects are restored by inhibiting protein tyrosine phosphatase 1B, which supports insulin receptor signaling. Mice fed a high fat diet (60% kcals from fat) displayed significantly higher fasting blood glucose 160 mg/dL, compared to 101 mg/dL for control-diet-fed mice, and high-fat-diet-fed mice showed reduced blood glucose clearance after an intraperitoneal glucose tolerance test. Using fast scan cyclic voltammetry to measure electrically evoked dopamine in brain slices containing the NAc core, high-fat-diet-fed mice exhibited slower dopamine reuptake compared to control-diet-fed mice (2.2 ± 0.1 and 2.67 ± 0.15 μM/s, respectively). Moreover, glucose clearance rate was negatively correlated with Vmax. Insulin (10 nM to 1 μM) dose dependently increased reuptake rates in control-diet-fed mice compared with in the high-fat-diet group; however, the small molecule insulin receptor sensitizing agent, TCS 401 (300 nM), restored reuptake in high-fat-diet-fed mice to control-diet levels, and a small molecule inhibitor of the insulin receptor, BMS 536924 (300 nM), attenuated reuptake, similar to high-fat-diet-fed mice. These data show that a high-fat diet impairs dopamine reuptake by attenuating insulin signaling at dopamine terminals.

  5. A receptor-based model for dopamine-induced fMRI signal.

    PubMed

    Mandeville, Joseph B; Sander, Christin Y M; Jenkins, Bruce G; Hooker, Jacob M; Catana, Ciprian; Vanduffel, Wim; Alpert, Nathaniel M; Rosen, Bruce R; Normandin, Marc D

    2013-07-15

    This report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine's effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET (11)C-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations.

  6. Decreased dopamine concentrations in the frontal cortex after ablative surgeries in patients exhibiting self-injurious behavior: a microdialysis study.

    PubMed

    Liu, Aijun; Li, Anmin; Zhang, Haitao; Zhang, Zhiwen

    2014-01-01

    The authors examined brain neurochemistry in four patients with mental retardation with self-injurious behaviors after ablative surgeries. The authors found that surgeries in the human limbic system can alter dopamine levels in the frontal cortex over a 36-hour period.

  7. Activation of dopamine D1 receptors in the medial septum improves scopolamine-induced amnesia in the dorsal hippocampus.

    PubMed

    Zarrindast, Mohammad Reza; Ardjmand, Abolfazl; Ahmadi, Shamseddin; Rezayof, Ameneh

    2012-04-01

    In the present study, we investigated the influence of intra-medial septum (intra-MS) injections of dopamine D1 receptor agents on amnesia induced by intra-CA1 injections of a muscarinic acetylcholine receptor antagonist, scopolamine. This study used a step-through inhibitory (passive) avoidance task to assess memory in adult male Wistar rats. The results showed that in the animals that received post-training intra-MS injections of saline, intra-CA1 administrations of scopolamine (0.75, 1, and 2 μg/rat) decreased inhibitory avoidance (IA) memory consolidation as evidenced by a decrease in step-through latency on the test day, which was suggestive of drug-induced amnesia. Post-training intra-MS injections of a dopamine D1 receptor agonist, SKF38393 at doses of 0.1, 0.15, and 0.3 μg/rat had no effect, but at dose of 0.5 μg/rat impaired IA memory consolidation. Interestingly, intra-MS injections of SKF38393 (0.15, 0.3 and 0.5 μg/rat) significantly prevented amnesia induced by intra-CA1 injections of scopolamine (1 μg/rat). Intra-MS injections of a dopamine D1 receptor antagonist, SCH23390 (0.5 and 0.75 μg/rat) by itself impaired IA memory consolidation, and also at dose of 0.75 μg/rat increased amnesia induced by intra-CA1 administrations of an ineffective dose of scopolamine (0.5 μg/rat). Post-training intra-MS injections of ineffective doses of SCH23390 (0.1, 0.3 and 0.5 μg/rat) prevented an effective dose of SKF38393 response to the impaired effect of scopolamine. These results suggest that dopamine D1 receptors in the MS via projection neurons to the hippocampus affect impairment of memory consolidation induced by intra-CA injections of scopolamine.

  8. Development of conditioned place preference induced by intra-accumbens infusion of amphetamine is attenuated by co-infusion of dopamine D1 and D2 receptor antagonists.

    PubMed

    Liao, Ruey-Ming

    2008-05-01

    The present study investigated the role of dopamine receptors within the nucleus accumbens in place conditioning induced by D-amphetamine. Previous work has shown that conditioned place preference can be established by intra-accumbens infusion of amphetamine. The present study further examined whether bilateral co-infusion of the selective dopamine receptor antagonists with D-amphetamine into this region would disrupt the development of conditioned place preference induced by intra-accumbens amphetamine treatment. Bilateral infusions of D-amphetamine into the nucleus accumbens at the dose of 10 microg per side significantly induced conditioned place preference. At the tested doses of 1 microg and 10 microg, either the selective D1 dopamine receptor antagonist (SCH23390) or the selective D2 dopamine receptor antagonist (raclopride) infused with the high dose into the nucleus accumbens significantly blocked the development of conditioned place preference induced by intra-accumbens amphetamine treatment. Furthermore, the sole infusion of SCH23390 or raclopride into the nucleus accumbens produced little or no place conditioning effect. It is concluded that the dopamine D1 and D2 receptors in the nucleus accumbens are critically involved in the development of amphetamine induced conditioned place preference.

  9. Retrodialysis of N/OFQ into the nucleus accumbens shell blocks cocaine-induced increases in extracellular dopamine and locomotor activity.

    PubMed

    Vazquez-DeRose, Jacqueline; Stauber, Gregory; Khroyan, Taline V; Xie, Xinmin Simon; Zaveri, Nurulain T; Toll, Lawrence

    2013-01-15

    Nociceptin (N/OFQ) has been implicated in a variety of neurological disorders, most notably in reward processes and drug abuse. N/OFQ suppresses extracellular dopamine in the nucleus accumbens (NAc) after intracerebroventricular injection. This study sought to examine the effects of retrodialyzed N/OFQ on the cocaine-induced increase in extracellular dopamine levels in the NAc, as well as locomotor activity, in freely moving rats. 1.0μM, 10μM, and 1mM N/OFQ, in the NAc shell, significantly suppressed the cocaine-induced dopamine increase in the NAc, while N/OFQ alone had no significant effect on dopamine levels. Co-delivery of the selective NOP receptor antagonist SB612111 ([(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] reversed the N/OFQ suppression of cocaine-induced dopamine in the NAc, suggesting that this is an NOP receptor-mediated effect. Using a novel system to assess locomotion, we measured various motor activities of the animals with simultaneous microdialysis from the home cage. Cocaine produced an expected increase in total activity, including horizontal movement and rearing behavior. Retrodialysis of N/OFQ with cocaine administration affected all motor activities, initially showing no effect on behavior, but over time inhibiting cocaine-induced motor behaviors. These results suggest that N/OFQ can act directly in the NAc shell to block cocaine-induced increases in extracellular dopamine levels. Extracellular dopamine and locomotor activity can be dissociated within the NAc and may reflect motor output differences in shell versus core regions of the NAc. These studies confirm the widespread involvement of NOP receptors in drug addiction and further validate the utility of an NOP receptor agonist as a medication for treatment of drug addiction.

  10. Diabetic retinopathy alters light-induced clock gene expression and dopamine levels in the mouse retina

    PubMed Central

    Lahouaoui, Hasna; Coutanson, Christine; Cooper, Howard M.; Bennis, Mohamed

    2016-01-01

    Purpose Diabetic retinopathy is one of the most common consequences of diabetes that affects millions of working-age adults worldwide and leads to progressive degeneration of the retina, visual loss, and blindness. Diabetes is associated with circadian disruption of the central and peripheral circadian clocks, but the mechanisms responsible for such alterations are unknown. Using a streptozotocin (STZ)-induced model of diabetes, we investigated whether diabetes alters 1) the circadian regulation of clock genes in the retina and in the central clocks, 2) the light response of clock genes in the retina, and/or 3) light-driven retinal dopamine (DA), a major output marker of the retinal clock. Methods To quantify circadian expression of clock and clock-controlled genes, retinas and suprachiasmatic nucleus (SCN) from the same animals were collected every 4 h in circadian conditions, 12 weeks post-diabetes. Induction of Per1, Per2, and c-fos mRNAs was quantified in the retina after the administration of a pulse of monochromatic light (480 nm, 1.17×1014 photons/cm2/s, 15 min) at circadian time 16. Gene expression was assessed with real-time reverse transcription PCR (RT–PCR). Pooled retinas from the control and STZ-diabetic mice were collected 2 h after light ON and light OFF (Zeitgeber time (ZT)2 and ZT14), and DA and its metabolite were analyzed with high-performance liquid chromatography (HPLC). Results We found variable effects of diabetes on the expression of clock genes in the retina and only slight differences in phase and/or amplitude in the SCN. c-fos and Per1 induction by a 480 nm light pulse was abolished in diabetic animals at 12 weeks post-induction of diabetes in comparison with the control mice, suggesting a deficit in light-induced neuronal activation of the retinal clock. Finally, we quantified a 56% reduction in the total number of tyrosine hydroxylase (TH) immunopositive cells, associated with a decrease in DA levels during the subjective day (ZT2

  11. Up-regulation of TRPV1 in mononuclear cells of end-stage kidney disease patients increases susceptibility to N-arachidonoyl-dopamine (NADA)-induced cell death.

    PubMed

    Saunders, Cassandra I; Fassett, Robert G; Geraghty, Dominic P

    2009-10-01

    Transient receptor potential vanilloid (TRPV) 1 channels function as sensors for a variety of noxious and inflammatory signals, including capsaicin, heat and protons, and are up-regulated under inflammatory conditions. As end-stage kidney disease (ESKD) is associated with chronic inflammation, impaired immunity and depressed lymphocyte numbers, we sought to determine whether altered TRPV1 (and related TRPV2) expression in immune cells might be a contributing factor. TRPV1 and TRPV2 mRNA expression in peripheral blood mononuclear cells (PBMC) was similar in controls and ESKD patients by quantitative real-time RT-PCR. However, using immunocytochemistry, TRPV1-immunoreactivity was significantly higher and TRPV2-immunoreactivity was significantly lower in PBMC from ESKD patients compared to controls. The plant-derived TRPV1 agonists, capsaicin and resiniferatoxin (RTX) and the putative endovanilloid/endocannabinoids, N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine (OLDA), induced concentration-dependent death of PBMC from healthy donors with a rank order of potency of RTX>NADA>OLDA>capsaicin. TRPV1 (5'-iodoresiniferatoxin) and cannabinoid (CB2; AM630) receptor antagonists blocked the cytotoxic effect of NADA. In subsequent experiments, PBMC from ESKD patients exhibited significantly increased susceptibility to NADA-induced death compared to PBMC from controls. The apparent up-regulation of TRPV1 may be a response to the inflammatory milieu in which PBMC exist in ESKD and may be responsible for the increased susceptibility of these cells to NADA-induced death, providing a possible explanation as to why ESKD patients have reduced lymphocyte counts and impaired immune function. Thus, TRPV1 (and possibly CB2) antagonists may have potential for the treatment of immune dysfunction in ESKD.

  12. Involvement of dopamine receptors in binge methamphetamine-induced activation of endoplasmic reticulum and mitochondrial stress pathways.

    PubMed

    Beauvais, Genevieve; Atwell, Kenisha; Jayanthi, Subramaniam; Ladenheim, Bruce; Cadet, Jean Lud

    2011-01-01

    Single large doses of methamphetamine (METH) cause endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D(1) receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D(1) and D(2) receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D(1) or D(2) receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58(IPK), in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins (HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D(2)-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors.

  13. Involvement of Dopamine Receptors in Binge Methamphetamine-Induced Activation of Endoplasmic Reticulum and Mitochondrial Stress Pathways

    PubMed Central

    Beauvais, Genevieve; Atwell, Kenisha; Jayanthi, Subramaniam; Ladenheim, Bruce; Cadet, Jean Lud

    2011-01-01

    Single large doses of methamphetamine (METH) cause endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D1 receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D1 and D2 receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D1 or D2 receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58IPK, in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins (HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D2-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors. PMID:22174933

  14. Dopamine actions in vitro on enzyme and electrolyte secretion from normal and sympathectomized rat parotid glands.

    PubMed Central

    Danielsson, A; Henriksson, R; Sundström, S; Wester, P

    1988-01-01

    1. Adult rats were denervated unilaterally by removal of the left superior cervical ganglion or chemically denervated with 6-hydroxydopamine or reserpine. Two weeks later the parotid glands were used for in vitro secretory studies and their catecholamines and major metabolites were measured. 2. Noradrenaline concentrations were reduced 2 weeks after surgical sympathectomy and reserpine pre-treatment 18 h previously, whereas 6-hydroxydopamine pre-treatment for 3 days reduced both noradrenaline and dopamine concentrations. 3. Dopamine caused a prominent amylase release from incubated control glands. However, a subsensitivity for dopamine-induced amylase release was recorded on the denervated side. 4. Dopamine caused a prominent potassium efflux measured as 86Rb+ efflux from control glands, but was without effect in denervated glands. This is in contrast to noradrenaline-induced 86Rb+ efflux which was equally effective in both denervated and control glands. 5. Dopamine caused [3H]noradrenaline efflux in control glands, but was without effect in surgically denervated glands and in glands pre-treated with reserpine or 6-hydroxydopamine. 6. It is concluded that dopamine-induced potassium release is caused by a presynaptic action on noradrenergic nerves, whereas dopamine-induced amylase release has a presynaptic and a postsynaptic component. The results suggest a specific action of dopamine in salivary glands, with different effects on enzyme release and ionic fluxes. PMID:2473198

  15. Signaling Pathways that Medicine Neurotoxin-Induced Death of Dopamine Neurons

    DTIC Science & Technology

    2007-11-01

    4-phenyl-1,2,3,tetrahydropyridine (MPTP) or the pesticide rotenone . These neurotoxins inhibit complex I of the mitochondrial respiratory chain...neurodegeneration, apoptosis, dopamine neurons, MPTP, rotenone , intrinsic death pathway 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF...prevent death. Our overall working hypothesis is that the Parkinsonian neurotoxins, MPP+ and rotenone , share a common mechanism of action to

  16. Dopamine, Working Memory, and Training Induced Plasticity: Implications for Developmental Research

    ERIC Educational Resources Information Center

    Soderqvist, Stina; Bergman Nutley, Sissela; Peyrard-Janvid, Myriam; Matsson, Hans; Humphreys, Keith; Kere, Juha; Klingberg, Torkel

    2012-01-01

    Cognitive deficits and particularly deficits in working memory (WM) capacity are common features in neuropsychiatric disorders. Understanding the underlying mechanisms through which WM capacity can be improved is therefore of great importance. Several lines of research indicate that dopamine plays an important role not only in WM function but also…

  17. Dopamine, Working Memory, and Training Induced Plasticity: Implications for Developmental Research

    ERIC Educational Resources Information Center

    Soderqvist, Stina; Bergman Nutley, Sissela; Peyrard-Janvid, Myriam; Matsson, Hans; Humphreys, Keith; Kere, Juha; Klingberg, Torkel

    2012-01-01

    Cognitive deficits and particularly deficits in working memory (WM) capacity are common features in neuropsychiatric disorders. Understanding the underlying mechanisms through which WM capacity can be improved is therefore of great importance. Several lines of research indicate that dopamine plays an important role not only in WM function but also…

  18. 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

  19. A Brain on Cannabinoids: The Role of Dopamine Release in Reward Seeking

    PubMed Central

    Oleson, Erik B.; Cheer, Joseph F.

    2012-01-01

    Increases in mesolimbic dopamine transmission are observed when animals are treated with all known drugs of abuse, including cannabis, and to conditioned stimuli predicting their availability. In contrast, decreases in mesolimbic dopamine function are observed during drug withdrawal, including cannabis-withdrawal syndrome. Thus, despite general misconceptions that cannabis is unique from other drugs of abuse, cannabis exerts identical effects on the mesolimbic dopamine system. The recent discovery that endogenous cannabinoids modulate the mesolimbic dopamine system, however, might be exploited for the development of potential pharmacotherapies designed to treat disorders of motivation. Indeed, disrupting endocannabinoid signaling decreases drug-induced increases in dopamine release in addition to dopamine concentrations evoked by conditioned stimuli during reward seeking. PMID:22908200

  20. A receptor-based model for dopamine-induced fMRI signal

    PubMed Central

    Mandeville, Joseph. B.; Sander, Christin Y. M.; Jenkins, Bruce G.; Hooker, Jacob M.; Catana, Ciprian; Vanduffel, Wim; Alpert, Nathaniel M.; Rosen, Bruce R.; Normandin, Marc D.

    2013-01-01

    This report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine’s effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET 11C-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations. PMID:23466936

  1. Effects of dopamine and dobutamine on isoflurane-induced hypotension in Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Schnellbacher, Rodney W; da Cunha, Anderson F; Beaufrère, Hugues; Queiroz, Patricia; Nevarez, Javier G; Tully, Thomas N

    2012-07-01

    To assess the effects of dopamine and dobutamine on the blood pressure of isoflurane-anesthetized Hispaniolan Amazon parrots (Amazona ventralis). 8 Hispaniolan Amazon parrots. A randomized crossover study was conducted. Each bird was anesthetized (anesthesia maintained by administration of 2.5% isoflurane in oxygen) and received 3 doses of each drug during a treatment period of 20 min/dose. Treatments were constant rate infusions (CRIs) of dobutamine (5, 10, and 15 μg/kg/min) and dopamine (5, 7, and 10 μg/kg/min). Direct systolic, diastolic, and mean arterial pressure measurements, heart rate, esophageal temperature, and end-tidal partial pressure of CO(2) were recorded throughout the treatment periods. Mean ± SD of the systolic, mean, and diastolic arterial blood pressures at time 0 (initiation of a CRI) were 132.9 ± 22.1 mm Hg, 116.9 ± 20.5 mm Hg, and 101.9 ± 22.0 mm Hg, respectively. Dopamine resulted in significantly higher values than did dobutamine for the measured variables, except for end-tidal partial pressure of CO(2). Post hoc multiple comparisons revealed that the changes in arterial blood pressure were significantly different 4 to 7 minutes after initiation of a CRI. Overall, dopamine at rates of 7 and 10 μg/kg/min and dobutamine at a rate of 15 μg/kg/min caused the greatest increases in arterial blood pressure. Dobutamine CRI at 5, 10, and 15 μg/kg/min and dopamine CRI at 5, 7, and 10 μg/kg/min may be useful in correcting severe hypotension in Hispaniolan Amazon parrots caused by anesthesia maintained with 2.5% isoflurane.

  2. Seasonal changes in circadian peripheral plasma concentrations of melatonin, serotonin, dopamine and cortisol in aged horses with Cushing's disease under natural photoperiod.

    PubMed

    Haritou, S J A; Zylstra, R; Ralli, C; Turner, S; Tortonese, D J

    2008-08-01

    Equine pituitary pars intermedia dysfunction (PPID) is a common and serious condition that gives rise to Cushing's disease. In the older horse, it results in hyperadrenocorticism and disrupted energy metabolism, the severity of which varies with the time of year. To gain insight into the mechanism of its pathogenesis, 24-h profiles for peripheral plasma melatonin, serotonin, dopamine and cortisol concentrations were determined at the winter and summer solstices, and the autumn and spring equinoxes in six horses diagnosed with Cushing's disease and six matched controls. The nocturnal rises in plasma melatonin concentrations, although different across seasons, were broadly of the same duration and similar amplitude in both groups of animals (P > 0.05). The plasma concentrations of cortisol did not show seasonal variation and were different in diseased horses only in the summer when they were higher across the entire 24-h period (P < 0.05). Serotonin concentrations were not significantly affected by time of year but tended to be lower in Cushingoid horses (P = 0.07). By contrast, dopamine output showed seasonal variation and was significantly lower in the Cushing's group in the summer and autumn (P < 0.05). The finding that the profiles of circulating melatonin are similar in Cushingoid and control horses reveals that the inability to read time of year by animals suffering from Cushing's syndrome is an unlikely reason for the disease. In addition, the results provide evidence that alterations in the dopaminergic and serotoninergic systems may participate in the pathogenesis of PPID.

  3. Renal hemodynamics in radiocontrast medium-induced renal dysfunction: A role for dopamine-1 receptors.

    PubMed

    Bakris, G L; Lass, N A; Glock, D

    1999-07-01

    Radiocontrast medium (RCM) administration induces a transient increase in renal blood flow (RBF), followed by a prolonged vasoconstriction. This vasoconstrictor phase in RBF is accompanied by a decrement in glomerular filtration rate (GFR). Nonselective dopamine (DA) receptor stimulation is known to increase RBF and GFR. Clinical studies, however, fail to demonstrate a renoprotective effect of DA following RCM administration. This lack of renoprotection may relate to nonspecific adrenergic stimulation by DA. The effect of select DA-1 receptor stimulation on renal hemodynamics following RCM administration has not been evaluated. This study tests the hypothesis that selective DA-1 receptor stimulation blunts the declines in RBF and GFR that follow RCM injections, independent of changes in baseline RBF and GFR. Experiments were performed in six anesthetized, volume-depleted dogs. RBF was measured by an electromagnetic flow probe around the renal artery and GFR by inulin clearance. After a 60-minute equilibration period, baseline values of RBF, GFR, and arterial pressure were determined. Two separate intrarenal bolus injections of the ionic RCM Renograffin were then given in the presence of saline infusion. After a 60-minute recovery period, intra-arterial infusions of either the selective DA-1 receptor agonist fenoldopam or the selective DA-1 receptor antagonist Schering 23390 were started in random order, and experiments were repeated. Neither agent significantly altered baseline values of arterial pressure, RBF, or GFR rate. Fenoldopam prevented reductions in GFR (-17 +/- 2 Deltaml/min, control vs. 2 +/- 1 Deltaml/min, fenoldopam, P < 0.001). Conversely, GFR was further reduced in the presence of Schering 23390 (-15 +/- 2 Deltaml/min, control vs. -23 +/- 1 Deltaml/min, Schering 23390, P < 0.05). Similarly, the maximal reduction in RBF was blunted with fenoldopam (-71 +/- 12 Deltaml/min, control vs. -3 +/- 2 Deltaml/min, fenoldopam, P < 0. 01), whereas Schering 23390

  4. Relationship between dopamine transporter occupancy and methylphenidate induced high in humans

    SciTech Connect

    Volkow, N.D.; Wang, G.J.; Fowler, J.S. |

    1996-05-01

    The inhibition of the dopamine transporter (DAT) by cocaine has been shown to be indispensable for its reinforcing properties. The development of drugs that inibit the DAT has become a major target to prevent cocaine`s effects. However prevention of the {open_quotes}high{close_quotes} by DAT inhibitors has never been demonstrated. This study evaluates the ability to block methylphenidate (MP), a DAT inhibitor drug with similar reinforcing properties to cocaine, induced {open_quotes}high{close_quotes} by prior DAT inhibition. It uses PET and [{sup 11}C]d-threo-methylphenidate to measure the relationship between DAT occupancy prior to administration of MP and the intensity of the subjective perception of the {open_quotes}high{close_quotes} in 8 controls. MP (0.375 mg/kg iv) which was administered as a single injection and also as two sequential doses given 60 minutes apart significantly reduced the ratio of the distribution volume for [{sup 11}C]d-threo-methylphenidate in striatum to that in cerebellum from a baseline of 2.83 {plus_minus} 0.2 to 1.29 {plus_minus} 0.1 at 7 minutes and to 1.37 {plus_minus} 0.2 at 60 minutes after a single injection of MP and to 1.14 {plus_minus} 0.1 at 7 minutes after the second of two sequential MP doses. This corresponds to a DAT occupancy by MP of 84% {plus_minus} 7 at 7 minutes and of 77% {plus_minus} 6 at 60 minutes after a single injection of MP and of 93% {plus_minus} 7 at 7 after the second of two sequential MP doses. The subjective perception of {open_quotes}high{close_quotes} experienced after the second injection of MP was of a similar magnitude to that experienced after the first injection of MP was of a similar magnitude to that experienced after the first injection, in spite of the very different starting DAT occupancies (0 and 77%, respectively). DAT occupancy was not correlated with the {open_quotes}high{close_quotes}; and one subject with 100% DAT occupancy did not perceive the {open_quotes}high{close_quotes}.

  5. Taurine fails to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced striatal dopamine depletion in mice.

    PubMed

    Navneet, A K; Appukuttan, T A; Pandey, M; Mohanakumar, K P

    2008-08-01

    Taurine, a known antioxidant and neuroprotector has been investigated for its free radical scavenging action in vitro in isolated mitochondria, and tested whether it protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in mice. Taurine (0.1-10 mM) did not affect 1-methyl-4-phenyl pyridinium-induced hydroxyl radical production in isolated mitochondria. Systemic administration of taurine (250 mg/kg, i.p.) caused a small, but significant loss of dopamine levels in the striatum of mice. Taurine failed to reverse MPTP-induced striatal dopamine depletion, but caused significant increase in dopamine turnover in these animals. In the light of the present study it may be suggested that consumption of taurine may neither help in scavenging of neurotoxic hydroxyl radicals in the brain mitochondria, nor would it help in blocking the process of neurodegeneration.

  6. Dopamine agonist-induced penile erection and yawning: a comparative study in outbred Roman high- and low-avoidance rats.

    PubMed

    Sanna, Fabrizio; Corda, Maria Giuseppa; Melis, Maria Rosaria; Piludu, Maria Antonietta; Löber, Stefan; Hübner, Harald; Gmeiner, Peter; Argiolas, Antonio; Giorgi, Osvaldo

    2013-08-01

    The effects on penile erection and yawning of subcutaneous (SC) injections of the mixed dopamine D1/D2-like agonist apomorphine (0.02-0.2 mg/kg) were studied in outbred Roman high- (RHA) and low-avoidance (RLA) male rats, two lines selectively bred for their respectively rapid versus poor acquisition of the active avoidance response in the shuttle-box, and compared with the effects observed in male Sprague-Dawley (SD) rats. Apomorphine dose-response curves were bell-shaped in all rat lines/strains. Notably, more penile erections and yawns were recorded mainly in the ascending part of these curves (e.g., apomorphine 0.02-0.08 mg/kg) in both RLA and RHA rats compared to SD rats, with RLA rats showing the higher response (especially for yawning) with respect to RHA rats. Similar results were found with PD-168,077 (0.02-0.2 mg/kg SC), a D4 receptor agonist, which induced penile erection but not yawning. In all rat lines/strains, apomorphine responses were markedly reduced by the D2 antagonist L-741,626, but not by the D3 antagonist, SB277011A, whereas the D4 antagonists L-745,870 and FAUC213 elicited a partial, yet statistically significant, inhibitory effect. In contrast, the pro-erectile effect of PD-168,077 was completely abolished by L-745,870 and FAUC213, as expected. The present study confirms and extends previously reported differences in dopamine transmission between RLA and RHA rats and between the SD strain and the Roman lines. Moreover, it confirms previous studies supporting the view that dopamine receptors of the D2 subtype play a predominant role in the pro-yawning and pro-erectile effect of apomorphine, and that the selective stimulation of D4 receptors induces penile erection. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence

    PubMed Central

    Kenny, Jonathan D.; Taylor, Norman E.; Brown, Emery N.; Solt, Ken

    2015-01-01

    Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg IV), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg IV) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1–4 Hz) to θ (4–8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes

  8. Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.

    PubMed

    Kenny, Jonathan D; Taylor, Norman E; Brown, Emery N; Solt, Ken

    2015-01-01

    Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg i.v.), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg i.v.) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1-4 Hz) to θ (4-8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes

  9. Dopamine D1 and D2 dopamine receptors regulate immobilization stress-induced activation of the hypothalamus-pituitary-adrenal axis.

    PubMed

    Belda, Xavier; Armario, Antonio

    2009-10-01

    Whereas the role of most biogenic amines in the control of the hypothalamus-pituitary-adrenal (HPA) response to stress has been extensively studied, the role of dopamine has not. We studied the effect of different dopamine receptor antagonists on HPA response to a severe stressor (immobilization, IMO) in adult male Sprague-Dawley rats. Haloperidol administration reduced adrenocorticotropin hormone and corticosterone responses to acute IMO, particularly during the post-IMO period. This effect cannot be explained by a role of dopamine to maintain a sustained activation of the HPA axis as haloperidol did not modify the response to prolonged (up to 6 h) IMO. Administration of more selective D1 and D2 receptor antagonists (SCH23390 and eticlopride, respectively) also resulted in lower and/or shorter lasting HPA response to IMO. Dopamine, acting through both D1 and D2 receptors, exerts a stimulatory role on the activation of the HPA axis in response to a severe stressor. The finding that dopamine is involved in the maintenance of post-stress activation of the HPA axis is potentially important because the actual pathological impact of HPA activation is likely to be related to the area under the curve of plasma glucocorticoid levels, which is critically dependent on how long after stress high levels of glucocorticoid are maintained.

  10. Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study.

    PubMed

    Kuepper, Rebecca; Ceccarini, Jenny; Lataster, Johan; van Os, Jim; van Kroonenburgh, Marinus; van Gerven, Joop M A; Marcelis, Machteld; Van Laere, Koen; Henquet, Cécile

    2013-01-01

    Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and (18)F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ(9)-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ(9)-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in (18)F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ(9)-THC administration, reflecting dopamine release. While Δ(9)-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ(9)-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ(9)-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis.

  11. Delta-9-Tetrahydrocannabinol-Induced Dopamine Release as a Function of Psychosis Risk: 18F-Fallypride Positron Emission Tomography Study

    PubMed Central

    Kuepper, Rebecca; Ceccarini, Jenny; Lataster, Johan; van Os, Jim; van Kroonenburgh, Marinus; van Gerven, Joop M. A.; Marcelis, Machteld; Van Laere, Koen; Henquet, Cécile

    2013-01-01

    Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and 18F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ9-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in 18F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ9-THC administration, reflecting dopamine release. While Δ9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ9-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis. PMID:23936196

  12. 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

    SciTech Connect

    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 the 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.

  13. Autocrine activation of neuronal NMDA receptors by aspartate mediates dopamine- and cAMP-induced CREB-dependent gene transcription

    PubMed Central

    Almeida, Luis E. F.; Murray, Peter D.; Zielke, H. Ronald; Roby, Clinton D.; Kingsbury, Tami J.; Krueger, Bruce K.

    2009-01-01

    Cyclic AMP can stimulate the transcription of many activity-dependent genes via activation of the transcription factor, CREB. However, in mouse cortical neuron cultures, prior to synaptogenesis, neither cAMP nor dopamine, which acts via cAMP, stimulated CREB-dependent gene transcription when NR2B-containing NMDA receptors (NMDARs) were blocked. Stimulation of transcription by cAMP was potentiated by inhibitors of excitatory amino acid uptake, suggesting a role for extracellular glutamate or aspartate in cAMP-induced transcription. Aspartate was identified as the extracellular messenger: enzymatic scavenging of L-aspartate, but not glutamate, blocked stimulation of CREB-dependent gene transcription by cAMP; moreover, cAMP induced aspartate but not glutamate release. Taken together, these results suggest that cAMP acts via an autocrine or paracrine pathway to release aspartate, which activates NR2B-containing NMDARs, leading to Ca2+ entry and activation of transcription. This cAMP/aspartate/NMDAR signaling pathway may mediate the effects of transmitters such as dopamine on axon growth and synaptogenesis in developing neurons or on synaptic plasticity in mature neural networks. PMID:19812345

  14. Amantadine protects dopamine neurons by a dual action: reducing activation of microglia and inducing expression of GDNF in astroglia [corrected].

    PubMed

    Ossola, Bernardino; Schendzielorz, Nadia; Chen, Shih-Heng; Bird, Gary S; Tuominen, Raimo K; Männistö, Pekka T; Hong, Jau-Shyong

    2011-09-01

    Amantadine is commonly given to alleviate L-DOPA-induced dyskinesia of Parkinson's disease (PD) patients. Animal and human evidence showed that amantadine may also exert neuroprotection in several neurological disorders. Additionally, it is generally believed that this neuroprotection results from the ability of amantadine to inhibit glutamatergic NMDA receptor. However, several lines of evidence questioned the neuroprotective capacity of NMDA receptor antagonists in animal models of PD. Thus the cellular and molecular mechanism of neuroprotection of amantadine remains unclear. Using primary cultures with different composition of neurons, microglia, and astroglia we investigated the direct role of these glial cell types in the neuroprotective effect of amantadine. First, amantadine protected rat midbrain cultures from either MPP(+) or lipopolysaccharide (LPS), two toxins commonly used as PD models. Second, our studies revealed that amantadine reduced both LPS- and MPP(+)-induced toxicity of dopamine neurons through 1) the inhibition of the release of microglial pro-inflammatory factors, 2) an increase in expression of neurotrophic factors such as GDNF from astroglia. Lastly, differently from the general view on amantadine's action, we provided evidence suggesting that NMDA receptor inhibition was not crucial for the neuroprotective effect of amantadine. In conclusion, we report that amantadine protected dopamine neurons in two PD models through a novel dual mechanism, namely reducing the release of pro-inflammatory factors from activated microglia and increasing the expression of GNDF in astroglia.

  15. The Role of Endogenous Serotonin in Methamphetamine-Induced Neurotoxicity to Dopamine Nerve Endings of the Striatum

    PubMed Central

    Thomas, David M.; Angoa-Pérez, Mariana; Francescutti-Verbeem, Dina M.; Shah, Mrudang M.; Kuhn, Donald M.

    2010-01-01

    Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the striatum where long-term DA depletion and microglial activation are maximal. Endogenous DA has been implicated as a critical participant in METH-induced neurotoxicity, most likely as a substrate for non-enzymatic oxidation by METH-generated reactive oxygen species (ROS). The striatum is also extensively innervated by serotonin (5HT) nerve endings and this neurochemical system is modified by METH in much the same manner as seen in DA nerve endings (i.e., increased release of 5HT, loss of function in tryptophan hydroxylase and the serotonin transporter, long-term depletion of 5HT stores). 5HT can also be modified by ROS to form highly reactive species that damage neurons but its role in METH neurotoxicity has not been assessed. Increases in 5HT levels with 5HTP do not change METH-induced neurotoxicity to the DA nerve endings as revealed by reductions in DA, tyrosine hydroxylase and dopamine transporter levels. Partial reductions in 5HT with p-chlorophenylalanine (PCPA) are without effect on METH toxicity, despite the fact that PCPA largely prevents METH-induced hyperthermia. Mice lacking the gene for brain tryptophan hydroxylase 2 are devoid of brain 5HT and respond to METH in the same manner as wild-type controls, despite showing enhanced drug-induced hyperthermia. Taken together, the present results indicate that endogenous 5HT does not appear to play a role in METH-induced damage to DA nerve endings of the striatum. PMID:20722968

  16. The role of endogenous serotonin in methamphetamine-induced neurotoxicity to dopamine nerve endings of the striatum.

    PubMed

    Thomas, David M; Angoa Pérez, Mariana; Francescutti-Verbeem, Dina M; Shah, Mrudang M; Kuhn, Donald M

    2010-11-01

    Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the striatum where long-term DA depletion and microglial activation are maximal. Endogenous DA has been implicated as a critical participant in METH-induced neurotoxicity, most likely as a substrate for non-enzymatic oxidation by METH-generated reactive oxygen species. The striatum is also extensively innervated by serotonin (5HT) nerve endings and this neurochemical system is modified by METH in much the same manner as seen in DA nerve endings (i.e., increased release of 5HT, loss of function in tryptophan hydroxylase and the serotonin transporter, long-term depletion of 5HT stores). 5HT can also be modified by reactive oxygen species to form highly reactive species that damage neurons but its role in METH neurotoxicity has not been assessed. Increases in 5HT levels with 5-hydroxytryptophan do not change METH-induced neurotoxicity to the DA nerve endings as revealed by reductions in DA, tyrosine hydroxylase and dopamine transporter levels. Partial reductions in 5HT with p-chlorophenylalanine are without effect on METH toxicity, despite the fact that p-chlorophenylalanine largely prevents METH-induced hyperthermia. Mice lacking the gene for brain tryptophan hydroxylase 2 are devoid of brain 5HT and respond to METH in the same manner as wild-type controls, despite showing enhanced drug-induced hyperthermia. Taken together, the present results indicate that endogenous 5HT does not appear to play a role in METH-induced damage to DA nerve endings of the striatum.

  17. Pharmacology of Signaling Induced by Dopamine D1-Like Receptor Activation

    PubMed Central

    Undieh, Ashiwel S.

    2010-01-01

    Dopamine D1-like receptors consisting of D1 and D5 subtypes are intimately implicated in dopaminergic regulation of fundamental neurophysiologic processes such as mood, motivation, cognitive function, and motor activity. Upon stimulation, D1-like receptors initiate signal transduction cascades that are mediated through adenylyl cyclase or phosphoinositide metabolism, with subsequent enhancement of multiple downstream kinase cascades. The latter actions propagate and further amplify the receptor signals, thus predisposing D1-like receptors to multifaceted interactions with various other mediators and receptor systems. The adenylyl cyclase response to dopamine or selective D1-like receptor agonists is reliably associated with the D1 subtype, while emerging evidence indicates that the phosphoinositide responses in native brain tissues may be preferentially mediated through stimulation of the D5 receptor. Besides classic coupling of each receptor subtype to specific G proteins, additional biophysical models are advanced in attempts to account for differential subcellular distribution, heteromolecular oligomerization, and activity-dependent selectivity of the receptors. It is expected that significant advances in understanding of dopamine neurobiology will emerge from current and anticipated studies directed at uncovering the molecular mechanisms of D5 coupling to phosphoinositide signaling, the structural features that might enhance pharmacological selectivity for D5 versus D1 subtypes, the mechanism by which dopamine may modulate phosphoinositide synthesis, the contributions of the various responsive signal mediators to D1 or D5 interactions with D2-like receptors, and the spectrum of dopaminergic functions that may be attributed to each receptor subtype and signaling pathway. PMID:20547182

  18. Anti-dopamine beta-hydroxylase immunotoxin-induced sympathectomy in adult rats

    NASA Technical Reports Server (NTRS)

    Picklo, M. J.; Wiley, R. G.; Lonce, S.; Lappi, D. A.; Robertson, D.

    1995-01-01

    Anti-dopamine beta-hydroxylase immunotoxin (DHIT) is an antibody-targeted noradrenergic lesioning tool comprised of a monoclonal antibody against the noradrenergic enzyme, dopamine beta-hydroxylase, conjugated to saporin, a ribosome-inactivating protein. Noradrenergic-neuron specificity and completeness and functionality of sympathectomy were assessed. Adult, male Sprague-Dawley rats were given 28.5, 85.7, 142 or 285 micrograms/kg DHIT i.v. Three days after injection, a 6% to 73% decrease in the neurons was found in the superior cervical ganglia of the animals. No loss of sensory, nodose and dorsal root ganglia, neurons was observed at the highest dose of DHIT. In contrast, the immunotoxin, 192-saporin (142 micrograms/kg), lesioned all three ganglia. To assess the sympathectomy, 2 wk after treatment (285 micrograms/kg), rats were anesthetized with urethane (1 g/kg) and cannulated in the femoral artery and vein. DHIT-treated animals' basal systolic blood pressure and heart rate were significantly lower than controls. Basal plasma norepinephrine levels were 41% lower in DHIT-treated animals than controls. Tyramine-stimulated release of norepinephrine in DHIT-treated rats was 27% of controls. Plasma epinephrine levels of DHIT animals were not reduced. DHIT-treated animals exhibited a 2-fold hypersensitivity to the alpha-adrenergic agonist phenylephrine. We conclude that DHIT selectively delivered saporin to noradrenergic neurons resulting in destruction of these neurons. Anti-dopamine beta-hydroxylase immunotoxin administration produces a rapid, irreversible sympathectomy.

  19. Reward-Induced Phasic Dopamine Release in the Monkey Ventral Striatum and Putamen.

    PubMed

    Yoshimi, Kenji; Kumada, Shiori; Weitemier, Adam; Jo, Takayuki; Inoue, Masato

    2015-01-01

    In-vivo voltammetry has successfully been used to detect dopamine release in rodent brains, but its application to monkeys has been limited. We have previously detected dopamine release in the caudate of behaving Japanese monkeys using diamond microelectrodes (Yoshimi 2011); however it is not known whether the release pattern is the same in various areas of the forebrain. Recent studies have suggested variations in the dopaminergic projections to forebrain areas. In the present study, we attempted simultaneous recording at two locations in the striatum, using fast-scan cyclic voltammetry (FSCV) on carbon fibers, which has been widely used in rodents. Responses to unpredicted food and liquid rewards were detected repeatedly. The response to the liquid reward after conditioned stimuli was enhanced after switching the prediction cue. These characteristics were generally similar between the ventral striatum and the putamen. Overall, the technical application of FSCV recording in multiple locations was successful in behaving primates, and further voltammetric recordings in multiple locations will expand our knowledge of dopamine reward responses.

  20. Reward-Induced Phasic Dopamine Release in the Monkey Ventral Striatum and Putamen

    PubMed Central

    Weitemier, Adam; Inoue, Masato

    2015-01-01

    In-vivo voltammetry has successfully been used to detect dopamine release in rodent brains, but its application to monkeys has been limited. We have previously detected dopamine release in the caudate of behaving Japanese monkeys using diamond microelectrodes (Yoshimi 2011); however it is not known whether the release pattern is the same in various areas of the forebrain. Recent studies have suggested variations in the dopaminergic projections to forebrain areas. In the present study, we attempted simultaneous recording at two locations in the striatum, using fast-scan cyclic voltammetry (FSCV) on carbon fibers, which has been widely used in rodents. Responses to unpredicted food and liquid rewards were detected repeatedly. The response to the liquid reward after conditioned stimuli was enhanced after switching the prediction cue. These characteristics were generally similar between the ventral striatum and the putamen. Overall, the technical application of FSCV recording in multiple locations was successful in behaving primates, and further voltammetric recordings in multiple locations will expand our knowledge of dopamine reward responses. PMID:26110516

  1. Electrophysiological and amperometric evidence that modafinil blocks the dopamine uptake transporter to induce behavioral activation.

    PubMed

    Federici, M; Latagliata, E C; Rizzo, F R; Ledonne, A; Gu, H H; Romigi, A; Nisticò, R; Puglisi-Allegra, S; Mercuri, N B

    2013-11-12

    Although the wake-promoting drug modafinil has been shown to bind quite exclusively to the dopamine transporter (DAT), its action in the brain has been thought to be partially independent from the facilitation of the dopaminergic signals. Here we used electrophysiological and amperometric techniques to investigate the effects of modafinil on the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and on the synaptic overflow of dopamine in the dorsal striatum from the sliced tissue of wild-type and cocaine-insensitive genetically modified mice (DAT-CI). Moreover, we examined the consequences of modafinil administration on the locomotor behavior of wild-type and DAT-CI mice. In in vitro experiments, modafinil inhibited the spontaneous firing discharge of the dopaminergic neurons. More consistently, it potentiated firing inhibition and the membrane responses caused by exogenously applied dopamine on these cells. Furthermore, it augmented the stimulus-evoked outflow of DA in the striatum. Noteworthy, modafinil caused locomotor activation in wild-type mice. On the other hand, neither the electrophysiological nor the behavioral effects of modafinil were detected in DAT-CI animals. These results demonstrate that modafinil potentiates brain dopaminergic signals via DAT inhibition by acting at the same binding site of cocaine. Therefore, this mechanism of action explains most of the pharmacological properties of this compound in the clinical setting.

  2. Effect of morphine and lacosamide on levels of dopamine and 5-HIAA in brain regions of rats with induced hypoglycemia.

    PubMed

    Guzman, D Calderon; Garcia, E Hernandez; Mejia, G Barragan; Olguin, H Juarez; Gonzalez, J A Saldivar; Labra Ruiz, N A

    2014-01-15

    The study aimed to determine the effect of morphine and lacosamide on levels of dopamine and 5-HIAA in a hypoglycemic model. Female Wistar rats (n = 30), mean weight of 180 g were treated as follow: Group 1 (control) received 0.9% NaCl, Group II; morphine (10 mg kg(-1)), Group III; lacosamide (10 mg kg(-1)), Group IV; insulin (10 U.I. per rat), Group V; morphine (10 mg kg(-1))+insulin, Group VI; lacosamide (10 mg kg(-1))+ insulin. All administrations were made intraperitoneally every 24 h, for 5 days. Animals were sacrificed after the last dose to measure the levels of glucose in blood; dopamine and 5-HIAA in cortex, hemispheres and cerebellum/medulla oblongata regions. Levels of glucose decreased significantly in animals treated with morphine, lacosamide and all groups that received insulin alone or combined with respect to control group. Levels of Dopamine diminished significantly in cortex and increased significantly in hemispheres of animals that received morphine. In cortex, 5-HIAA increase significantly in the groups treated with morphine, morphine+insulin and lacosamide+insulin, however a significant decrease of the same substance was witnessed in cerebellum and medulla oblongata of animals that received morphine or lacosamide plus insulin. GSH increased significantly in cortex and cerebellum/medulla oblongata of animals treated with morphine and lacosamide alone or combined with insulin. Lipid peroxidation decreased significantly in cortex and cerebellum/medulla oblongata of groups that received lacosamide alone or combined with insulin. These results indicate that hypoglycemia induced changes in cellular regulation while morphine and lacosamide are accompanied by biochemical responses.

  3. Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

    PubMed Central

    Marcus, Monica M; Jardemark, Kent; Malmerfelt, Anna; Björkholm, Carl; Svensson, Torgny H

    2010-01-01

    Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D2/3 antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl--aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain. PMID:20463659

  4. [The pharmacological differences between kynurenine- and korazol-induced seizures (the participation of GABA-B receptors and dopamine)].

    PubMed

    Lapin, I P

    1998-01-01

    In experiments of male SHR (nonbred) and C57B1/6 mice [correction of rats] bicucullin intensified corasole-induced convulsions but had no effect on kynurenine convulsions, removed the anticonvulsive effect of phenibut against kynurenine and did not affect the anticonvulsive effect of diazepam against corasole. Phenibut and baclofen reduced the anticonvulsive effect of diazepam against corasole and caffeine. Haloperidol increased kynurenine-induced convulsions and had no effect on those caused by corasole. Dopamine removed the effect of haloperidol. Haloperidol and 6-oxydopamine weakened the sedative effect of phenibut. Blockade of GAMAB-receptors and weakening of dopaminergic activity are important in the mechanisms of kynurenine convulsions, and blockage of GABAA-receptors unrelated to it is important in the mechanisms of corasole convulsions. A functional antagonism in anticonvulsive activity may exist between these receptors. Bicucullin may probably have an effect both on GABAA- and GABAB-receptors.

  5. Dopamine uptake dynamics are preserved under isoflurane anesthesia.

    PubMed

    Brodnik, Zachary D; España, Rodrigo A

    2015-10-08

    Fast scan cyclic voltammetry is commonly used for measuring the kinetics of dopamine release and uptake. For experiments using an anesthetized preparation, urethane is preferentially used because it does not alter dopamine uptake kinetics compared to freely moving animals. Unfortunately, urethane is highly toxic, can induce premature death during experiments, and cannot be used for recovery surgeries. Isoflurane is an alternative anesthetic that is less toxic than urethane, produces a stable level of anesthesia over extended periods, and is often used for recovery surgeries. Despite these benefits, the effects of isoflurane on dopamine release and uptake have not been directly characterized. In the present studies, we assessed the utility of isoflurane for voltammetry experiments by testing dopamine signaling parameters under baseline conditions, after treatment with the dopamine uptake inhibitor cocaine, and after exposure to increasing concentrations of isoflurane. Our results indicate that surgical levels of isoflurane do not significantly alter terminal mechanisms of dopamine release and uptake over prolonged periods of time. Consequently, we propose that isoflurane is an acceptable anesthetic for voltammetry experiments, which in turn permits the design of studies in which dopamine signaling is examined under anesthesia prior to recovery and subsequent experimentation in the same animals.

  6. Effect of metoclopramide in guinea-pig ileum longitudinal muscle: evidence against dopamine-mediation.

    PubMed Central

    Zar, M A; Ebong, O; Bateman, D N

    1982-01-01

    The investigation examines the hypothesis that metoclopramide-induced potentiation of gastrointestinal motility is mediated through dopamine receptors. In vitro studies on the longitudinal muscle of the guinea-pig ileum were performed. Metoclopramide, in concentrations comparable with those seen in plasma after therapeutic doses in man, selectively potentiated the cholinergic response Dopamine (1-100 microM) inhibited cholinergic transmission by inhibiting neuronal acetylcholine release. The inhibitory action of dopamine was antagonised by phentolamine, and alpha-adrenoceptor antagonist, but not by the dopamine receptor antagonists metoclopramide or primozide. Bromocriptine inhibited cholinergic responses by a postsynaptic mechanism which was not antagonised by metoclopramide, primozide, or phentolamine. The results are consistent with the view that metoclopramide-induced potentiation of gastrointestinal motility does not involve local dopamine receptors. PMID:7056499

  7. Dopamine, T cells and multiple sclerosis (MS).

    PubMed

    Levite, Mia; Marino, Franca; Cosentino, Marco

    2017-03-10

    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

  8. Dopamine dysregulation syndrome and levodopa-induced dyskinesias in Parkinson disease: common consequences of anomalous forms of neural plasticity.

    PubMed

    Linazasoro, Gurutz

    2009-01-01

    Four to 10% of patients with Parkinson disease and chronically treated with levodopa undergo an addictionlike behavioral disturbance named dopamine dysregulation syndrome (DDS). This article suggests that patients with Parkinson disease could be especially prone to develop DDS due to the dopamine deficiency and the "priming" of neural networks by the chronic use of drugs with a short half-life, such as levodopa. These suggestions are based on the clinical and molecular similarities between levodopa-induced dyskinesias and behavioral alterations seen in DDS and addiction to illegal drugs. Motor and behavioral abnormalities can be seen as the consequence of common mechanisms involving anomalous forms of neural plasticity. These forms affect parts of the cortical-basal ganglia-thalamocortical circuits that are topographically organized to differently modulate emotional and motor functions. Recent evidence using positron emission tomography provides support to this idea. By contrast, molecular data suggest that functional segregation may be lost in addiction, DDS, and dyskinesias. The existence of common pathogenic mechanisms for both phenomena could provide the basis for common therapeutic strategies.

  9. The relationship between the daily dose, the plasma concentration of blonanserin, and its plasma anti-dopamine D2 and anti-serotonin 5-HT2A activity.

    PubMed

    Suzuki, Hidenobu; Gen, Keishi

    2010-01-01

    Blonanserin (BNS) possesses anti-serotonin 5-HT(2A) activity in addition to anti-dopamine D(2) activity, which is characteristic of second-generation antipsychotics, little information is available on its pharmacologic profile in vivo. We investigated the BNS daily dose, plasma concentration, plasma anti-D(2) activity, and plasma anti-5-HT(2A) activity in schizophrenia in a total of 14 subjects. Blood samples were taken 14 days after the BNS dose was fixed, and the plasma concentration was measured by means of high-performance liquid chromatographic (HPLC) method. In addition, the plasma anti-D(2) activity and anti-5-HT(2A) activity were measured by means of radioreceptor assays in which [(3)H]-spiperone and [(3)H]-ketanserin were used. The results revealed a statistically significant correlation between the daily dose and the plasma concentration (p = 0.04). Statistically significant correlations were also observed between the plasma concentration and the anti-D(2) activity and between the plasma concentration and the anti-5-HT(2A) activity (p = 0.003 and 0.04). It is therefore believed that both the anti-D(2) activity in plasma and the anti-5-HT(2A) activity in plasma are regulated almost solely by the unchanged principal. Moreover, the mean plasma serotonin/dopamine (S/D) ratio was 0.9 and BNS exhibited both anti-D(2) activity and also anti-5-HT(2A) activity in vivo, as well, so it was clear that the in vitro pharmacological profile was retained in vivo.

  10. Dopamine Signaling in the Nucleus Accumbens of Animals Self-Administering Drugs of Abuse

    PubMed Central

    Willuhn, Ingo; Wanat, Matthew J.; Clark, Jeremy J.; Phillips, Paul E. M.

    2013-01-01

    Abuse of psychoactive substances can lead to drug addiction. In animals, addiction is best modeled by drug self-administration paradigms. It has been proposed that the crucial common denominator for the development of drug addiction is the ability of drugs of abuse to increase extracellular concentrations of dopamine in the nucleus accumbens (NAcc). Studies using in vivo microdialysis and chronoamperometry in the behaving animal have demonstrated that drugs of abuse increase tonic dopamine concentrations in the NAcc. However, it is known that dopamine neurons respond to reward-related stimuli on a subsecond timescale. Thus, it is necessary to collect neurochemical information with this level of temporal resolution, as achieved with in vivo fast-scan cyclic voltammetry (FSCV), to fully understand the role of phasic dopamine release in normal behavior and drug addiction. We review studies that investigated the effects of drugs of abuse on NAcc dopamine levels in freely-moving animals using in vivo microdialysis, chronoamperometry and FSCV. After a brief introduction of dopamine anatomy and signal transduction, and a section on current theories of dopamine in natural goal-directed behavior, a discussion of techniques for the in vivo assessment of extracellular dopamine behaving animals is presented. Then, we review studies using these techniques to investigate changes in phasic and tonic dopamine signaling in the NAcc during 1) response-dependent and –independent administration of abused drugs, 2) drug-conditioned stimuli and operant behavior in self-administration paradigms, 3) drug withdrawal, and 4) cue-induced reinstatement of drug seeking. These results are then integrated with current ideas on the role of dopamine in addiction with an emphasis on a model illustrating phasic and tonic NAcc dopamine signaling during different stages of drug addiction. This model predicts that phasic dopamine release in response to drug-related stimuli will be enhanced over

  11. 3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: β-ketoamphetamine modulation of neurotoxicity by the dopamine transporter.

    PubMed

    Anneken, John H; Angoa-Pérez, Mariana; Kuhn, Donald M

    2015-04-01

    Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of 'bath salts' and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity. METH (a) enters DA nerve endings via the DAT, causes leakage of DA into the cytoplasm and then into the synapse via DAT-mediated reverse transport. Methylone (METHY) and mephedrone (MEPH; b), like METH, are substrates for the DAT but release

  12. Dopamine and binge eating behaviors

    PubMed Central

    Bello, Nicholas T.; Hajnal, Andras

    2010-01-01

    Central dopaminergic mechanisms are involved in the motivational aspects of eating and food choices. This review focuses on human and animal data examining the importance of dopamine on binge eating behaviors. Early works examining dopamine metabolites in the cerebrospinal fluid and plasma of bulimic individuals suggested decreased dopamine turnover during the active phase of the illness. While neuroimaging studies of dopamine mechanisms in bulimia nervosa (BN) and binge eating disorder (BED) are limited, genetic studies in humans have implicated an increased frequency of dopamine transporter and associated D2 receptor polymorphisms with binge pathology. Recent examinations of rodent models of dietary-induced binge eating (DIBE) have investigated plausible dopamine mechanisms involved in sustaining binge eating behaviors. In DIBE models, highly palatable foods (fats, sugars and their combination), as well as restricted access conditions appear to promote ingestive responses and result in sustained dopamine stimulation within the nucleus accumbens. Taken together with studies examining the comorbidity of illicit drug use and eating disorders, the data reviewed here support a role for dopamine in perpetuating the compulsive feeding patterns of BN and BED. As such, we propose that sustained stimulation of the dopamine systems by bingeing promoted by preexisting conditions (e.g., genetic traits, dietary restraint, stress, etc.) results in progressive impairments of dopamine signaling. To disrupt this vicious cycle, novel research-based treatment options aiming at the neural substrates of compulsive eating patterns are necessary. PMID:20417658

  13. (-)-1-(Benzofuran-2-yl)-2-propylaminopentane enhances locomotor activity in rats due to its ability to induce dopamine release.

    PubMed

    Shimazu, S; Takahata, K; Katsuki, H; Tsunekawa, H; Tanigawa, A; Yoneda, F; Knoll, J; Akaike, A

    2001-06-15

    "Catecholaminergic and serotoninergic activity enhancer" effects are newly found mechanisms of action of a class of compound that enhance impulse propagation-mediated release of catecholamines and serotonin in the brain. In the present study, (-)-1-(benzofuran-2-yl)-2-propylaminopentane hydrochloride [(-)-BPAP HCl], a compound with selective and potent "catecholaminergic and serotoninergic activity enhancer" effects, was tested for its efficacy to potentiate locomotor activity in normal rats and to attenuate hypolocomotion in reserpine-treated rats. (-)-BPAP HCl potentiated locomotor activity in non-habituated rats during a 2-h observation period dose-dependently (0.3-10 mg/kg). (-)-BPAP HCl (1-3 mg/kg) was also effective to reverse reserpine-induced hypolocomotion. The effects of (-)-BPAP HCl in normal and reserpine-treated rats were attenuated by the dopamine D1 receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390), suggesting that the effects of (-)-BPAP HCl were mediated by activation of the dopaminergic system. In addition, the administration of (-)-BPAP HCl increased ipsilateral turning in unilaterally 6-hydroxydopamine-lesioned rats, implying presynaptic activation of nigrostriatal dopaminergic terminals by (-)-BPAP HCl. Furthermore, although antiparkinsonian agents, such as apomorphine and amantadine, failed to improve reserpine-induced ptosis, (-)-BPAP HCl significantly improved ptosis. These findings suggested that a "catecholaminergic and serotoninergic activity enhancer" compound, (-)-BPAP, stimulates motor function in rats and improves motor deficits in animal models of Parkinson's disease due to its ability to induce dopamine release.

  14. Parkinsonian monkeys with prior levodopa-induced dyskinesias followed by fetal dopamine precursor grafts do not display graft-induced dyskinesias.

    PubMed

    Kordower, Jeffrey H; Vinuela, Angel; Chu, Yaping; Isacson, Ole; Redmond, D Eugene

    2017-02-15

    Clinical trials testing the hypothesis that fetal dopamine grafts would provide antiparkinsonian benefit in patients who had already developed side effects from their long-term use of L-dopa revealed, in some cases, the presence of dyskinesias even in the absence of L-dopa. The form, intensity, and frequency of these dyskinesias were quite variable, but their manifestation slowed the clinical development of cell replacement therapies. Rodent models of graft-induced dyskinesias (GIDs) have been proposed, but their accuracy in modeling GIDs has been questioned because they usually require amphetamine for their presentation. The present study attempted to model GIDs in parkinsonian monkeys and, for the first time, to test the effect of grafts on previously dyskinetic monkeys. Toward this end, monkeys were rendered parkinsonian with n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and dyskinetic with levodopa. They then received intraputamenal grafts of fetal dopaminergic cells, control cerebellar cells, or vehicle bilaterally and were studied for 18 months. Dopaminergic cells were grafted in a manner designed to produce either "hot spot" or "widespread" striatal innervation. Although levodopa-induced dyskinesias could be elicited postoperatively, GIDs were never observed in any animal at any time after grafting. Grafted monkeys were also challenged with levodopa but did not show any greater responses to these challenges than before grafting. These studies support the development of future dopamine neuron cell transplantation therapy-based approaches, indicating that in relevant primate models with appropriate cell preparation methodology, with successful graft survival and putamenal dopamine innervation, there is no evidence of graft-induced dyskinesias. J. Comp. Neurol. 525:498-512, 2017. © 2016 Wiley Periodicals, Inc.

  15. Dynamic Nigrostriatal Dopamine Biases Action Selection.

    PubMed

    Howard, Christopher D; Li, Hao; Geddes, Claire E; Jin, Xin

    2017-03-22

    Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn't reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons or optogenetic manipulation of dopamine concentration alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions, and they have important implications for neurological disorders, including Parkinson's disease and substance dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Endoplasmic Reticulum Stress as a Mediator of Neurotoxin-Induced Dopamine Neuron Death

    DTIC Science & Technology

    2005-07-01

    mediators of an ER stress response in PC12 cells: ATF4, CHOP, BiP, phosphorylated PERK and others (3). A similar induction was noted on treatment of the cells...neurons derived from mice null for PERK , a mediator of a protective pathway in ER stress, were more sensitive to 6OHDA (3). Very similar findings were...they are not (Macaya et al. 1994;Kelly and Burke 1996; Stefanis and Burke 1996). Therefore, during this postnatal period, the death of SN dopamine

  17. D1 receptors play a major role in the dopamine modulation of mouse ileum contractility.

    PubMed

    Zizzo, Maria Grazia; Mulè, Flavia; Mastropaolo, Mariangela; Serio, Rosa

    2010-05-01

    Since the role of dopamine in the bowel motility is far from being clear, our aim was to analyse pharmacologically the effects of dopamine on mouse ileum contractility. Contractile activity of mouse ileum was examined in vitro as changes in isometric tension. Dopamine caused a concentration-dependent reduction of the spontaneous contraction amplitude of ileal muscle up to their complete disappearance. SCH-23390, D1 receptor antagonist, which per se increased basal tone and amplitude of spontaneous contractions, antagonized the responses to dopamine, whilst sulpiride or domperidone, D2 receptor antagonists, were without effects. The application of both D1 and D2 antagonists had additive effects. SKF-38393, D1 receptor agonist, mimicked dopamine-induced effects. Dopamine responses were insensitive to tetrodotoxin, atropine, nitric oxide synthase inhibitor or adenosine receptor antagonists, but they were reduced by adenylyl cyclase inhibition or apamin. Dopamine at a concentration which did not cause a significant reduction of phasic contractions inhibited the cholinergic contractions in response to field stimulation. SCH-23390 per se induced an increase of the neural cholinergic contraction and antagonized the dopamine effects, whilst sulpiride or domperidone did not. The application of D1 and D2 antagonists had additive effects. In conclusion, mouse ileum is under basal inhibitory control by dopamine, through D1 receptor activation, linked to adenylyl cyclase and activation of apamin-sensitive potassium channels. An agonistic interaction of the dopamine receptor subtypes in the regulation intestinal contractility has being also highlighted. This study would provide new insight on the pharmacology of the modulation of the gastrointestinal contractility by dopamine. (c) 2010 Elsevier Ltd. All rights reserved.

  18. Seasonal Changes in Circadian Peripheral Plasma Concentrations of Melatonin, Serotonin, Dopamine and Cortisol in Aged Horses with Cushing’s Disease under Natural Photoperiod

    PubMed Central

    Haritou, S J A; Zylstra, R; Ralli, C; Turner, S; Tortonese, D J

    2008-01-01

    Equine pituitary pars intermedia dysfunction (PPID) is a common and serious condition that gives rise to Cushing’s disease. In the older horse, it results in hyperadrenocorticism and disrupted energy metabolism, the severity of which varies with the time of year. To gain insight into the mechanism of its pathogenesis, 24-h profiles for peripheral plasma melatonin, serotonin, dopamine and cortisol concentrations were determined at the winter and summer solstices, and the autumn and spring equinoxes in six horses diagnosed with Cushing’s disease and six matched controls. The nocturnal rises in plasma melatonin concentrations, although different across seasons, were broadly of the same duration and similar amplitude in both groups of animals (P > 0.05). The plasma concentrations of cortisol did not show seasonal variation and were different in diseased horses only in the summer when they were higher across the entire 24-h period (P < 0.05). Serotonin concentrations were not significantly affected by time of year but tended to be lower in Cushingoid horses (P = 0.07). By contrast, dopamine output showed seasonal variation and was significantly lower in the Cushing’s group in the summer and autumn (P < 0.05). The finding that the profiles of circulating melatonin are similar in Cushingoid and control horses reveals that the inability to read time of year by animals suffering from Cushing’s syndrome is an unlikely reason for the disease. In addition, the results provide evidence that alterations in the dopaminergic and serotoninergic systems may participate in the pathogenesis of PPID. PMID:18540997

  19. Music and Methamphetamine: Conditioned Cue-induced Increases in Locomotor Activity and Dopamine Release in Rats

    PubMed Central

    Polston, J.E.; Rubbinaccio, H.Y.; Morra, J.T.; Sell, E.M.; Glick, S.D.

    2011-01-01

    Associations between drugs of abuse and cues facilitate the acquisition and maintenance of addictive behaviors. Although significant research has been done to elucidate the role that simple discriminative or discrete conditioned stimuli (e.g., a tone or a light) play in addiction, less is known about complex environmental cues. The purpose of the present study was to examine the role of a musical conditioned stimulus by assessing locomotor activity and in vivo microdialysis. Two groups of rats were given non-contingent injections of methamphetamine (1.0 mg/kg) or vehicle and placed in standard conditioning chambers. During these conditioning sessions both groups were exposed to a continuous conditioned stimulus, in the form of a musical selection (“Four” by Miles Davis) played repeatedly for ninety minutes. After seven consecutive conditioning days subjects were given one day of rest, and subsequently tested for locomotor activity or dopamine release in the absence of drug while the musical conditioned stimulus was continually present. The brain regions examined included the basolateral amygdala, nucleus accumbens, and prefrontal cortex. The results show that music is an effective contextual conditioned stimulus, significantly increasing locomotor activity after repeated association with methamphetamine. Furthermore, this musical conditioned stimulus significantly increased extracellular dopamine levels in the basolateral amygdala and nucleus accumbens. These findings support other evidence showing the importance of these brain regions in conditioned learning paradigms, and demonstrate that music is an effective conditioned stimulus warranting further investigation. PMID:21145911

  20. Music and methamphetamine: conditioned cue-induced increases in locomotor activity and dopamine release in rats.

    PubMed

    Polston, J E; Rubbinaccio, H Y; Morra, J T; Sell, E M; Glick, S D

    2011-03-01

    Associations between drugs of abuse and cues facilitate the acquisition and maintenance of addictive behaviors. Although significant research has been done to elucidate the role that simple discriminative or discrete conditioned stimuli (e.g., a tone or a light) play in addiction, less is known about complex environmental cues. The purpose of the present study was to examine the role of a musical conditioned stimulus by assessing locomotor activity and in vivo microdialysis. Two groups of rats were given non-contingent injections of methamphetamine (1.0 mg/kg) or vehicle and placed in standard conditioning chambers. During these conditioning sessions both groups were exposed to a continuous conditioned stimulus, in the form of a musical selection ("Four" by Miles Davis) played repeatedly for 90 min. After seven consecutive conditioning days subjects were given one day of rest, and subsequently tested for locomotor activity or dopamine release in the absence of drugs while the musical conditioned stimulus was continually present. The brain regions examined included the basolateral amygdala, nucleus accumbens, and prefrontal cortex. The results show that music is an effective contextual conditioned stimulus, significantly increasing locomotor activity after repeated association with methamphetamine. Furthermore, this musical conditioned stimulus significantly increased extracellular dopamine levels in the basolateral amygdala and nucleus accumbens. These findings support other evidence showing the importance of these brain regions in conditioned learning paradigms, and demonstrate that music is an effective conditioned stimulus warranting further investigation. Copyright © 2010 Elsevier Inc. All rights reserved.

  1. Dopamine triggers Heterosynaptic Plasticity

    PubMed Central

    Ishikawa, Masago; Otaka, Mami; Huang, Yanhua; Neumann, Peter A.; Winters, Bradley D.; Grace, Anthony A.; Schlüter, Oliver M.; Dong, Yan

    2013-01-01

    As a classic neuromodulator, dopamine has long been thought to modulate, rather than trigger, synaptic plasticity. In contrast, our present results demonstrate that within the parallel projections of dopaminergic and GABAergic terminals from the ventral tegmental area (VTA) to nucleus accumbens core (NAcCo), action potential-activated release of dopamine heterosynaptically triggers LTD at GABAergic synapses, which is likely mediated by activating presynaptically-located dopamine D1 class receptors and expressed by inhibiting presynaptic release of GABA. Moreover, this dopamine-mediated heterosynaptic LTD is abolished after withdrawal from cocaine exposure. These results suggest that action potential-dependent dopamine release triggers very different cellular consequences from those induced by volume release or pharmacological manipulation. Activation of the VTA-to-NAcCo projections is essential for emotional and motivational responses. This dopamine-mediated LTD allows a flexible output of NAcCo neurons, whereas disruption of this LTD may contribute to the rigid emotional and motivational state observed in addicts during cocaine withdrawal. PMID:23595734

  2. Cortical regulation of striatal medium spiny neuron dendritic remodeling in parkinsonism: modulation of glutamate release reverses dopamine depletion-induced dendritic spine loss.

    PubMed

    Garcia, Bonnie G; Neely, M Diana; Deutch, Ariel Y

    2010-10-01

    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.

  3. 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).

  4. Rapid substrate-induced down-regulation in function and surface localization of dopamine transporters: rat dorsal striatum versus nucleus accumbens

    PubMed Central

    Richards, Toni L.; Zahniser, Nancy R.

    2010-01-01

    The dopamine transporter (DAT) substrates dopamine, d-amphetamine (AMPH), and methamphetamine are known to rapidly and transiently reduce DAT activity and/or surface expression in dorsal striatum and heterologous expression systems. We sought to determine if similar substrate-induced regulation of DATs occurs in rat nucleus accumbens. In dorsal striatum synaptosomes, brief (15-min) in vitro substrate pre-exposure markedly decreased maximal [3H]dopamine uptake velocity whereas identical substrate pre-exposure in nucleus accumbens synaptosomes produced a smaller, non-significant reduction. However, 45 min after systemic AMPH administration, maximal ex vivo [3H]dopamine uptake velocity was significantly reduced in both brain regions. Protein kinase C inhibition blocked AMPH’s down-regulation of DAT activity. DAT synaptosomal surface expression was not modified following either the brief in vitro or in vivo AMPH pre-exposure but was reduced after a longer (1-h) in vitro pre-exposure in both brain regions. Together, our findings suggest that relatively brief substrate exposure results in greater down-regulation of DAT activity in dorsal striatum than in nucleus accumbens. Moreover, exposure to AMPH appears to regulate striatal dopamine transporters in a biphasic manner, with an initial protein kinase C-dependent decrease in DAT-mediated uptake velocity and then, with longer exposure, a reduction in DAT expression. PMID:19183252

  5. Serotonin-dopamine antagonism ameliorates impairments of spontaneous alternation and locomotor hyperactivity induced by repeated electroconvulsive seizures in rats.

    PubMed

    Hidaka, Noriaki; Suemaru, Katsuya; Araki, Hiroaki

    2010-08-01

    We have shown that seven consecutive administrations of electroconvulsive shock (ECS) produce impairment of spontaneous alternation behavior in a Y-maze test and a locomotor hyperactivity in an open-field test even 24h after the last administration in rats. To clarify the mechanisms of the behavioral impairments, we investigated the effect of drugs acting on dopaminergic and serotonergic nervous systems. The dopamine-2 (D(2)) receptor antagonists haloperidol and sulpiride abolished locomotor hyperactivity, but did not show effects on the impairment of spontaneous alternation behavior. The serotonin-2 (5-HT(2)) receptor antagonist ketanserin suppressed the impairment of spontaneous alternation behavior without affecting locomotor hyperactivity. The 5-HT(2) and D(2) receptor antagonist risperidone significantly ameliorated both behavioral impairments. These results suggest that 5-HT(2) receptors and D(2) receptors are associated with repeated ECS-induced impairment of spontaneous alternation behavior and locomotor hyperactivity, respectively.

  6. Not all boronic acids with a five-membered cycle induce tremor, neuronal damage and decreased dopamine.

    PubMed

    Pérez-Rodríguez, Maribel; García-Mendoza, Esperanza; Farfán-García, Eunice D; Das, Bhaskar C; Ciprés-Flores, Fabiola J; Trujillo-Ferrara, José G; Tamay-Cach, Feliciano; Soriano-Ursúa, Marvin A

    2017-06-06

    Several striatal toxins can be used to induce motor disruption. One example is MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), whose toxicity is accepted as a murine model of parkinsonism. Recently, 3-Thienylboronic acid (3TB) was found to produce motor disruption and biased neuronal damage to basal ganglia in mice. The aim of this study was to examine the toxic effects of four boronic acids with a close structural relationship to 3TB (all having a five-membered cycle), as well as boric acid and 3TB. These boron-containing compounds were compared to MPTP regarding brain access, morphological disruption of the CNS, and behavioral manifestations of such disruption. Data was collected through acute toxicity evaluations, motor behavior tests, necropsies, determination of neuronal survival by immunohistochemistry, Raman spectroscopic analysis of brain tissue, and HPLC measurement of dopamine in substantia nigra and striatum tissue. Each compound showed a distinct profile for motor disruption. For example, motor activity was not disrupted by boric acid, but was decreased by two boronic acids (caused by a sedative effect). 3TB, 2-Thienyl and 2-furanyl boronic acid gave rise to shaking behavior. The various manifestations generated by these compounds can be linked, in part, to different levels of dopamine (measured by HPLC) and degrees of neuronal damage in the basal ganglia and cerebellum. Clearly, motor disruption is not induced by all boronic acids with a five-membered cycle as substituent. Possible explanations are given for the diverse chemico-morphological changes and degrees of disruption of the motor system, considering the role of boron and the structure-toxicity relationship. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. The dopamine receptor antagonist levo-tetrahydropalmatine attenuates heroin self-administration and heroin-induced reinstatement in rats.

    PubMed

    Yue, Kai; Ma, Baomiao; Ru, Qin; Chen, Lin; Gan, Yongping; Wang, Daisong; Jin, Guozhang; Li, Chaoying

    2012-07-01

    Opiate addiction is a chronic recrudescent disorder characterized by a high rate of relapse. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance extracted from Corydalis and Stephania and is contained in a number of traditional Chinese herbal preparations. Compared to other dopamine receptor antagonists, l-THP has lower affinity for D2 receptors than for D1 receptors, and a recent study showed that l-THP also binds to D3 receptors, possibly functioning as an antagonist. The unique pharmacological profile of l-THP suggests that l-THP may be effective for the treatment of opiate addiction. In this study, we investigated the effects of l-THP on heroin self-administration and reinstatement triggered by a priming injection of heroin in abstinent rats trained to stably self-administer heroin under an extinction/reinstatement protocol, and found that l-THP (2.5 and 5 mg/kg, i.p.) decreased heroin self-administration on the fixed-ratio 1 schedule and dose-dependently (1.25, 2.5 and 5 mg/kg, i.p.) inhibited heroin-induced reinstatement of heroin-seeking behavior. Importantly, l-THP (1.25 and 2.5 mg/kg, i.p.) did not affect locomotion, indicating that the observed effects of l-THP on reinstatement do not appear to be due to motor impairments. The present results demonstrated that dopamine receptor antagonist l-THP attenuates heroin self-administration and heroin-induced reinstatement.

  8. Dopamine-melanin induces apoptosis in PC12 cells; possible implications for the etiology of Parkinson's disease.

    PubMed

    Offen, D; Ziv, I; Barzilai, A; Gorodin, S; Glater, E; Hochman, A; Melamed, E

    1997-08-01

    The function of neuromelanin (NM), the oxidized dopamine (DA) polymer, within the DA-producing cells in the human and primate substantia nigra (SN), is still an enigma. Some studies show that the vulnerability of nigral neurons in Parkinson's disease is correlated to their toxic NM content, while others suggest that it contributes to cellular protection. We showed recently that DA, the endogenous nigral neurotransmitter, triggers apoptosis, an active program of cellular self-destruction, in neuronal cultures. In the present study, we exposed cells to synthetic dopamine-melanin (DA-M) and analysed the cellular and genetic changes. We found that exposure of PC12 cells to DA-M (0.5 mg/ml for 24 h) caused 50% cell death, as indicated by trypan blue exclusion assay and 3H-thymidine incorporation. Gel electrophoresis DNA analysis of PC12 cells treated with DA-M showed the typical apoptotic DNA ladder, indicating inter-nucleosomal DNA degradation. The DNA fragmentation also was visualized histochemically in situ by DNA end-labeling staining (the TUNEL method). The FeCl2 (0.05 mM) significantly increased DA-M toxicity, while desferrioxamine, an iron chelator, totally abolished the additive toxicity of iron. The contribution of oxidative stress in this model of DA-M-induced cell death was examined using various antioxidants. In contrast to DA, inhibition of DA-M toxicity antioxidants by reduced glutathione (GSH), N-acetyl cysteine, catalase and Zn/Cu superoxide dismutase (SOD) was very limited. In conclusion, we found that DA-M may induce typical apoptotic death in PC12 cells. Our findings support a possible role of NM in the vulnerability of the dopaminergic neural degeneration in Parkinson's disease. The differential protective effect by antioxidants against toxicity of DA and DA-M may have implications for future neuroprotective therapeutic approaches for this common neurological disorder.

  9. Kappa Opioid Receptor Activation Potentiates the Cocaine-Induced Increase in Evoked Dopamine Release Recorded In Vivo in the Mouse Nucleus Accumbens

    PubMed Central

    Ehrich, Jonathan M; Phillips, Paul E M; Chavkin, Charles

    2014-01-01

    Behavioral stressors increase addiction risk in humans and increase the rewarding valence of drugs of abuse including cocaine, nicotine and ethanol in animal models. Prior studies have established that this potentiation of drug reward was mediated by stress-induced release of the endogenous dynorphin opioids and subsequent kappa opioid receptor (KOR) activation. In this study, we used in vivo fast scan cyclic voltammetry to test the hypothesis that KOR activation before cocaine administration might potentiate the evoked release of dopamine from ventral tegmental (VTA) synaptic inputs to the nucleus accumbens (NAc) and thereby increase the rewarding valence of cocaine. The KOR agonist U50488 inhibited dopamine release evoked by either medial forebrain bundle (MFB) or pedunculopontine tegmental nucleus (PPTg) activation of VTA inputs to the shell or core of the mouse NAc. Cocaine administration increased the dopamine response recorded in either the shell or core evoked by either MFB or PPTg stimulation. Administration of U50488 15 min before cocaine blocked the conditioned place preference (CPP) to cocaine, but only significantly reduced the effect of cocaine on the dopamine response evoked by PPTg stimulation to NAc core. In contrast, administration of U50488 60 min before cocaine significantly potentiated cocaine CPP and significantly increased the effects of cocaine on the dopamine response evoked by either MFB or PPTg stimulation, recorded in either NAc shell or core. Results of this study support the concept that stress-induced activation of KOR by endogenous dynorphin opioids may enhance the rewarding valence of drugs of abuse by potentiating the evoked dopamine response. PMID:24971603

  10. Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms.

    PubMed

    dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

    2015-10-05

    The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs.

  11. Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms

    PubMed Central

    dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

    2015-01-01

    The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs. PMID:26209364

  12. The dopamine D3 receptor regulates the effects of methamphetamine on LPS-induced cytokine production in murine mast cells.

    PubMed

    Xue, Li; Li, Xia; Ren, Hui-Xun; Wu, Feng; Li, Ming; Wang, Biao; Chen, Fang-Yuan; Cheng, Wei-Ying; Li, Ju-Ping; Chen, Yan-Jiong; Chen, Teng

    2015-06-01

    Previous studies have demonstrated that methamphetamine (METH) alter inflammatory and anti-inflammatory cytokine production in the periphery. However, the effect of METH on lipopolysaccharide (LPS)-induced immune responses and its underlying mechanism of action remains unclear. The dopamine D3 receptor (D3R) plays an important role in METH addiction, indicating that the D3R may regulate METH-mediated immune responses. In this study, we examined the effect of METH on mast cell released cytokines in the lungs and thymi of mice stimulated by LPS, and on LPS-induced murine bone marrow-derived mast cells (BMMCs). Moreover, we used D3R-deficient mice to investigate the effect of this receptor on LPS-stimulated mast cell released cytokine production after METH treatment in the lungs and thymi. The effects of a D3R agonist and antagonist on LPS-induced cytokine production after METH treatment in murine BMMCs were also evaluated. METH suppressed LPS-induced cytokine production in the lungs and thymi of wild-type (WT) mice and BMMCs. However, METH did not alter LPS-induced cytokine production in the lungs and thymi of D3R-deficient mice. When BMMCs were treated with the D3R receptor antagonist, NGB2904 hydrochloride (NGB-2904), METH did not alter LPS-induced cytokine production. However, treatment with the D3R agonist, 7-hydroxy-(di-n-propylamino) tetralin (7-OH-DPAT), significantly enhanced the effects of METH on LPS-induced cytokine production. Our results suggest that METH regulates mast cell released cytokines production in an LPS-induced mouse model via the D3R. Copyright © 2015 Elsevier GmbH. All rights reserved.

  13. Levodopa acts centrally to induce an antinociceptive action against colonic distension through activation of D2 dopamine receptors and the orexinergic system in the brain in conscious rats.

    PubMed

    Okumura, Toshikatsu; Nozu, Tsukasa; Kumei, Shima; Takakusaki, Kaoru; Miyagishi, Saori; Ohhira, Masumi

    2016-02-01

    Levodopa possesses antinociceptive actions against several somatic pain conditions. However, we do not know at this moment whether levodopa is also effective to visceral pain. The present study was therefore performed to clarify whether levodopa is effective to visceral pain and its mechanisms. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously (80 mg/rat) or intracisternally (2.5 μg/rat) administered levodopa significantly increased the threshold of colonic distension-induced AWR in conscious rats. The dose difference to induce the antinociceptive action suggests levodopa acts centrally to exert its antinociceptive action against colonic distension. While neither sulpiride, a D2 dopamine receptor antagonist, nor SCH23390, a D1 dopamine receptor antagonist by itself changed the threshold of colonic distension-induced AWR, the intracisternally injected levodopa-induced antinociceptive action was significantly blocked by pretreatment with subcutaneously administered sulpiride but not SCH23390. Treatment with intracisternal SB334867, an orexin 1 receptor antagonist, significantly blocked the subcutaneously administered levodopa-induced antinociceptive action. These results suggest that levodopa acts centrally to induce an antinociceptive action against colonic distension through activation of D2 dopamine receptors and the orexinergic system in the brain.

  14. L-stepholidine, a natural dopamine receptor D1 agonist and D2 antagonist, inhibits heroin-induced reinstatement.

    PubMed

    Ma, Baomiao; Yue, Kai; Chen, Lin; Tian, Xiang; Ru, Qin; Gan, Yongping; Wang, Daisong; Jin, Guozhang; Li, Chaoying

    2014-01-24

    L-Stepholidine (l-SPD), an alkaloid extract of the Chinese herb Stephania intermedia, is the first compound known to exhibit mixed dopamine D1 receptor agonist/D2 antagonist properties and is a potential medication for the treatment of opiate addiction. The aim of the present study was to investigate the effects of pretreatment with L-SPD on heroin-seeking behavior induced by heroin priming. Male Sprague-Dawley rats were trained to self-administer heroin (0.05mg/kg per infusion) under a fixed ratio 1 schedule for 12 consecutive days and nose-poke responding was extinguished for 12 days, after which reinstatement of drug seeking was induced by heroin priming. Pretreatment with L-SPD (2.5, 5.0 and 10.0mg/kg, i.p.) inhibited the heroin-induced reinstatement of heroin-seeking behavior. Importantly, L-SPD did not affect locomotion, indicating that the observed effects of L-SPD on reinstatement are not the result of motor impairments. The present data suggested that l-SPD inhibits heroin-induced reinstatement and its potential for the treatment of heroin relapse.

  15. The galanin receptor agonist, galnon, attenuates cocaine-induced reinstatement and dopamine overflow in the frontal cortex.

    PubMed

    Ogbonmwan, Yvonne E; Sciolino, Natale R; Groves-Chapman, Jessica L; Freeman, Kimberly G; Schroeder, Jason P; Edwards, Gaylen L; Holmes, Philip V; Weinshenker, David

    2015-07-01

    Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex. © 2014 Society for the Study of Addiction.

  16. Mechanisms of anti-inflammatory property of conserved dopamine neurotrophic factor: inhibition of JNK signaling in lipopolysaccharide-induced microglia.

    PubMed

    Zhao, Hua; Cheng, Lei; Liu, Yi; Zhang, Wen; Maharjan, Sailendra; Cui, Zhaoqiang; Wang, Xingli; Tang, Dongqi; Nie, Lin

    2014-02-01

    Microglia are important resident immune cells in the central nervous system (CNS) and involved in the neuroinflammation caused by CNS disorders, including brain trauma, ischemia, stroke, infections, inflammation, and neurodegenerative diseases. Our study explores the hypothesis that conserved dopamine neurotrophic factor (CDNF), a secretory neurotrophic factor, may provide a novel therapy for associated with neuroinflammation related to the microglia. We observed that CDNF was upregulated in rat primary microglia treated with 1 μg/mL lipopolysaccharide, an inflammatory inducer, for 24 h. Thus, we hypothesize that CDNF may play a role, mediator or inhibitor, in regulating the inflammation in microglial cells induced by LPS. Finally, our data showed that CDNF significantly attenuated the production of proinflammatory cytokines (PGE2 and IL-1β) and remarkably alleviated the cytotoxicity (percentage of lactate dehydrogenase released) in the LPS-induced microglia by suppressing the phosphorylation of JNK, but not the P38 or ERK pathways. These results demonstrate the anti-inflammatory property of CDNF by inhibition of JNK signaling in LPS-induced microglia, suggesting that CDNF may be a potential novel agent for the treatment of neuroinflammation in the CNS disorders.

  17. Compromising σ-1 receptors at the endoplasmic reticulum render cytotoxicity to physiologically relevant concentrations of dopamine in a nuclear factor-κB/Bcl-2-dependent mechanism: potential relevance to Parkinson's disease.

    PubMed

    Mori, Tomohisa; Hayashi, Teruo; Su, Tsung-Ping

    2012-06-01

    The endoplasmic reticulum (ER) chaperone σ-1 receptor (Sig-1R) is cytoprotective against ER stress-induced apoptosis. The level of Sig-1Rs in the brain was reported to be lower in early parkinsonian patients. Because dopamine (DA) toxicity is well known to be involved in the etiology of Parkinson's disease, we tested in this study whether a relationship might exist between Sig-1Rs and DA-induced cytotoxicity in a cellular model by using Chinese hamster ovary (CHO) cells. DA in physiological concentrations (e.g., lower than 10 μM) does not cause apoptosis. However, the same concentrations of DA cause apoptosis in Sig-1R knockdown CHO cells. In search of a mechanistic explanation, we found that unfolded protein response is not involved. Rather, the level of protective protein Bcl-2 is critically involved in this DA/Sig-1R knockdown-induced apoptosis. Specifically, the DA/Sig-1R knockdown causes a synergistic proteasomal conversion of nuclear factor κB (NF-κB) p105 to the active form of p50, which is known to down-regulate the transcription of Bcl-2. It is noteworthy that the DA/Sig-1R knockdown-induced apoptosis is blocked by the overexpression of Bcl-2. Our results therefore indicate that DA is involved in the activation of NF-κB and suggest that endogenous Sig-1Rs are tonically inhibiting the proteasomal conversion/activation of NF-κB caused by physiologically relevant concentrations of DA that would otherwise cause apoptosis. Thus, Sig-1Rs and associated ligands may represent new therapeutic targets for the treatment of parkinsonism.

  18. Compromising σ-1 Receptors at the Endoplasmic Reticulum Render Cytotoxicity to Physiologically Relevant Concentrations of Dopamine in a Nuclear Factor-κB/Bcl-2-Dependent Mechanism: Potential Relevance to Parkinson's Disease

    PubMed Central

    Mori, Tomohisa; Hayashi, Teruo

    2012-01-01

    The endoplasmic reticulum (ER) chaperone σ-1 receptor (Sig-1R) is cytoprotective against ER stress-induced apoptosis. The level of Sig-1Rs in the brain was reported to be lower in early parkinsonian patients. Because dopamine (DA) toxicity is well known to be involved in the etiology of Parkinson's disease, we tested in this study whether a relationship might exist between Sig-1Rs and DA-induced cytotoxicity in a cellular model by using Chinese hamster ovary (CHO) cells. DA in physiological concentrations (e.g., lower than 10 μM) does not cause apoptosis. However, the same concentrations of DA cause apoptosis in Sig-1R knockdown CHO cells. In search of a mechanistic explanation, we found that unfolded protein response is not involved. Rather, the level of protective protein Bcl-2 is critically involved in this DA/Sig-1R knockdown-induced apoptosis. Specifically, the DA/Sig-1R knockdown causes a synergistic proteasomal conversion of nuclear factor κB (NF-κB) p105 to the active form of p50, which is known to down-regulate the transcription of Bcl-2. It is noteworthy that the DA/Sig-1R knockdown-induced apoptosis is blocked by the overexpression of Bcl-2. Our results therefore indicate that DA is involved in the activation of NF-κB and suggest that endogenous Sig-1Rs are tonically inhibiting the proteasomal conversion/activation of NF-κB caused by physiologically relevant concentrations of DA that would otherwise cause apoptosis. Thus, Sig-1Rs and associated ligands may represent new therapeutic targets for the treatment of parkinsonism. PMID:22399814

  19. Methamphetamine induces Shati/Nat8L expression in the mouse nucleus accumbens via CREB- and dopamine D1 receptor-dependent mechanism

    PubMed Central

    Uno, Kyosuke; Miyazaki, Toh; Sodeyama, Kengo; Miyamoto, Yoshiaki

    2017-01-01

    Shati/Nat8L significantly increased in the nucleus accumbens (NAc) of mice after repeated methamphetamine (METH) treatment. We reported that Shati/Nat8L overexpression in mouse NAc attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference. We recently found that Shati/Nat8L overexpression in NAc regulates the dopaminergic neuronal system via the activation of group II mGluRs by elevated N-acetylaspartylglutamate following N-acetylaspartate increase due to the overexpression. These findings suggest that Shati/Nat8L suppresses METH-induced responses. However, the mechanism by which METH increases the Shati/Nat8L mRNA expression in NAc is unclear. To investigate the regulatory mechanism of Shati/Nat8L mRNA expression, we performed a mouse Shati/Nat8L luciferase assay using PC12 cells. Next, we investigated the response of METH to Shati/Nat8L expression and CREB activity using mouse brain slices of NAc, METH administration to mice, and western blotting for CREB activity of specific dopamine receptor signals in vivo and ex vivo. We found that METH activates CREB binding to the Shati/Nat8L promoter to induce the Shati/Nat8L mRNA expression. Furthermore, the dopamine D1 receptor antagonist SCH23390, but not the dopamine D2 receptor antagonist sulpiride, inhibited the upregulation of Shati/Nat8L and CREB activities in the mouse NAc slices. Thus, the administration of the dopamine D1 receptor agonist SKF38393 increased the Shati/Nat8L mRNA expression in mouse NAc. These results showed that the Shati/Nat8L mRNA was increased by METH-induced CREB pathway via dopamine D1 receptor signaling in mouse NAc. These findings may contribute to development of a clinical tool for METH addiction. PMID:28319198

  20. Deriving the therapeutic concentrations for clozapine and haloperidol: the apparent dissociation constant of a neuroleptic at the dopamine D2 or D4 receptor varies with the affinity of the competing radioligand.

    PubMed

    Seeman, P; Van Tol, H H

    1995-10-15

    The apparent dissociation constant, Ki, for a neuroleptic at the dopamine D2 or D4 receptor was consistently higher when competed against [3H]nemonapride than against [3H]spiperone which was in turn higher than that against [3H]raclopride. This finding obtained for all four types of dopamine receptors studied, including the native dopamine D2 receptor in the anterior pituitary tissue, the human D2long receptor, the human D2short receptor and the human D4.4 receptor. Some neuroleptics revealed a difference of over 10-fold between the Ki using [3H]nemonapride and the Ki using [3H]raclopride. The KD values of the three 3H-ligands and the neuroleptic Ki values were lower when using a much lower concentration of tissue, indicating that depletion of ligand presumably accounted for the phenomenon. The Ki values of each neuroleptic were related to the the tissue/buffer partition coefficients of the three 3H-ligands. Extrapolating the neuroleptic Ki value down to a tissue/buffer partition coefficient of unity or zero led to a Ki value for competition versus a water-soluble ligand such as dopamine. Clozapine extrapolated to a Ki value of 1.3 nM. Direct measurement gave a Ki value of 1.6 nM for [3H]clozapine at the dopamine D4 receptor. When competing versus endogenous dopamine, this clozapine value of 1.6 nM would rise to 20 nM for the blockade of 75% of dopamine D4 receptors, matching the observed therapeutic concentration of 18 nM. These data also explain why clozapine occupies 48% of the D2 receptors in patients when measured with [11C]raclopride, but between 0% and 22% when measured with [18F]methylspiperone or [18F]fluoroethylspiperone.

  1. Dopamine D3 Receptor Mediates Preadolescent Stress-Induced Adult Psychiatric Disorders

    PubMed Central

    Seo, Joon H.; Kuzhikandathil, Eldo V.

    2015-01-01

    Several studies have shown that repeated stressful experiences during childhood increases the likelihood of developing depression- and anxiety-related disorders in adulthood; however, the underlying mechanisms are not well understood. We subjected drd3-EGFP and drd3-null mice to daily, two hour restraint stress episodes over a five day period during preadolescence (postnatal day 35 to 39), followed by social isolation. When these mice reached adulthood (post-natal day > 90), we assessed locomotor behavior in a novel environment, and assessed depression-related behavior in the Porsolt Forced Swim test. We also measured the expression and function of dopamine D3 receptor in limbic brain areas such as hippocampus, nucleus accumbens and amygdala in control and stressed drd3-EGFP mice in adulthood. Adult male mice subjected to restraint stress during preadolescence exhibited both anxiety- and depression-related behaviors; however, adult female mice subjected to preadolescent restraint stress exhibited only depression-related behaviors. The development of preadolescent stress-derived psychiatric disorders was blocked by D3 receptor selective antagonist, SB 277011-A, and absent in D3 receptor null mice. Adult male mice that experienced stress during preadolescence exhibited a loss of D3 receptor expression and function in the amygdala but not in hippocampus or nucleus accumbens. In contrast, adult female mice that experienced preadolescent stress exhibited increased D3 receptor expression in the nucleus accumbens but not in amygdala or hippocampus. Our results suggest that the dopamine D3 receptor is centrally involved in the etiology of adult anxiety- and depression-related behaviors that arise from repeated stressful experiences during childhood. PMID:26619275

  2. A comparative evaluation of the dopamine D(2/3) agonist radiotracer [11C](-)-N-propyl-norapomorphine and antagonist [11C]raclopride to measure amphetamine-induced dopamine release in the human striatum.

    PubMed

    Narendran, Rajesh; Mason, N Scott; Laymon, Charles M; Lopresti, Brian J; Velasquez, Natalie D; May, Maureen A; Kendro, Steve; Martinez, Diana; Mathis, Chester A; Frankle, W Gordon

    2010-05-01

    (-)-N-Propyl-norapomorphine (NPA) is a full dopamine D(2/3) receptor agonist, and [(11)C]NPA is a suitable radiotracer to image D(2/3) receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study, the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic dopamine was assessed with PET in healthy humans and compared with that of the reference D(2/3) receptor antagonist radiotracer [11C]raclopride. Ten subjects (eight females and two males) were studied on two separate days, a minimum of 1 week apart, both with [11C]raclopride and [11C]NPA at baseline and after the administration of 0.5 mg x kg(-1) oral d-amphetamine. Kinetic modeling with an arterial input function was used to derive the binding potential relative to nonspecific uptake (BPND) in the ventral striatum (VST), caudate (CAD), and putamen (PUT). [11C]Raclopride BPND was significantly reduced by 9.7 +/- 4.4, 8.4 +/- 4.2, and 14.7 +/- 4.8% after amphetamine administration in the VST, CAD, and PUT. [11C]NPA BPND was also reduced significantly, by 16.0 +/- 7.0, 16.1 +/- 6.1, and 21.9 +/- 4.9% after the same dose of amphetamine in the VST, CAD, and PUT. Although these results suggest that [11C]NPA is more vulnerable to endogenous competition by dopamine compared with [11C]raclopride by a factor of 1.49 to 1.90, the same data for a related outcome measure, binding potential relative to plasma concentration, was not significant. Nevertheless, these data add to the growing literature that suggests D(2/3) agonist radiotracers are more vulnerable to endogenous competition by dopamine than existing D(2/3) antagonist radiotracers.

  3. N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2.

    PubMed

    Wang, Ya; Plastina, Pierluigi; Vincken, Jean-Paul; Jansen, Renate; Balvers, Michiel; Ten Klooster, Jean Paul; Gruppen, Harry; Witkamp, Renger; Meijerink, Jocelijn

    2017-03-15

    Several studies indicate that the n-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) contributes to an attenuated inflammatory status in the development of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. To explain these effects, different mechanisms are being proposed, including those involving endocannabinoids and related signaling molecules. Many of these compounds belong to the fatty acid amides, conjugates of fatty acids with biogenic amines. Conjugates of DHA with ethanolamine or serotonin have previously been shown to possess anti-inflammatory and potentially neuroprotective properties. Here, we synthesized another amine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and tested its immune-modulatory properties in both RAW 264.7 macrophages and BV-2 microglial cells. N-Docosahexaenoyl dopamine significantly suppressed the production of nitric oxide (NO), the cytokine interleukin-6 (IL-6), and the chemokines macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1), whereas its parent compounds, dopamine and DHA, were ineffective. Further exploration of potential effects of DHDA on key inflammatory mediators revealed that cyclooxygenase-2 (COX-2) mRNA level and production of prostaglandin E2 (PGE2) were concentration-dependently inhibited in macrophages. In activated BV-2 cells, PGE2 production was also reduced, without changes in COX-2 mRNA levels. In addition, DHDA did not affect NF-kB activity in a reporter cell line. Finally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in both cell types. Taken together, our data suggest that DHDA, a potentially endogenous endocannabinoid, may be an additional member of the group of immune-modulating n-3 fatty acid-derived lipid mediators.

  4. Anterior hypothalamic dopamine D2 receptors modulate adolescent anabolic/androgenic steroid-induced offensive aggression in the Syrian hamster.

    PubMed

    Schwartzer, Jared J; Melloni, Richard H

    2010-07-01

    In the Syrian hamster, treatment with anabolic/androgenic steroids (AAS) throughout adolescence increases dopamine and D2 receptor expression in the anterior hypothalamus (AH), a brain region implicated in the control of aggression. D2 receptor antagonists have reduced aggression in various species and animal models. However, these studies used systemic administration of drugs and reported concomitant changes in mobility. These data complicate the question of whether pharmacology targeting D2 receptors is specific to aggression or whether these drugs exert their antiaggressive effects through nonspecific mechanisms. To resolve this discrepancy, the current studies investigate whether administration of the D2 receptor antagonist eticlopride (0.01-10.0 microg in a final volume of 0.5 microl) into the AH modulates AAS-induced aggression. Antagonism of AH D2 receptors effectively suppressed AAS-induced aggression beginning at the 0.1 microg dose, with higher doses producing a floor effect, when compared with AAS-treated animals injected with saline into the AH. Importantly, these reductions in aggressive responding occurred in the absence of changes in locomotor behavior. Our findings identify a neuroanatomical locus where D2 receptor antagonism suppresses adolescent AAS-induced aggression in the absence of alterations to general mobility.

  5. SKF-38393, a dopamine receptor agonist, attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity.

    PubMed

    Muralikrishnan, D; Ebadi, M

    2001-02-23

    Parkinson's disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic neurons. Several factors such as inhibition of the mitochondrial respiration, generation of hydroxyl radicals and reduced free radical defense mechanisms causing oxidative stress, have been postulated to contribute to the degeneration of dopaminergic neurons. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated animals is a useful experimental model of PD, exhibiting most of the clinical features, as well as the main biochemical and pathologic symptoms of the disease. In the present study, we have examined a dopaminergic (D1) receptor agonist, SKF-38393 HCl (SKF) for its possible neuroprotective action against MPTP-induced insults on dopaminergic neurons. MPTP is converted by monoamine oxidase-B (MAO-B) to its neurotoxic metabolite 1-methyl-4-phenyl-pyridinium (MPP+), which is then taken up into the dopaminergic neurons. SKF-38393 had no effects either on total or monoamine oxidase B in the striatum. SKF-38393 blocked the MPTP-induced depletion of glutathione and attenuated MPTP-induced depletion of dopamine. Furthermore, it enhanced the activity of superoxide dismutase and hence mimicked the action of selegiline. The results of these studies are interpreted to suggest that SKF-38393 may prove a valuable drug in the treatment of Parkinson's disease.

  6. Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism.

    PubMed

    Bello, E P; Casas-Cordero, R; Galiñanes, G L; Casey, E; Belluscio, M A; Rodríguez, V; Noaín, D; Murer, M G; Rubinstein, M

    2017-04-01

    Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2(-/-) mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson's disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette's syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.

  7. Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats: role of dopamine transporter.

    PubMed

    Fachinetto, Roselei; Villarinho, Jardel G; Wagner, Caroline; Pereira, Romaiana P; Avila, Daiana Silva; Burger, Marilise E; Calixto, João Batista; Rocha, João B T; Ferreira, Juliano

    2007-10-01

    Chronic treatment with classical neuroleptics in humans can produce a serious side effect, known as tardive dyskinesia (TD). Here, we examined the effects of V. officinalis, a medicinal herb widely used as calming and sleep-promoting, in an animal model of orofacial dyskinesia (OD) induced by long-term treatment with haloperidol. Adult male rats were treated during 12 weeks with haloperidol decanoate (38 mg/kg, i.m., each 28 days) and with V. officinalis (in the drinking water). Vacuous chewing movements (VCMs), locomotor activity and plus maze performance were evaluated. Haloperidol treatment produced VCM in 40% of the treated rats and the concomitant treatment with V. officinalis did not alter either prevalence or intensity of VCMs. The treatment with V. officinalis increased the percentage of the time spent on open arm and the number of entries into open arm in the plus maze test. Furthermore, the treatment with haloperidol and/or V. officinalis decreased the locomotor activity in the open field test. We did not find any difference among the groups when oxidative stress parameters were evaluated. Haloperidol treatment significantly decreased [(3)H]-dopamine uptake in striatal slices and V. officinalis was not able to prevent this effect. Taken together, our data suggest a mechanism involving the reduction of dopamine transport in the maintenance of chronic VCMs in rats. Furthermore, chronic treatment with V. officinalis seems not produce any oxidative damage to central nervous system (CNS), but it also seems to be devoid of action to prevent VCM, at least in the dose used in this study.

  8. Neuroprotective effects of stemazole in the MPTP-induced acute model of Parkinson's disease: Involvement of the dopamine system.

    PubMed

    Guo, Zhirui; Xu, Shasha; Du, Na; Liu, Jia; Huang, Yiyun; Han, Mei

    2016-03-11

    Parkinson's disease is a neurodegenerative disorder characterized by a loss of nigrostriata dopaminergic neurons, which has been thought, at least in part, to result from oxidative stress. The present study aims to investigate the neuroprotective effects of stemazole (ST) on the dopamine (DA) system and its possible mechanisms of action in a mouse model of PD. Mice were injected intraperitoneally with MPTP (20mg/kg) four times at 2-h intervals for one day to induce Parkinsonism, and then treated with ST (10, 30 and 50mg/kg) or Madopar (120mg/kg) for 7days. Behavioral analyses were performed with locomotor activity measures and rotarod test. Tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels were detected by immunohistochemistry method. DA and its metabolites were determined by high-performance liquid chromatography with an electrochemical detector. Oxidative stress levels were assessed by measuring the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX). Our results demonstrated that ST treatment improved locomotor activity and motor coordination in MPTP mice. There was also a significant increase in TH-positive cells (∼24%, P<0.01) and DAT levels (∼26%, P<0.01) in MPTP mice treated with ST (50mg/kg) compared with the vehicle group. Madopar treatment showed weaker effects on TH-positive cells (∼21%, P<0.05) and DAT levels (∼21%, P<0.05). DA and its metabolite levels were significantly increased with ST (50mg/kg) treatment (P<0.01, compared with the vehicle group). In addition, SOD and GSH-PX activities were elevated notably in ST treatment groups compared with the vehicle group. In conclusion, these results suggest that ST has neuroprotective effect on the impaired DA system, potentially through enhancement of the cell's anti-oxidative capacity. Hence it may be used as a potential therapeutic agent for Parkinson's disease.

  9. Effects of dopamine antagonists on drug cue-induced reinstatement of nicotine-seeking behavior in rats.

    PubMed

    Liu, Xiu; Jernigen, Courtney; Gharib, Maysa; Booth, Sheri; Caggiula, Anthony R; Sved, Alan F

    2010-03-01

    Dopaminergic neurotransmission has been implicated in associative learning processes related to drugs of abuse. However, it is not clear whether blockade of activation of dopamine receptors alters conditioned incentive properties of nicotine-associated cues. Using a response-reinstatement procedure, this study examined the effects of antagonists selective for the D1 and the D2 subtypes of dopamine receptors on cue-induced reinstatement of nicotine-seeking behavior. Male Sprague-Dawley rats were trained in 30 daily 1 h sessions to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed ratio 5 schedule and associate a conditioned stimulus (cue) with each nicotine delivery. After extinction of responding by withholding nicotine (saline substitution) and its cue, the reinstatement tests were conducted following subcutaneous administration of a D1 antagonist SCH23390 (0, 5, 10, 30 microg/kg) or a D2 antagonist eticlopride (0, 5, 10, 30 microg/kg) in different groups of animals. Both SCH23390 and eticlopride significantly attenuated the magnitude of cue-elicited reinstatement of nicotine-seeking responding. These results indicate that activation of dopaminergic D1 and D2 receptors may play a role in mediating the conditioned motivational effects of nicotine-associated cues as measured in the response-reinstatement procedure. These findings suggest that manipulation of dopaminergic neurotransmission at D1 and/or D2 receptors may prove to be a potential target for the development of pharmacotherapy for prevention of environmental nicotine cue-triggered smoking relapse.

  10. Dopamine-induced tyrosine phosphorylation of NR2B (Tyr1472) is essential for ERK1/2 activation and processing of novel taste information.

    PubMed

    David, Orit; Barrera, Iliana; Chinnakkaruppan, Adaikkan; Kaphzan, Hanoch; Nakazawa, Takanobu; Yamamoto, Tadashi; Rosenblum, Kobi

    2014-01-01

    Understanding the heterosynaptic interaction between glutamatergic and neuromodulatory synapses is highly important for revealing brain function in health and disease. For instance, the interaction between dopamine and glutamate neurotransmission is vital for memory and synaptic plasticity consolidation, and it is known to converge on extracellular signal-regulated kinase (ERK)-MAPK signaling in neurons. Previous studies suggest that dopamine induces N-methyl-D-aspartate (NMDA) receptor phosphorylation at the NR2B Y1472 subunit, influencing receptor internalization at the synaptic plasma membrane. However, it is unclear whether this phosphorylation is upstream to and/or necessary for ERK1/2 activation, which is known to be crucial for synaptic plasticity and memory consolidation. Here, we tested the hypothesis that tyrosine phosphorylation of NR2B at Y1472 is correlated with ERK1/2 activation by dopamine and necessar