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Sample records for rat brain striatal

  1. Effects of isomers of apomorphines on dopamine receptors in striatal and limbic tissue of rat brain

    SciTech Connect

    Kula, N.S.; Baldessarini, R.J.; Bromley, S.; Neumeyer, J.L.

    1985-09-16

    The optical isomers of apomorphine (APO) and N-propylnorapomorphine (NPA) were interacted with three biochemical indices of dopamine (Da) receptors in extrapyramidal and limbic preparations of rat brain tissues. There were consistent isomeric preferences for the R(-) configuration of both DA analogs in stimulation adenylate cyclase (D-1 sites) and in competing for high affinity binding of /sup 3/H-spiroperidol (D-2 sites) and of /sup 3/H-ADTN (DA agonist binding sites) in striatal tissue, with lesser isomeric differences in the limbic tissue. The S(+) apomorphines did not inhibit stimulation of adenylate cyclase by DA. The tendency for greater activity of higher apparent affinity of R(-) apomorphines in striatum may reflect the evidently greater abundance of receptor sites in that region. There were only small regional differences in interactions of the apomorphine isomers with all three receptor sites, except for a strong preference of (-)NPA for striatal D-2 sites. These results do not parallel our recent observations indicating potent and selective antidopaminergic actions of S(+) apomorphines in the rat limbic system. They suggest caution in assuming close parallels between current biochemical functional, especially behavioral, methods of evaluating dopamine receptors of mammalian brain.

  2. Effects of mercuric chloride on (/sup 3/H)dopamine release from rat brain striatal synaptosomes

    SciTech Connect

    Hare, M.F.; Minnema, D.J.; Cooper, G.P.; Michaelson, I.A.

    1989-06-15

    Electrophysiological studies employing amphibian neuromuscular preparations have shown that mercuric chloride (HgCl2) in vitro increases both spontaneous and evoked neurotransmitter release. The present study examines the effect of HgCl2 on the release of (/sup 3/H)dopamine from synaptosomes prepared from mammalian brain tissue. Mercuric chloride (3-10 microM) produces a concentration-dependent increase in spontaneous (/sup 3/H)dopamine release from ''purified'' rat striatal synaptosomes, in both the presence and absence of extra-synaptosomal calcium. The effects of HgCl2 on transmitter release from amphibian neuromuscular junction preparations resemble those produced by the Na+, K+-ATPase inhibitor ouabain. Experiments were performed to determine whether the HgCl2 effects on mammalian synaptosomal dopamine release are a consequence of Na+, K+-ATPase inhibition. Na+, K+-ATPase activity in lysed synaptosomal membranes is inhibited by HgCl2 (IC50 = 160 nM). However, mercuric chloride in the presence of 1 mM ouabain still increased (3H)dopamine release. The specific inhibitor of Na+-dependent, high-affinity dopamine transport, RMI81,182 inhibited ouabain-induced (3H)dopamine release whereas it had no effect on HgCl2-induced (/sup 3/H)dopamine release. These data suggest that augmentation of spontaneous (/sup 3/H)dopamine release by HgCl2 probably is not mediated by an inhibition of Na+, K+-ATPase and HgCl2 does not act directly on the dopamine transporter.

  3. In vivo brain microdialysis studies on the striatal dopamine and serotonin release in zitter mutant rats.

    PubMed

    Yoshimoto, Kanji; Nishimura, Akira; Hattori, Hiroyuki; Joyce, Jeffery N; Yoshida, Toshihide; Hioki, Chizuko; Kogure, Akinori; Ueda, Shuichi

    2006-07-01

    In the present study, using in vivo brain microdialysis, we investigated the basal extracellular dopamine (DA) and serotonin (5-HT) release in the caudal striatum (cSTR) of young (4-6 months old) and aged (10-12 months old) zitter mutant rats. The basal extracellular levels of DA release in both young and aged zitter rats were significantly lower than that of age-matched Sprague-Dawley (SD) rats, whereas only aged zitter rats showed a significant difference in the basal 5-HT release. Dopaminergic neurons were more vulnerable than serotonergic neurons in the cSTR of zitter mutant rats during aging. Perfusion of 60 mM potassium (K+) enhanced the extracellular levels of cSTR DA in the young zitter rats and the extracellular levels of both DA and 5-HT in the cSTR of the aged zitter rats. The firing rate of K+-stimulated monoamine release in the cSTR was significantly higher in the zitter rats than in the age-matched SD rats. These findings suggest that there are innate quantitative differences in the releasable pool and the availability of monoamines in the cSTR of zitter mutant rats.

  4. Involvement of striatal lipid peroxidation and inhibition of calcium influx into brain slices in neurobehavioral alterations in a rat model of short-term oral exposure to manganese.

    PubMed

    Avila, Daiana Silva; Gubert, Priscila; Fachinetto, Roselei; Wagner, Caroline; Aschner, Michael; Rocha, João Batista Teixeira; Soares, Félix Alexandre Antunes

    2008-11-01

    Manganese is an essential element for biological systems, nevertheless occupational exposure to high levels of Mn can lead to neurodegenerative disorder, characterized by excessive Mn accumulation, especially in astrocytes of basal ganglia and symptoms closely resembling idiopathic Parkinson's disease (PD). The purpose of this study was to evaluate behavioral and biochemical alterations in adult rats exposed for 30 days to 10 and 25mg/mL of MnCl(2) in their drinking water. MnCl(2) intoxicated rats showed impaired locomotor activity in comparison to control animals. Furthermore, lipid peroxidation were increased, delta-aminolevulinate dehydratase (delta-ALA-D, an enzyme sensitive to pro-oxidant situations) activity was inhibited and (45)Ca(2+) influx into striatal slices was decreased in rats exposed to 25mg/mL of Mn, indicating that this brain region was markedly affected by short-term Mn exposure. In contrast, Mn exposure was not associated with characteristic extrapyramidal effects and did not modify protein oxidation, suggesting that the striatal damage represents early stages of Mn-induced damage. In addition, treatment with Mn was associated with reduced body weight gain, but there were no discernible alterations in liver and kidney function. In conclusion, Mn caused increased oxidative stress and decreased (45)Ca(2+) influx into the striatum, which are likely linked to impaired locomotor activity, but not with the occurrence of orofacial dyskinesia.

  5. Effects of the adenosine A2A receptor antagonist SCH 58621 on cyclooxygenase-2 expression, glial activation, and brain-derived neurotrophic factor availability in a rat model of striatal neurodegeneration.

    PubMed

    Minghetti, Luisa; Greco, Anita; Potenza, Rosa Luisa; Pezzola, Antonella; Blum, David; Bantubungi, Kadiombo; Popoli, Patrizia

    2007-05-01

    Inhibition of adenosine A2A receptors (A2ARs) is neuroprotective in several experimental models of striatal diseases. However, the mechanisms elicited by A2AR blockade are only partially known, and critical aspects about the potential beneficial effects of A2AR antagonism in models of neurodegeneration still await elucidation. In the present study, we analyzed the influence of the selective A2AR antagonist SCH 58261 in a rat model of striatal excitotoxicity obtained by unilateral intrastriatal injection of quinolinic acid (QA). We found that SCH 58261 differently affected the expression of cyclooxygenase-2 (COX-2) induced by QA in cortex and striatum. The antagonist enhanced COX-2 expression in cortical neurons and prevented it in striatal microglia-like cells. Similarly, SCH 58261 differently regulated astrogliosis and microglial activation in the 2 brain regions. In addition, the A2AR antagonist prevented the QA-induced increase in striatal brain-derived neurotrophic factor levels. Because COX-2 activity has been linked to excitotoxic processes and because brain-derived neurotrophic factor depletion has been observed in mouse models as well as in patients with Huntington disease, we suggest that the final outcome of A2AR blockade (namely neuroprotection vs neurodegeneration) is likely to depend on the balance among its various and region-specific effects.

  6. Excessive S-Adenosyl-L-Methionine-Dependent Methylation Increases Levels of Methanol, Formaldehyde and Formic Acid in Rat Brain Striatal Homogenates: Possible role in S-adenosyl-L-methionine-induced Parkinson’s disease-like disorders

    PubMed Central

    Lee, Eun-Sook; Chen, Hongtao; Hardman, Chadwick; Simm, Anthony; Charlton, Clivel

    2009-01-01

    Aims Excessive methylation may be a precipitating factor for Parkinson’s disease (PD) since S-adenosylmethionine (SAM), the endogenous methyl donor, induces PD-like changes when injected into the rat brain. The hydrolysis of the methyl ester bond of the methylated proteins produces methanol. Since methanol is oxidized into formaldehyde, and formaldehyde into formic acid in the body, we investigated the effects of SAM on the production of methanol, formaldehyde and formic acid in rat brain striatal homogenates and the toxicity of these products in PC12 cells. Main methods radio-enzymatic and colorimetric assays, cell viability, Western blot. Key findings SAM increased the formation of methanol, formaldehyde and formic acid in a concentration and time-dependent manner. Concentrations of [3H-methyl]-SAM at 0.17, 0.33, 0.67 and 1.34 nM produced 3.8, 8.0, 18.3 and 34.4 fmol/mg protein/h of [3H] methanol in rat striatal homogenates, respectively. SAM also significantly generated formaldehyde and formic acid in striatal homogenates. Formaldehyde was the most toxic metabolite to differentiated PC12 pheochromocytoma cells in cell culture studies, indicating that formaldehyde formed endogenously may contribute to neuronal damage in excessive methylation conditions. Subtoxic concentration of formaldehyde decreased the expression of tyrosine hydroxylase, the limiting factor in dopamine synthesis. Formaldehyde was more toxic to catecholaminergic PC12 cells than C6 glioma cells, indicating that neurons are more vulnerable to formaldehyde than glia cells. Significance We suggest that excessive carboxylmethylation of proteins might be involved in the SAM-induced PD-like changes and in the aging process via the toxic effects of formaldehyde. PMID:18930743

  7. Exercise training reinstates cortico-cortical sensorimotor functional connectivity following striatal lesioning: Development and application of a subregional-level analytic toolbox for perfusion autoradiographs of the rat brain

    NASA Astrophysics Data System (ADS)

    Peng, Yu-Hao; Heintz, Ryan; Wang, Zhuo; Guo, Yumei; Myers, Kalisa; Scremin, Oscar; Maarek, Jean-Michel; Holschneider, Daniel

    2014-12-01

    Current rodent connectome projects are revealing brain structural connectivity with unprecedented resolution and completeness. How subregional structural connectivity relates to subregional functional interactions is an emerging research topic. We describe a method for standardized, mesoscopic-level data sampling from autoradiographic coronal sections of the rat brain, and for correlation-based analysis and intuitive display of cortico-cortical functional connectivity (FC) on a flattened cortical map. A graphic user interface “Cx-2D” allows for the display of significant correlations of individual regions-of-interest, as well as graph theoretical metrics across the cortex. Cx-2D was tested on an autoradiographic data set of cerebral blood flow (CBF) of rats that had undergone bilateral striatal lesions, followed by 4 weeks of aerobic exercise training or no exercise. Effects of lesioning and exercise on cortico-cortical FC were examined during a locomotor challenge in this rat model of Parkinsonism. Subregional FC analysis revealed a rich functional reorganization of the brain in response to lesioning and exercise that was not apparent in a standard analysis focused on CBF of isolated brain regions. Lesioned rats showed diminished degree centrality of lateral primary motor cortex, as well as neighboring somatosensory cortex--changes that were substantially reversed in lesioned rats following exercise training. Seed analysis revealed that exercise increased positive correlations in motor and somatosensory cortex, with little effect in non-sensorimotor regions such as visual, auditory, and piriform cortex. The current analysis revealed that exercise partially reinstated sensorimotor FC lost following dopaminergic deafferentation. Cx-2D allows for standardized data sampling from images of brain slices, as well as analysis and display of cortico-cortical FC in the rat cerebral cortex with potential applications in a variety of autoradiographic and histologic

  8. Exercise training reinstates cortico-cortical sensorimotor functional connectivity following striatal lesioning: development and application of a subregional-level analytic toolbox for perfusion autoradiographs of the rat brain

    PubMed Central

    Peng, Yu-Hao; Heintz, Ryan; Wang, Zhuo; Guo, Yumei; Myers, Kalisa G.; Scremin, Oscar U.; Maarek, Jean-Michel I.; Holschneider, Daniel P.

    2015-01-01

    Current rodent connectome projects are revealing brain structural connectivity with unprecedented resolution and completeness. How subregional structural connectivity relates to subregional functional interactions is an emerging research topic. We describe a method for standardized, mesoscopic-level data sampling from autoradiographic coronal sections of the rat brain, and for correlation-based analysis and intuitive display of cortico-cortical functional connectivity (FC) on a flattened cortical map. A graphic user interface “Cx-2D” allows for the display of significant correlations of individual regions-of-interest, as well as graph theoretical metrics across the cortex. Cx-2D was tested on an autoradiographic data set of cerebral blood flow (CBF) of rats that had undergone bilateral striatal lesions, followed by 4 weeks of aerobic exercise training or no exercise. Effects of lesioning and exercise on cortico-cortical FC were examined during a locomotor challenge in this rat model of Parkinsonism. Subregional FC analysis revealed a rich functional reorganization of the brain in response to lesioning and exercise that was not apparent in a standard analysis focused on CBF of isolated brain regions. Lesioned rats showed diminished degree centrality of lateral primary motor cortex, as well as neighboring somatosensory cortex—changes that were substantially reversed in lesioned rats following exercise training. Seed analysis revealed that exercise increased positive correlations in motor and somatosensory cortex, with little effect in non-sensorimotor regions such as visual, auditory, and piriform cortex. The current analysis revealed that exercise partially reinstated sensorimotor FC lost following dopaminergic deafferentation. Cx-2D allows for standardized data sampling from images of brain slices, as well as analysis and display of cortico-cortical FC in the rat cerebral cortex with potential applications in a variety of autoradiographic and histologic

  9. Cortical regulation of striatal projection neurons and interneurons in a Parkinson's disease rat model

    PubMed Central

    Wu, Jia-jia; Chen, Si; Ouyang, Li-si; Jia, Yu; Liu, Bing-bing; Mu, Shu-hua; Ma, Yu-xin; Wang, Wei-ping; Wei, Jia-you; Li, You-lan; Chen, Zhi; Lei, Wan-long

    2016-01-01

    Striatal neurons can be either projection neurons or interneurons, with each type exhibiting distinct susceptibility to various types of brain damage. In this study, 6-hydroxydopamine was injected into the right medial forebrain bundle to induce dopamine depletion, and/or ibotenic acid was injected into the M1 cortex to induce motor cortex lesions. Immunohistochemistry and western blot assay showed that dopaminergic depletion results in significant loss of striatal projection neurons marked by dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein, molecular weight 32 kDa, calbindin, and μ-opioid receptor, while cortical lesions reversed these pathological changes. After dopaminergic deletion, the number of neuropeptide Y-positive striatal interneurons markedly increased, which was also inhibited by cortical lesioning. No noticeable change in the number of parvalbumin-positive interneurons was found in 6-hydroxydopamine-treated rats. Striatal projection neurons and interneurons show different susceptibility to dopaminergic depletion. Further, cortical lesions inhibit striatal dysfunction and damage induced by 6-hydroxydopamine, which provides a new possibility for clinical treatment of Parkinson's disease. PMID:28197194

  10. The effects of systemically administered taurine and N-pivaloyltaurine on striatal extracellular dopamine and taurine in freely moving rats.

    PubMed

    Salimäki, J; Scriba, G; Piepponen, T P; Rautolahti, N; Ahtee, L

    2003-08-01

    The second most abundant cerebral amino acid, taurine, is widely consumed in the so-called "energy drinks". Therefore, its possible actions on the brain are of great interest. In the present experiments taurine was given intraperitoneally to rats in order to study if it can be administered systemically in large enough amounts to alter cerebral dopaminergic transmission or to induce hypothermia. In addition, the effects of subcutaneously administered lipophilic taurine analogue, N-pivaloyltaurine, were studied. The extracellular striatal taurine and dopamine concentrations were estimated using in vivo microdialysis in awake and freely moving rats, and the rectal temperatures were measured. Taurine at the total dose of 45 mmol/kg i.p. led to a maximally 8-fold increased striatal extracellular taurine concentration, induced a long-lasting hypothermia, and significantly reduced the striatal extracellular dopamine concentration. The latter effect was strengthened by co-treatment with reuptake inhibitor nomifensine. N-pivaloyltaurine (15 mmol/kg in total, s.c.) only slightly elevated the striatal extracellular taurine concentration, failed to alter the rectal temperature, and in contrast to taurine somewhat elevated the striatal extracellular dopamine concentration suggesting a different mechanism or locus of action from that of taurine. Finally, our experiments using brain microdialysis confirmed the earlier findings that taurine is slowly eliminated from the brain. The results clearly indicate that systemically given taurine enters the brain in concentrations that induce pharmacological effects.

  11. Motor tics evoked by striatal disinhibition in the rat

    PubMed Central

    Bronfeld, Maya; Yael, Dorin; Belelovsky, Katya; Bar-Gad, Izhar

    2013-01-01

    Motor tics are sudden, brief, repetitive movements that constitute the main symptom of Tourette syndrome (TS). Multiple lines of evidence suggest the involvement of the cortico-basal ganglia system, and in particular the basal ganglia input structure—the striatum in tic formation. The striatum receives somatotopically organized cortical projections and contains an internal GABAergic network of interneurons and projection neurons' collaterals. Disruption of local striatal GABAergic connectivity has been associated with TS and was found to induce abnormal movements in model animals. We have previously described the behavioral and neurophysiological characteristics of motor tics induced in monkeys by local striatal microinjections of the GABAA antagonist bicuculline. In the current study we explored the abnormal movements induced by a similar manipulation in freely moving rats. We targeted microinjections to different parts of the dorsal striatum, and examined the effects of this manipulation on the induced tic properties, such as latency, duration, and somatic localization. Tics induced by striatal disinhibition in monkeys and rats shared multiple properties: tics began within several minutes after microinjection, were expressed solely in the contralateral side, and waxed and waned around a mean inter-tic interval of 1–4 s. A clear somatotopic organization was observed only in rats, where injections to the anterior or posterior striatum led to tics in the forelimb or hindlimb areas, respectively. These results suggest that striatal disinhibition in the rat may be used to model motor tics such as observed in TS. Establishing this reliable and accessible animal model could facilitate the study of the neural mechanisms underlying motor tics, and the testing of potential therapies for tic disorders. PMID:24065893

  12. Striatal and extrastriatal microPET imaging of D2/D3 dopamine receptors in rat brain with [¹⁸F]fallypride and [¹⁸F]desmethoxyfallypride.

    PubMed

    Constantinescu, Cristian C; Coleman, Robert A; Pan, Min-Liang; Mukherjee, Jogeshwar

    2011-08-01

    In this study, we compared two different D(2/3) receptor ligands, [¹⁸F]fallypride and [¹⁸F]desmethoxyfallypride ([¹⁸F]DMFP) with respect to the duration of the scan, visualization of extrastriatal receptors, and binding potentials (BP(ND) ) in the rat brain. In addition, we studied the feasibility of using these tracers following a period of awake tracer uptake, during which the animal may perform a behavioral task. Male Sprague-Dawley rats were imaged with [¹⁸F]fallypride and with [¹⁸F]DMFP in four different studies using microPET. All scans were performed under isoflurane anesthesia. The first (test) and second (retest) study were 150-min baseline scans. No retest scans were performed with [¹⁸F]DMFP. A third study was a 60-min awake uptake of radiotracer followed by a 90-min scan. A fourth study was a 150-min competition scan with haloperidol (0.2 mg/kg) administered via tail vein at 90-min post-[¹⁸F]fallypride injection and 60-min post-[¹⁸F]DMFP. For the test-retest studies, BP(ND) was measured using both Logan noninvasive (LNI) method and the interval ratios (ITR) method. Cerebellum was used as a reference region. For the third study, the binding was measured only with the ITR method, and the results were compared to the baseline results. Studies showed that the average transient equilibrium time in the dorsal striatum (DSTR) was at 90 min for [¹⁸F]fallypride and 30 min for [¹⁸F]DMFP. The average BP(ND) for [¹⁸F]fallypride was 14.4 in DSTR, 6.8 in ventral striatum (VSTR), 1.3 in substantia nigra/ventral tegmental area (SN/VTA), 1.4 in colliculi (COL), and 1.5 in central gray area. In the case of [¹⁸F]DMFP, the average BP(ND) values were 2.2 in DSTR, 2.7 in VSTR, and 0.8 in SN/VTA. The haloperidol blockade showed detectable decrease in binding of both tracers in striatal regions with a faster displacement of [¹⁸F]DMFP. No significant changes in BP(ND) of [¹⁸F]fallypride due to the initial awake state of the animal were

  13. Populations of striatal medium spiny neurons encode vibrotactile frequency in rats: modulation by slow wave oscillations.

    PubMed

    Hawking, Thomas G; Gerdjikov, Todor V

    2013-01-01

    Dorsolateral striatum (DLS) is implicated in tactile perception and receives strong projections from somatosensory cortex. However, the sensory representations encoded by striatal projection neurons are not well understood. Here we characterized the contribution of DLS to the encoding of vibrotactile information in rats by assessing striatal responses to precise frequency stimuli delivered to a single vibrissa. We applied stimuli in a frequency range (45-90 Hz) that evokes discriminable percepts and carries most of the power of vibrissa vibration elicited by a range of complex fine textures. Both medium spiny neurons and evoked potentials showed tactile responses that were modulated by slow wave oscillations. Furthermore, medium spiny neuron population responses represented stimulus frequency on par with previously reported behavioral benchmarks. Our results suggest that striatum encodes frequency information of vibrotactile stimuli which is dynamically modulated by ongoing brain state.

  14. In Vitro Manganese Exposure Disrupts MAPK Signaling Pathways in Striatal and Hippocampal Slices from Immature Rats

    PubMed Central

    Peres, Tanara Vieira; Pedro, Daniela Zótico; de Cordova, Fabiano Mendes; Lopes, Mark William; Gonçalves, Filipe Marques; Mendes-de-Aguiar, Cláudia Beatriz Nedel; Walz, Roger; Farina, Marcelo; Aschner, Michael; Leal, Rodrigo Bainy

    2013-01-01

    The molecular mechanisms mediating manganese (Mn)-induced neurotoxicity, particularly in the immature central nervous system, have yet to be completely understood. In this study, we investigated whether mitogen-activated protein kinases (MAPKs) and tyrosine hydroxylase (TH) could represent potential targets of Mn in striatal and hippocampal slices obtained from immature rats (14 days old). The aim of this study was to evaluate if the MAPK pathways are modulated after subtoxic Mn exposure, which do not significantly affect cell viability. The concentrations of manganese chloride (MnCl2; 10–1,000 μM) caused no change in cell viability in slices exposed for 3 or 6 hours. However, Mn exposure significantly increased extracellular signal-regulated kinase (ERK) 1/2, as well as c-Jun N-terminal kinase (JNK) 1/2/3 phosphorylation at both 3 and 6 hours incubations, in both brain structures. Furthermore, Mn exposure did not change the total content or phosphorylation of TH at the serine 40 site in striatal slices. Thus, Mn at concentrations that do not disrupt cell viability causes activation of MAPKs (ERK1/2 and JNK1/2/3) in immature hippocampal and striatal slices. These findings suggest that altered intracellular MAPKs signaling pathways may represent an early event concerning the effects of Mn in the immature brain. PMID:24324973

  15. Protective effect of melatonin upon neuropathology, striatal function, and memory ability after intracerebral hemorrhage in rats.

    PubMed

    Lekic, Tim; Hartman, Richard; Rojas, Hugo; Manaenko, Anatol; Chen, Wanqiu; Ayer, Robert; Tang, Jiping; Zhang, John H

    2010-03-01

    Since free radicals play a role in the mechanisms of brain injury after hemorrhagic stroke, the effect of melatonin (a potent antioxidant and free-radical scavenger) on outcomes was investigated after intracerebral hemorrhage (ICH) in rats. ICH was induced by clostridial collagenase infusion into the right caudate putamen, and several time points and doses of melatonin were studied. Brain edema and neurological function at 24 h were unchanged in comparison with vehicle-treated groups, in spite of oxidative stress reductions. Repeated treatment with the lower dose of melatonin (5 mg/kg) given at 1 h and every 24 h thereafter for 3 days after ICH, led to normalization of striatal function and memory ability over the course of 8 weeks, and less brain atrophy 2 weeks later. These results suggest that melatonin is safe for use after ICH, reduces oxidative stress, provides brain protection, and could be used for future investigations of free radical mechanisms after cerebral hemorrhage.

  16. Graft-induced Recovery of Inhibitory Avoidance Conditioning in Striatal Lesioned Rats is Related to Choline Acetyltransferase Activity

    PubMed Central

    Piña, Ana Luisa; Ormsby, Christopher Edward; Miranda, María Isabel; Jiménez, Nicolás; Tapia, Ricardo; Bermúdez-Rattoni, Federico

    1994-01-01

    Four groups of male Wistar rats showing disrupted inhibitory avoidance conditioning due to striatal lesions received either striatal or ventral mesencephalic brain grafts. Two additional non-lesioned groups were used as controls. Half of the groups was retrained in an inhibitory avoidance task at fifteen days postgraft and the other half at sixty days postgraft. Those animals receiving striatal grafts significantly improved their ability to acquire the inhibitory avoidance task at fifteen and sixty days postgraft, as opposed to those receiving mesencephalic grafts, which did not show behavioral recovery. Choline acetyltransferase and glutamate decarboxylase activities, as well as dopamine content, were measured in the grafted tissue. Striatal grafts showed levels of choline acetyltransferase activity similar to the control group. Moreover, a positive correlation was found between the choline acetyltransferase activity and the behavioral recovery. In contrast, both glutamate decarboxylase activity and dopamine levels were significantly lower in striatal and in mesencephalic grafts, as compared to the controls. These results show that striatal but not mesencephalic grafts can promote the restoration of the ability to acquire an inhibitory avoidance task even at early stages (15 days) of the development of the grafts. The results also suggest that acetylcholine plays an important role in behavioral recovery. PMID:7819369

  17. Up-regulation of striatal adenosine A2A receptors with iron deficiency in rats. Effects on locomotion and cortico-striatal neurotransmission

    PubMed Central

    Quiroz, César; Pearson, Virginia; Gulyani, Seema; Allen, Richard; Earley, Christopher; Ferré, Sergi

    2010-01-01

    Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A2A receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A2A receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A2A receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A2A receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A2A receptors was found in rats fed during three weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A2A receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A2A receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A2A receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A2A receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS. PMID:20385128

  18. Up-regulation of striatal adenosine A(2A) receptors with iron deficiency in rats: effects on locomotion and cortico-striatal neurotransmission.

    PubMed

    Quiroz, César; Pearson, Virginia; Gulyani, Seema; Allen, Richard; Earley, Christopher; Ferré, Sergi

    2010-07-01

    Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A(2A) receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A(2A) receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A(2A) receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A(2A) receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A(2A) receptors was found in rats fed during 3 weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A(2A) receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A(2A) receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A(2A) receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A(2A) receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS.

  19. Exercise-induced rescue of tongue function without striatal dopamine sparing in a rat neurotoxin model of Parkinson disease.

    PubMed

    Ciucci, Michelle R; Schaser, Allison J; Russell, John A

    2013-09-01

    Unilateral lesions to the medial forebrain bundle with 6-hydroxydopamine (6-OHDA) lead to force and timing deficits during a complex licking task. We hypothesized that training targeting tongue force generation during licking would improve timing and force measures and also lead to striatal dopamine sparing. Nine month-old male Fisher344/Brown Norway rats were used in this experiment. Sixteen rats were in the control condition and received tongue exercise (n=8) or no exercise (n=8). Fourteen rats were in the 6-OHDA lesion condition and underwent tongue exercise (n=7) and or no exercise (n=7). Following 4 weeks of training and post-training measures, all animals underwent bilateral stimulation of the hypoglossal nerves to measure muscle contractile properties and were then transcardially perfused and brain tissues collected for immunohistochemistry to examine striatal dopamine content. Results demonstrated that exercise animals performed better for maximal force, average force, and press rate than their no-exercise counterparts, and the 6-OHDA animals that underwent exercise performed as well as the Control No Exercise group. Interestingly, there were no group differences for tetanic muscle force, despite behavioral recovery of forces. Additionally, behavioral and neurochemical analyses indicate that there were no differences in striatal dopamine. Thus, targeted exercise can improve tongue force and timing deficits related to 6-OHDA lesions and this exercise likely has a central, versus peripheral (muscle strength) mechanism. However, this mechanism is not related to sparing of striatal dopamine content.

  20. Striatal dysfunction increases basal ganglia output during motor cortex activation in parkinsonian rats.

    PubMed

    Belluscio, Mariano A; Riquelme, Luis A; Murer, M Gustavo

    2007-05-01

    During movement, inhibitory neurons in the basal ganglia output nuclei show complex modulations of firing, which are presumptively driven by corticostriatal and corticosubthalamic input. Reductions in discharge should facilitate movement by disinhibiting thalamic and brain stem nuclei while increases would do the opposite. A proposal that nigrostriatal dopamine pathway degeneration disrupts trans-striatal pathways' balance resulting in sustained overactivity of basal ganglia output nuclei neurons and Parkinson's disease clinical signs is not fully supported by experimental evidence, which instead shows abnormal synchronous oscillatory activity in animal models and patients. Yet, the possibility that variation in motor cortex activity drives transient overactivity in output nuclei neurons in parkinsonism has not been explored. In Sprague-Dawley rats with 6-hydroxydopamine (6-OHDA)-induced nigrostriatal lesions, approximately 50% substantia nigra pars reticulata (SNpr) units show abnormal cortically driven slow oscillations of discharge. Moreover, these units selectively show abnormal responses to motor cortex stimulation consisting in augmented excitations of an odd latency, which overlapped that of inhibitory responses presumptively mediated by the trans-striatal direct pathway in control rats. Delivering D1 or D2 dopamine agonists into the striatum of parkinsonian rats by reverse microdialysis reduced these abnormal excitations but had no effect on pathological oscillations. The present study establishes that dopamine-deficiency related changes of striatal function contribute to producing abnormally augmented excitatory responses to motor cortex stimulation in the SNpr. If a similar transient overactivity of basal ganglia output were driven by motor cortex input during movement, it could contribute to impeding movement initiation or execution in Parkinson's disease.

  1. Striatal Enkephalinergic Differences in Rats Selectively Bred for Intrinsic Running Capacity

    PubMed Central

    Monroe, Derek C.; Holmes, Philip V.; Koch, Lauren G.; Britton, Steven L.; Dishman, Rodney K.

    2014-01-01

    Rats selectively bred for high- and low-capacity for running on a treadmill (HCR; LCR) also differ in wheel-running behavior, but whether wheel-running can be explained by intrinsic or adaptive brain mechanisms is not as yet understood. It is established that motivation of locomotory behavior is driven by dopaminergic transmission in mesolimbic and mesostriatal systems. However, whether voluntary wheel running is associated with enkephalinergic activity in the ventral striatum is not known. Materials & Methods 40 male (20 HCR and 20 LCR) and 40 female (20 HCR and 20 LCR) rats were randomly assigned to 3 weeks of activity wheel exposure or sedentary conditions without wheel access. After 3 weeks of activity-wheel running, rats were decapitated and brains were extracted. Coronal sections were analyzed utilizing in situ hybridization histochemistry for enkephalin (ENK) mRNA in the ventral striatum. Results HCR rats expressed less ENK than LCR rats in the nucleus accumbens among females (p <.01) and in the olfactory tubercle among both females (p <.05) and males (p<.05). There was no effect of wheel running on ENK mRNA expression. Conclusion Line differences in ENK expression in the olfactory tubercle, and possibly the nucleus accumbens, partly explain divergent wheel-running behavior. The lower striatal ENK in the HCR line is consistent with enhanced dopaminergic tone, which may explain the increased motivation for wheel running observed in the HCR line. PMID:24842004

  2. β-asarone and levodopa co-administration increase striatal dopamine level in 6-hydroxydopamine induced rats by modulating P-glycoprotein and tight junction proteins at the blood-brain barrier and promoting levodopa into the brain.

    PubMed

    Huang, Liping; Deng, Minzhen; He, Yuping; Lu, Shiyao; Ma, Ruanxin; Fang, Yongqi

    2016-06-01

    Levodopa (L-dopa) is widely considered as one of the most effective drug constituents in the treatment of Parkinson's disease (PD), but the blood-brain barrier (BBB) permeability of L-dopa is <5%, which causes low efficacy. Neuroprotective effects of β-asarone on 6-hydroxydopamine (6-OHDA)-induced PD rats were demonstrated by our previous studies. Co-administration of β-asarone and L-dopa has not been explored until being investigated on PD rats in this study. PD rats were divided into four groups: untreated, L-dopa-treated, β-asarone-treated and co-administered-treated groups. All of the treatments were administered to the rats twice per day for 30 days. The L-dopa, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), S100β and neuron-specific enolase (NSE) levels were subsequently determined. The P-glycoprotein (P-gp), zonula occludens-1 (ZO-1), claudin-5, occludin and actin expression was also assessed in cortex. Changes in BBB ultrastructure were observed using transmission electron microscopy. Our results showed that the co-administered treatment increased levels of L-dopa, DA, DOPAC and HVA in striatum, and S100β in plasma, but down-regulated NSE, P-gp, ZO-1, occludin, actin and claudin-5 in cortex. Crevices were observed between capillary endothelial cells at intercellular tight junction of the striatum in co-administered-treated group, while the endothelial cells in untreated group were tightly jointing each other. In addition, the correlations of L-dopa or DA and P-gp or tight junction proteins respectively were significantly negative in co-administered- and β-asarone-treated groups. These findings suggest that co-administered treatment may enhance the L-dopa BBB permeability and attenuate brain injury, which may be beneficial to PD treatment.

  3. Early Deficits in Glycolysis Are Specific to Striatal Neurons from a Rat Model of Huntington Disease

    PubMed Central

    Gouarné, Caroline; Tardif, Gwenaëlle; Tracz, Jennifer; Latyszenok, Virginie; Michaud, Magali; Clemens, Laura Emily; Yu-Taeger, Libo; Nguyen, Huu Phuc; Bordet, Thierry; Pruss, Rebecca M.

    2013-01-01

    In Huntington disease (HD), there is increasing evidence for a link between mutant huntingtin expression, mitochondrial dysfunction, energetic deficits and neurodegeneration but the precise nature, causes and order of these events remain to be determined. In this work, our objective was to evaluate mitochondrial respiratory function in intact, non-permeabilized, neurons derived from a transgenic rat model for HD compared to their wild type littermates by measuring oxygen consumption rates and extracellular acidification rates. Although HD striatal neurons had similar respiratory capacity as those from their wild-type littermates when they were incubated in rich medium containing a supra-physiological glucose concentration (25 mM), pyruvate and amino acids, respiratory defects emerged when cells were incubated in media containing only a physiological cerebral level of glucose (2.5 mM). According to the concept that glucose is not the sole substrate used by the brain for neuronal energy production, we provide evidence that primary neurons can use lactate as well as pyruvate to fuel the mitochondrial respiratory chain. In contrast to glucose, we found no major deficits in HD striatal neurons’ capacity to use pyruvate as a respiratory substrate compared to wild type littermates. Additionally, we used extracellular acidification rates to confirm a reduction in anaerobic glycolysis in the same cells. Interestingly, the metabolic disturbances observed in striatal neurons were not seen in primary cortical neurons, a brain region affected in later stages of HD. In conclusion, our results argue for a dysfunction in glycolysis, which might precede any defects in the respiratory chain itself, and these are early events in the onset of disease. PMID:24303051

  4. Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury

    PubMed Central

    Duan, Chun‐Ling; Liu, Chong‐Wei; Shen, Shu‐Wen; Yu, Zhang; Mo, Jia‐Lin; Chen, Xian‐Hua

    2015-01-01

    To determine whether reactive astrocytes stimulated by brain injury can transdifferentiate into functional new neurons, we labeled these cells by injecting a glial fibrillary acidic protein (GFAP) targeted enhanced green fluorescence protein plasmid (pGfa2‐eGFP plasmid) into the striatum of adult rats immediately following a transient middle cerebral artery occlusion (MCAO) and performed immunolabeling with specific neuronal markers to trace the neural fates of eGFP‐expressing (GFP+) reactive astrocytes. The results showed that a portion of striatal GFP+ astrocytes could transdifferentiate into immature neurons at 1 week after MCAO and mature neurons at 2 weeks as determined by double staining GFP‐expressing cells with βIII‐tubulin (GFP+‐Tuj‐1+) and microtubule associated protein‐2 (GFP+‐MAP‐2+), respectively. GFP+ neurons further expressed choline acetyltransferase, glutamic acid decarboxylase, dopamine receptor D2‐like family proteins, and the N‐methyl‐d‐aspartate receptor subunit R2, indicating that astrocyte‐derived neurons could develop into cholinergic or GABAergic neurons and express dopamine and glutamate receptors on their membranes. Electron microscopy analysis indicated that GFP+ neurons could form synapses with other neurons at 13 weeks after MCAO. Electrophysiological recordings revealed that action potentials and active postsynaptic currents could be recorded in the neuron‐like GFP+ cells but not in the astrocyte‐like GFP+ cells, demonstrating that new GFP+ neurons possessed the capacity to fire action potentials and receive synaptic inputs. These results demonstrated that striatal astrocyte‐derived new neurons participate in the rebuilding of functional neural networks, a fundamental basis for brain repair after injury. These results may lead to new therapeutic strategies for enhancing brain repair after ischemic stroke. GLIA 2015;63:1660–1670 PMID:26031629

  5. Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury.

    PubMed

    Duan, Chun-Ling; Liu, Chong-Wei; Shen, Shu-Wen; Yu, Zhang; Mo, Jia-Lin; Chen, Xian-Hua; Sun, Feng-Yan

    2015-09-01

    To determine whether reactive astrocytes stimulated by brain injury can transdifferentiate into functional new neurons, we labeled these cells by injecting a glial fibrillary acidic protein (GFAP) targeted enhanced green fluorescence protein plasmid (pGfa2-eGFP plasmid) into the striatum of adult rats immediately following a transient middle cerebral artery occlusion (MCAO) and performed immunolabeling with specific neuronal markers to trace the neural fates of eGFP-expressing (GFP(+)) reactive astrocytes. The results showed that a portion of striatal GFP(+) astrocytes could transdifferentiate into immature neurons at 1 week after MCAO and mature neurons at 2 weeks as determined by double staining GFP-expressing cells with βIII-tubulin (GFP(+)-Tuj-1(+)) and microtubule associated protein-2 (GFP(+)-MAP-2(+)), respectively. GFP(+) neurons further expressed choline acetyltransferase, glutamic acid decarboxylase, dopamine receptor D2-like family proteins, and the N-methyl-D-aspartate receptor subunit R2, indicating that astrocyte-derived neurons could develop into cholinergic or GABAergic neurons and express dopamine and glutamate receptors on their membranes. Electron microscopy analysis indicated that GFP(+) neurons could form synapses with other neurons at 13 weeks after MCAO. Electrophysiological recordings revealed that action potentials and active postsynaptic currents could be recorded in the neuron-like GFP(+) cells but not in the astrocyte-like GFP(+) cells, demonstrating that new GFP(+) neurons possessed the capacity to fire action potentials and receive synaptic inputs. These results demonstrated that striatal astrocyte-derived new neurons participate in the rebuilding of functional neural networks, a fundamental basis for brain repair after injury. These results may lead to new therapeutic strategies for enhancing brain repair after ischemic stroke.

  6. Adenosine receptor expression and function in rat striatal cholinergic interneurons.

    PubMed

    Preston, Z; Lee, K; Widdowson, L; Freeman, T C; Dixon, A K; Richardson, P J

    2000-06-01

    Cholinergic neurons were identified in rat striatal slices by their size, membrane properties, sensitivity to the NK(1) receptor agonist (Sar(9), Met(O(2))(11)) Substance P, and expression of choline acetyltransferase mRNA. A(1) receptor mRNA was detected in 60% of the neurons analysed, and A(2A) receptor mRNA in 67% (n=15). The A(1) receptor agonist R-N(6)-(2-phenylisopropyl)adenosine (R-PIA) hyperpolarized cholinergic neurons in a concentration dependent manner sensitive to the A(1) antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 100 nM). In dual stimulus experiments, the A(2A) receptor antagonist 8-(3-chlorostyryl)caffeine (CSC, 500 nM) decreased release of [(3)H]-acetylcholine from striatal slices (S2/S1 0.78+/-0.07 versus 0.95+/-0.05 in control), as did adenosine deaminase (S2/S1 ratio 0.69+/-0.05), whereas the A(1) receptor antagonist DPCPX (100 nM) had no effect (S2/S1 1.05+/-0.14). In the presence of adenosine deaminase the adenosine A(2A) receptor agonist 2-p-((carboxyethyl)phenylethylamino)-5'-N-ethylcarboxamidoadeno sin e (CGS21680, 10 nM) increased release (S2/S1 ratio 1.03+/-0.05 versus 0.88+/-0.05 in control), an effect blocked by the antagonist CSC (500 nM, S2/S1 0.68+/-0.05, versus 0.73+/-0.08 with CSC alone). The combined superfusion of bicuculline (10 microM), saclofen (1 microM) and naloxone (10 microM) had no effect on the stimulation by CGS21680 (S2/S1 ratio 0.99+/-0.04). The A(1) receptor agonist R-PIA (100 nM) inhibited the release of [(3)H]-acetylcholine (S2/S1 ratio 0.70+/-0.03), an effect blocked by DPCPX (S2/S1 ratio 1.06+/-0.07). It is concluded that both A(1) and A(2A) receptors are expressed on striatal cholinergic neurons where they are functionally active.

  7. Restorative effects of GDNF on striatal dopamine release in rats treated with neurotoxic doses of methamphetamine.

    PubMed

    Cass, W A; Manning, M W; Bailey, S L

    2000-09-01

    Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in striatal dopamine (DA) release and content. Glial cell line-derived neurotrophic factor (GDNF) has pronounced effects on dopaminergic systems in vivo, including neuroprotective effects against METH. The present experiments were designed to examine the ability of GDNF to reverse, or accelerate recovery from, METH-induced alterations in striatal DA release. Male Fischer-344 rats were administered METH (5 mg/kg, s.c.) or saline 4 times in one day at 2-hour intervals. Seven days later the animals were anesthetized and given a single injection of 10 microg GDNF, or vehicle, into the right striatum. Three weeks later microdialysis experiments were carried out in both the right and left striata to examine basal and evoked levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). In animals treated with METH followed by vehicle 7 days later, there were significant reductions in potassium- and amphetamine-evoked overflow of DA, and in basal levels of DOPAC and HVA, compared to control animals. In rats treated with METH followed 7 days later with GDNF, there were significant increases in potassium- and amphetamine-evoked overflow of DA on the right, GDNF-treated, side of the brain compared to the left side. Basal levels of DOPAC and HVA were also elevated on the GDNF-treated side of the brain. These results suggest that GDNF can accelerate recovery of dopaminergic release processes in the striatum of rats treated with neurotoxic doses of METH.

  8. Cell cycle activation in striatal neurons from Huntington's disease patients and rats treated with 3-nitropropionic acid.

    PubMed

    Pelegrí, Carme; Duran-Vilaregut, Joaquim; del Valle, Jaume; Crespo-Biel, Natàlia; Ferrer, Isidre; Pallàs, Mercè; Camins, Antoni; Vilaplana, Jordi

    2008-11-01

    This study was undertaken to investigate the potential role of cell cycle re-entry in an experimental model of Huntington's disease and in human brain samples. We found that after treatment of rats with the mitochondrial neurotoxin 3-nitropropionic acid, the expression of cell cycle markers of G1 phase measured by immunohistochemistry was induced in the striatal brain region. Furthermore, we detected an increase in the nuclear and also cytoplasmatic E2F-1 expression, suggesting that this protein could activate the apoptotic cascade in rat brain. Western blot analysis of post-mortem brain samples from patients also showed an increase in the expression of E2F-1 and cyclin D1 in comparison with control samples. These results indicate that cell cycle re-entry is activated in Huntington's disease and may contribute to the neurodegenerative process.

  9. Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat.

    PubMed

    Rupniak, N M; Hall, M D; Mann, S; Fleminger, S; Kilpatrick, G; Jenner, P; Marsden, C D

    1985-08-01

    Comparison has been made of the effects on brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1-12 months with haloperidol (1.4-1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months' treatment with clozapine (24-27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5-1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. Bmax for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. Bmax for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. Bmax for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 microM)-stimulated adenylate cyclase activity was inhibited after 1 month's haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitivity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.

  10. Protective effects of ginseng saponins on 3-nitropropionic acid-induced striatal degeneration in rats.

    PubMed

    Kim, Jong-Hoon; Kim, Sunoh; Yoon, In-Soo; Lee, Jong-Hwan; Jang, Byung-Jun; Jeong, Sang Min; Lee, Jun-Ho; Lee, Byung-Hwan; Han, Jin-Soo; Oh, Sekwan; Kim, Hyung-Chun; Park, Tae Kyu; Rhim, Hyewhon; Nah, Seung-Yeol

    2005-04-01

    The precise cause of neuronal cell death in Huntington's disease (HD) is not known. Systemic administration of 3-nitropropionic acid (3-NP), an irreversible succinate dehydrogenase inhibitor, not only induces a cellular ATP depletions but also causes a selective striatal degeneration similar to that seen in HD. Recent accumulating reports have shown that ginseng saponins (GTS), the major active ingredients of Panax ginseng, have protective effects against neurotoxin insults. In the present study, we examined in vitro and in vivo effects of GTS on striatal neurotoxicity induced by repeated treatment of 3-NP in rats. Here, we report that systemic administration of GTS produced significant protections against systemic 3-NP- and intrastriatal malonate-induced lesions in rat striatum with dose-dependent manner. GTS also improved significantly 3-NP-caused behavioral impairment and extended survival. However, GTS itself had no effect on 3-NP-induced inhibition of succinate dehydrogenase activity. To explain the mechanisms underlying in vivo protective effects of GTS against 3-NP-induced striatal degeneration, we examined in vitro effect of GTS against 3-NP-caused cytotoxicity using cultured rat striatal neurons. We found that GTS inhibited 3-NP-induced intracellular Ca(2+) elevations. GTS restored 3-NP-caused mitochondrial transmembrane potential reduction in cultured rat striatal neurons. GTS also prevented 3-NP-induced striatal neuronal cell deaths with dose-dependent manner. The EC(50) was 12.6 +/- 0. 7microg/ml. These results suggest that in vivo protective effects of GTS against 3-NP-induced rat striatal degeneration might be achieved via in vitro inhibition of 3-NP-induced intracellular Ca(2+) elevations and cytotoxicity of striatal neurons.

  11. Dopaminergic toxicity of the herbicide atrazine in rat striatal slices

    PubMed Central

    Filipov, Nikolay M.; Stewart, Molly A.; Carr, Russell L.; Sistrunk, Shannon C.

    2007-01-01

    A possible link between Parkinson’s disease and pesticide exposure has been suggested, and recently it was shown that the herbicide atrazine (ATR) modulates catecholamine metabolism in PC12 cells and affects basal ganglia function in vivo. Hence, the objectives of this study were to: (i) determine if ATR is capable of modulating dopamine (DA) metabolism in striatal tissue slices in vitro and (ii) to explore possible mechanisms of its effects. Striatal tissues from adult male Sprague Dawley rats were incubated with up to 500 μM ATR in a metabolic shaker bath at 37 °C and an atmosphere of 95% O2 and 5% CO2 for 4 h. At the end of incubation, samples were collected for both tissue and media levels of DA and its metabolites (3,4-dihydroxyphenylacetic acid, DOPAC and homovanillic acid, HVA), which were determined by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). To gain some mechanistic insight in to the way ATR affects DA metabolism, several pharmacological manipulations were performed. Striata exposed to ATR at concentrations of 100 μM and greater had a dose-dependent decrease of tissue levels of DA. At doses of ATR 50 μM and greater, the DOPAC+HVA/DA ratio was dose-dependently increased. Tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) protein levels and activity were not affected by ATR treatment. However, high potassium induced DA release into the medium was decreased, whereas the increase in media DA observed in the presence of the DA uptake inhibitor nomifensine was increased even further by ATR in a dose-dependent manner. All of these effects of ATR were observed at levels that were not toxic to the tissue, as LDH release into the medium (lactate dehydrogenase, an index of non-specific cytotoxicity) was not affected by ATR. Taken together, results from this study suggest that ATR decreases tissue DA levels not by affecting TH activity, but possibly by interfering with the vesicular storage and

  12. Regulation of dopamine synthesis and release in striatal and prefrontal cortical brain slices

    SciTech Connect

    Wolf, M.E.

    1986-01-01

    Brain slices were used to investigate the role of nerve terminal autoreceptors in modulating dopamine (DA) synthesis and release in striatum and prefrontal cortex. Accumulation of dihydroxyphenylalanine (DOPA) was used as an index of tyrosine hydroxylation in vitro. Nomifensine, a DA uptake blocker, inhibited DOPA synthesis in striatal but not prefrontal slices. This effect was reversed by the DA antagonist sulpiride, suggesting it involved activation of DA receptors by elevated synaptic levels of DA. The autoreceptor-selective agonist EMD-23-448 also inhibited striatal but not prefrontal DOPA synthesis. DOPA synthesis was stimulated in both brain regions by elevated K/sup +/, however only striatal synthesis could be further enhanced by sulpiride. DA release was measured by following the efflux of radioactivity from brain slices prelabeled with (/sup 3/H)-DA. EMD-23-448 and apomorphine inhibited, while sulpiride enhanced, the K/sup +/-evoked overflow of radioactivity from both striatal and prefrontal cortical slices. These findings suggest that striatal DA nerve terminals possess autoreceptors which modulate tyrosine hydroxylation as well as autoreceptors which modulate release. Alternatively, one site may be coupled to both functions through distinct transduction mechanisms. In contrast, autoreceptors on prefrontal cortical terminals appear to regulate DA release but not DA synthesis.

  13. Effects of striatal nitric oxide production on regional cerebral blood flow and seizure development in rats exposed to extreme hyperoxia.

    PubMed

    Gasier, Heath G; Demchenko, Ivan T; Allen, Barry W; Piantadosi, Claude A

    2015-12-01

    The endogenous vasodilator and signaling molecule nitric oxide has been implicated in cerebral hyperemia, sympathoexcitation, and seizures induced by hyperbaric oxygen (HBO2) at or above 3 atmospheres absolute (ATA). It is unknown whether these events in the onset of central nervous system oxygen toxicity originate within specific brain structures and whether blood flow is diverted to the brain from peripheral organs with high basal flow, such as the kidney. To explore these questions, total and regional cerebral blood flow (CBF) were measured in brain structures of the central autonomic network in anesthetized rats in HBO2 at 6 ATA. Electroencephalogram (EEG) recordings, cardiovascular hemodynamics, and renal blood flow (RBF) were also monitored. As expected, mean arterial blood pressure and total and regional CBF increased preceding EEG spikes while RBF was unaltered. Of the brain structures examined, the earliest rise in CBF occurred in the striatum, suggesting increased neuronal activation. Continuous unilateral or bilateral striatal infusion of the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester attenuated CBF responses in that structure, but global EEG discharges persisted and did not differ from controls. Our novel findings indicate that: 1) cerebral hyperemia in extreme HBO2 in rats does not occur at the expense of renal perfusion, highlighting the remarkable autoregulatory capability of the kidney, and 2) in spite of a sentinel increase in striatal blood flow, additional brain structure(s) likely govern the pathogenesis of HBO2-induced seizures because EEG discharge latency was unchanged by local blockade of striatal nitric oxide production and concomitant hyperemia.

  14. Prepuberal Stimulation of 5-HT7-R by LP-211 in a Rat Model of Hyper-Activity and Attention-Deficit: Permanent Effects on Attention, Brain Amino Acids and Synaptic Markers in the Fronto-Striatal Interface

    PubMed Central

    Treno, Concetta; Gironi Carnevale, Ugo A.; Arra, Claudio; Nieddu, Maria; Pagano, Cristina; Illiano, Placido; Barbato, Fabiana; Carboni, Ezio; Laviola, Giovanni; Lacivita, Enza; Leopoldo, Marcello; Adriani, Walter; Sadile, Adolfo G.

    2014-01-01

    The cross-talk at the prefronto-striatal interface involves excitatory amino acids, different receptors, transducers and modulators. We investigated long-term effects of a prepuberal, subchronic 5-HT7-R agonist (LP-211) on adult behaviour, amino acids and synaptic markers in a model for Attention-Deficit/Hyperactivity Disorder (ADHD). Naples High Excitability rats (NHE) and their Random Bred controls (NRB) were daily treated with LP-211 in the 5th and 6th postnatal week. One month after treatment, these rats were tested for indices of activity, non selective (NSA), selective spatial attention (SSA) and emotionality. The quantity of L-Glutamate (L-Glu), L-Aspartate (L-Asp) and L-Leucine (L-Leu), dopamine transporter (DAT), NMDAR1 subunit and CAMKIIα, were assessed in prefrontal cortex (PFC), dorsal (DS) and ventral striatum (VS), for their role in synaptic transmission, neural plasticity and information processing. Prepuberal LP-211 (at lower dose) reduced horizontal activity and (at higher dose) increased SSA, only for NHE but not in NRB rats. Prepuberal LP-211 increased, in NHE rats, L-Glu in the PFC and L-Asp in the VS (at 0.250 mg/kg dose), whereas (at 0.125 mg/kg dose) it decreased L-Glu and L-Asp in the DS. The L-Glu was decreased, at 0.125 mg/kg, only in the VS of NRB rats. The DAT levels were decreased with the 0.125 mg/kg dose (in the PFC), and increased with the 0.250 mg/kg dose (in the VS), significantly for NHE rats. The basal NMDAR1 level was higher in the PFC of NHE than NRB rats; LP-211 treatment (at 0.125 mg/kg dose) decreased NMDAR1 in the VS of NRB rats. This study represents a starting point about the impact of developmental 5-HT7-R activation on neuro-physiology of attentive processes, executive functions and their neural substrates. PMID:24709857

  15. Prepuberal stimulation of 5-HT7-R by LP-211 in a rat model of hyper-activity and attention-deficit: permanent effects on attention, brain amino acids and synaptic markers in the fronto-striatal interface.

    PubMed

    Ruocco, Lucia A; Treno, Concetta; Gironi Carnevale, Ugo A; Arra, Claudio; Boatto, Gianpiero; Nieddu, Maria; Pagano, Cristina; Illiano, Placido; Barbato, Fabiana; Tino, Angela; Carboni, Ezio; Laviola, Giovanni; Lacivita, Enza; Leopoldo, Marcello; Adriani, Walter; Sadile, Adolfo G

    2014-01-01

    The cross-talk at the prefronto-striatal interface involves excitatory amino acids, different receptors, transducers and modulators. We investigated long-term effects of a prepuberal, subchronic 5-HT7-R agonist (LP-211) on adult behaviour, amino acids and synaptic markers in a model for Attention-Deficit/Hyperactivity Disorder (ADHD). Naples High Excitability rats (NHE) and their Random Bred controls (NRB) were daily treated with LP-211 in the 5th and 6th postnatal week. One month after treatment, these rats were tested for indices of activity, non selective (NSA), selective spatial attention (SSA) and emotionality. The quantity of L-Glutamate (L-Glu), L-Aspartate (L-Asp) and L-Leucine (L-Leu), dopamine transporter (DAT), NMDAR1 subunit and CAMKIIα, were assessed in prefrontal cortex (PFC), dorsal (DS) and ventral striatum (VS), for their role in synaptic transmission, neural plasticity and information processing. Prepuberal LP-211 (at lower dose) reduced horizontal activity and (at higher dose) increased SSA, only for NHE but not in NRB rats. Prepuberal LP-211 increased, in NHE rats, L-Glu in the PFC and L-Asp in the VS (at 0.250 mg/kg dose), whereas (at 0.125 mg/kg dose) it decreased L-Glu and L-Asp in the DS. The L-Glu was decreased, at 0.125 mg/kg, only in the VS of NRB rats. The DAT levels were decreased with the 0.125 mg/kg dose (in the PFC), and increased with the 0.250 mg/kg dose (in the VS), significantly for NHE rats. The basal NMDAR1 level was higher in the PFC of NHE than NRB rats; LP-211 treatment (at 0.125 mg/kg dose) decreased NMDAR1 in the VS of NRB rats. This study represents a starting point about the impact of developmental 5-HT7-R activation on neuro-physiology of attentive processes, executive functions and their neural substrates.

  16. Conditional ablation of brain-derived neurotrophic factor-TrkB signaling impairs striatal neuron development.

    PubMed

    Li, Yun; Yui, Daishi; Luikart, Bryan W; McKay, Renée M; Li, Yanjiao; Rubenstein, John L; Parada, Luis F

    2012-09-18

    Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), are associated with the physiology of the striatum and the loss of its normal functioning under pathological conditions. The role of BDNF and its downstream signaling in regulating the development of the striatum has not been fully investigated, however. Here we report that ablation of Bdnf in both the cortex and substantia nigra depletes BDNF in the striatum, and leads to impaired striatal development, severe motor deficits, and postnatal lethality. Furthermore, striatal-specific ablation of TrkB, the gene encoding the high-affinity receptor for BDNF, is sufficient to elicit an array of striatal developmental abnormalities, including decreased anatomical volume, smaller neuronal nucleus size, loss of dendritic spines, reduced enkephalin expression, diminished nigral dopaminergic projections, and severe deficits in striatal dopamine signaling through DARPP32. In addition, TrkB ablation in striatal neurons elicits a non-cell-autonomous reduction of tyrosine hydroxylase protein level in the axonal projections of substantia nigral dopaminergic neurons. Thus, our results establish an essential function for TrkB in regulating the development of striatal neurons.

  17. Opiate agonist-induced re-distribution of Wntless, a mu-opioid receptor interacting protein, in rat striatal neurons.

    PubMed

    Reyes, B A S; Vakharia, K; Ferraro, T N; Levenson, R; Berrettini, W H; Van Bockstaele, E J

    2012-01-01

    Wntless (WLS), a mu-opioid receptor (MOR) interacting protein, mediates Wnt protein secretion that is critical for neuronal development. We investigated whether MOR agonists induce re-distribution of WLS within rat striatal neurons. Adult male rats received either saline, morphine or [d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) directly into the lateral ventricles. Following thirty minutes, brains were extracted and tissue sections were processed for immunogold silver detection of WLS. In saline-treated rats, WLS was distributed along the plasma membrane and within the cytoplasmic compartment of striatal dendrites as previously described. The ratio of cytoplasmic to total dendritic WLS labeling was 0.70±0.03 in saline-treated striatal tissue. Morphine treatment decreased this ratio to 0.48±0.03 indicating a shift of WLS from the intracellular compartment to the plasma membrane. However, following DAMGO treatment, the ratio was 0.85±0.05 indicating a greater distribution of WLS intracellularly. The difference in the re-distribution of the WLS following different agonist exposure may be related to DAMGO's well known ability to induce internalization of MOR in contrast to morphine, which is less effective in producing receptor internalization. Furthermore, these data are consistent with our hypothesis that MOR agonists promote dimerization of WLS and MOR, thereby preventing WLS from mediating Wnt secretion. In summary, our findings indicate differential agonist-induced trafficking of WLS in striatal neurons following distinct agonist exposure. Adaptations in WLS trafficking may represent a novel pharmacological target in the treatment of opiate addiction and/or pain.

  18. Estradiol and striatal dopamine receptor antagonism influence memory system bias in the female rat.

    PubMed

    Quinlan, Matthew G; Almey, Anne; Caissie, Meghen; LaChappelle, Ivonne; Radiotis, George; Brake, Wayne G

    2013-11-01

    Estradiol (E2) has been shown to influence learning and memory systems used by female rats to find a reward. Rats with high levels of E2 tend to use allocentric, or place, memory while rats with low levels of E2 use egocentric, or response, memory. It has been shown that systemic dopamine receptor antagonism interacts with E2 to affect which memory system is used. Here, dopamine antagonists were administered directly into either the dorsal striatum or nucleus accumbens to determine where in the brain this interaction takes place. Seventy-four young adult, female, Sprague-Dawley rats were trained and tested in a modified plus-maze. All rats were ovariectomized, received a subcutaneous low E2 implant, and were implanted with bilateral cannulae into either the dorsal striatum or the nucleus accumbens. Additionally, high E2 rats received daily injections of E2 in a sesame oil solution while low E2 rats received daily injections of vehicle. After reaching criterion levels of performance in a plus-maze task, rats were administered microinjections of either a dopamine D1 receptor (SCH 23390; 0.1 μg/ml and 0.01 μg/ml) or D2 receptor (raclopride; 2 μg/ml and 0.5 μg/ml) antagonist or a vehicle control (saline) in a counterbalanced manner. High E2 rats exhibited a trend towards a place memory bias while low E2 rats showed a response memory bias. Dorsal striatal administration of a D1, but not D2, dopamine receptor antagonist caused a switch in the memory system used by both high and low E rats. There was no significant effect of dopamine receptor antagonism in the nucleus accumbens group. Thus, E2 determined which memory system controlled behavior in a plus-maze task. Moreover, this effect was modulated by dopamine D1R antagonism in the dorsal but not ventral striatum suggesting that memory systems are, in part, mediated by E2 and dopamine in this region. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Methamphetamine Self-Administration Is Associated with Persistent Biochemical Alterations in Striatal and Cortical Dopaminergic Terminals in the Rat

    PubMed Central

    Ladenheim, Bruce; Jayanthi, Subramaniam; McCoy, Michael T.; Barnes, Chanel; Warner, John E.; Goldberg, Steven R.; Cadet, Jean Lud

    2010-01-01

    Methamphetamine (meth) is an illicit psychostimulant that is abused throughout the world. Repeated passive injections of the drug given in a single day or over a few days cause significant and long-term depletion of dopamine and serotonin in the mammalian brain. Because meth self-administration may better mimic some aspects of human drug-taking behaviors, we examined to what extent this pattern of drug treatment might also result in damage to monoaminergic systems in the brain. Rats were allowed to intravenously self-administer meth (yoked control rats received vehicle) 15 hours per day for 8 days before being euthanized at either 24 hours or at 7 and 14 days after cessation of drug taking. Meth self-administration by the rats was associated with a progressive escalation of daily drug intake to 14 mg/kg per day. Animals that self-administered meth exhibited dose-dependent decreases in striatal dopamine levels during the period of observation. In addition, there were significant reductions in the levels of striatal dopamine transporter and tyrosine hydroxylase proteins. There were also significant decreases in the levels of dopamine, dopamine transporter, and tyrosine hydroxylase in the cortex. In contrast, meth self-administration caused only transient decreases in norepinephrine and serotonin levels in the two brain regions, with these values returning to normal at seven days after cessation of drug taking. Importantly, meth self-administration was associated with significant dose-dependent increases in glial fibrillary acidic protein in both striatum and cortex, with these changes being of greater magnitude in the striatum. These results suggest that meth self-administration by rats is associated with long-term biochemical changes that are reminiscent of those observed in post-mortem brain tissues of chronic meth abusers. PMID:20098750

  20. Gastric Bypass Surgery Recruits a Gut PPAR-α-Striatal D1R Pathway to Reduce Fat Appetite in Obese Rats.

    PubMed

    Hankir, Mohammed K; Seyfried, Florian; Hintschich, Constantin A; Diep, Thi-Ai; Kleberg, Karen; Kranz, Mathias; Deuther-Conrad, Winnie; Tellez, Luis A; Rullmann, Michael; Patt, Marianne; Teichert, Jens; Hesse, Swen; Sabri, Osama; Brust, Peter; Hansen, Harald S; de Araujo, Ivan E; Krügel, Ute; Fenske, Wiebke K

    2017-02-07

    Bariatric surgery remains the single most effective long-term treatment modality for morbid obesity, achieved mainly by lowering caloric intake through as yet ill-defined mechanisms. Here we show in rats that Roux-en-Y gastric bypass (RYGB)-like rerouting of ingested fat mobilizes lower small intestine production of the fat-satiety molecule oleoylethanolamide (OEA). This was associated with vagus nerve-driven increases in dorsal striatal dopamine release. We also demonstrate that RYGB upregulates striatal dopamine 1 receptor (D1R) expression specifically under high-fat diet feeding conditions. Mechanistically, interfering with local OEA, vagal, and dorsal striatal D1R signaling negated the beneficial effects of RYGB on fat intake and preferences. These findings delineate a molecular/systems pathway through which bariatric surgery improves feeding behavior and may aid in the development of novel weight loss strategies that similarly modify brain reward circuits compromised in obesity.

  1. Sex-Dependent Changes in Striatal Dopamine Transport in Preadolescent Rats Exposed Prenatally and/or Postnatally to Methamphetamine.

    PubMed

    Sirova, Jana; Kristofikova, Zdenka; Vrajova, Monika; Fujakova-Lipski, Michaela; Ripova, Daniela; Klaschka, Jan; Slamberova, Romana

    2016-08-01

    Methamphetamine (MA) is the most commonly used psychostimulant drug, the chronic abuse of which leads to neurodegenerative changes in the brain. The global use of MA is increasing, including in pregnant women. Since MA can cross both placental and haematoencephalic barriers and is also present in maternal milk, children of chronically abused mothers are exposed prenatally as well as postnatally. Women seem to be more vulnerable to some aspects of MA abuse than men. MA is thought to exert its effects among others via direct interactions with dopamine transporters (DATs) in the brain tissue. Sexual dimorphism of the DAT system could be a base of sex-dependent actions of MA observed in behavioural and neurochemical studies. Possible sex differences in the DATs of preadolescent offspring exposed to MA prenatally and/or postnatally have not yet been evaluated. We examined the striatal synaptosomal DATs (the activity and density of surface expressed DATs and total DAT expression) in preadolescent male and female Wistar rats (31-35-day old animals) exposed prenatally and/or postnatally to MA (daily 5 mg/kg, s.c. to mothers during pregnancy and lactation). To distinguish between specific and nonspecific effects of MA on DATs, we also evaluated the in vitro effects of lipophilic MA on the fluidity of striatal membranes isolated from preadolescent and young adult rats of both sexes. We observed similar changes in the DATs of preadolescent rats exposed prenatally or postnatally (MA-mediated drop in the reserve pool but no alterations in surface-expressed DATs). However, prenatal exposure evoked significant changes in males and postnatal exposure in females. A significant decrease in the activity of surface-expressed DATs was found only in postnatally exposed females sensitized to MA via prenatal exposure. MA applied in vitro increased the fluidity of striatal membranes of preadolescent female but not male rats. In summary, DATs of preadolescent males are more sensitive to

  2. BDNF over-expression induces striatal serotonin fiber sprouting and increases the susceptibility to l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats.

    PubMed

    Tronci, Elisabetta; Napolitano, Francesco; Muñoz, Ana; Fidalgo, Camino; Rossi, Francesca; Björklund, Anders; Usiello, Alessandro; Carta, Manolo

    2017-11-01

    In addition to its role in neuronal survival, the brain neurotrophic factor (BDNF) has been shown to influence serotonin transmission and synaptic plasticity, events strongly implicated in the appearance of l-DOPA-induced dyskinesia (LID), a motor complication occurring in parkinsonian patients after long-term treatment with the dopamine precursor. In order to evaluate a possible influence of BDNF in the appearance of LID, 6-OHDA-lesioned rats received a striatal injection of different concentrations of an adeno-associated viral (AAV) vector over-expressing either BDNF or GFP, as control vector. Eight weeks later, animals started to receive a daily treatment with l-DOPA (4-6mg/kg plus benserazide 4-6mg/kg, s.c.) or saline, and dyskinesias, as well as l-DOPA-induced rotations, were evaluated at several time-points. Moreover, molecular changes in striatal D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, as well as, sprouting of striatal serotonin axons, were measured. Results showed that the AAV-BDNF vector injection induced striatal over-expression of BDNF, as well as striatal and pallidal serotonin axon hyperinnervation. Moreover, rats that over-expressed BDNF were more prone to develop LID and l-DOPA-induced rotations, compared to the GFP-treated control group. Finally, rats that over-expressed BDNF showed increased levels of striatal D1R-dependent signaling phospho-proteins in response to l-DOPA administration. This study suggests that BDNF over-expression, by inducing changes in pre-synaptic serotonin axonal trophism, is able to exacerbate maladaptive responses to l-DOPA administration. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Role of 5-HT3 receptors in basal and K(+)-evoked dopamine release from rat olfactory tubercle and striatal slices.

    PubMed Central

    Zazpe, A; Artaiz, I; Del Río, J

    1994-01-01

    1. The present study was aimed at examining the role of 5-HT3 receptors in basal and depolarization-evoked dopamine release from rat olfactory tubercle and striatal slices. [3H]-dopamine ([3H]-DA) release was measured in both brain regions and endogenous dopamine release from striatal slices was also studied. 2. The selective 5-HT3 receptor agonist 2-methyl-5-HT (0.5-10 microM) produced a concentration-dependent increase in [3H]-DA efflux evoked by K+ (20 mM) from slices of rat olfactory tubercle. 1-Phenylbiguanide (PBG) and 5-HT also increased K(+)-evoked [3H]-DA efflux. 3. 5-HT (1-100 microM) increased in a concentration-dependent manner basal [3H]-DA release from olfactory tubercle and striatal slices as well as endogenous DA release from striatal slices. The selective 5-HT3 receptor agonists 2-methyl-5-HT and 1-phenylbiguanide were weaker releasing agents. In all cases, the release was Ca2+ independent and tetrodotoxin insensitive. 4. 5-HT3 receptor antagonists such as ondansetron, granisetron and tropisetron (0.2 microM) significantly blocked the enhanced K(+)-evoked [3H]-DA efflux from rat olfactory tubercle slices induced by 2-methyl-5HT. A ten fold higher concentration of the 5-HT2 receptor antagonist ketanserin was ineffective. 5. Much higher concentrations, up to 50 microM, of the same 5-HT3 receptor antagonists did not block the increase in basal [3H]-DA release from striatal or olfactory tubercle slices induced by 5-HT or the release of endogenous DA induced by 5-HT from striatal slices.2+ off PMID:7858893

  4. Carbachol inhibits basal and forskolin-evoked adult rat striatal acetylcholine release.

    PubMed

    Login, I S

    1997-05-27

    Acutely dissociated adult rat striatal cholinergic neurons labeled with [3H]choline were used in a perifusion system to study muscarinic regulation of basal and forskolin-stimulated fractional [3H]acetylcholine ([3H]-ACh) efflux in the absence of synaptic modulation. Carbachol inhibited basal (40% maximal inhibition; IC50 approximately 0.7 microM) and forskolin-evoked release (75% inhibition; IC50 approximately 0.05 microM) in a concentration-dependent manner, and both carbachol actions were abolished with atropine. Thus, activation of striatal muscarinic cholinergic autoreceptors potently inhibits basal and adenylate cyclase-stimulated ACh release. Tonic inhibitory control of cholinergic activity by functional striatal circuitry apparently prevents detection of these important physiological interactions in slices or in situ.

  5. Maternal obesity caused by overnutrition exposure leads to reversal learning deficits and striatal disturbance in rats.

    PubMed

    Wu, Ting; Deng, Shining; Li, Wei-Guang; Yu, Yongguo; Li, Fei; Mao, Meng

    2013-01-01

    Maternal obesity caused by overnutrition during pregnancy increases susceptibility to metabolic risks in adulthood, such as obesity, insulin resistance, and type 2 diabetes; however, whether and how it affects the cognitive system associated with the brain remains elusive. Here, we report that pregnant obesity induced by exposure to excessive high fatty or highly palatable food specifically impaired reversal learning, a kind of adaptive behavior, while leaving serum metabolic metrics intact in the offspring of rats, suggesting a much earlier functional and structural defects possibly occurred in the central nervous system than in the metabolic system in the offspring born in unfavorable intrauterine nutritional environment. Mechanically, we found that above mentioned cognitive inflexibility might be associated with significant striatal disturbance including impaired dopamine homeostasis and disrupted leptin signaling in the adult offspring. These collective data add a novel perspective of understanding the adverse postnatal sequelae in central nervous system induced by developmental programming and the related molecular mechanism through which priming of risk for developmental disorders may occur during early life.

  6. Maternal Obesity Caused by Overnutrition Exposure Leads to Reversal Learning Deficits and Striatal Disturbance in Rats

    PubMed Central

    Wu, Ting; Deng, Shining; Li, Wei-Guang; Yu, Yongguo; Li, Fei; Mao, Meng

    2013-01-01

    Maternal obesity caused by overnutrition during pregnancy increases susceptibility to metabolic risks in adulthood, such as obesity, insulin resistance, and type 2 diabetes; however, whether and how it affects the cognitive system associated with the brain remains elusive. Here, we report that pregnant obesity induced by exposure to excessive high fatty or highly palatable food specifically impaired reversal learning, a kind of adaptive behavior, while leaving serum metabolic metrics intact in the offspring of rats, suggesting a much earlier functional and structural defects possibly occurred in the central nervous system than in the metabolic system in the offspring born in unfavorable intrauterine nutritional environment. Mechanically, we found that above mentioned cognitive inflexibility might be associated with significant striatal disturbance including impaired dopamine homeostasis and disrupted leptin signaling in the adult offspring. These collective data add a novel perspective of understanding the adverse postnatal sequelae in central nervous system induced by developmental programming and the related molecular mechanism through which priming of risk for developmental disorders may occur during early life. PMID:24223863

  7. Environmental enrichment brings a beneficial effect on beam walking and enhances the migration of doublecortin-positive cells following striatal lesions in rats.

    PubMed

    Urakawa, S; Hida, H; Masuda, T; Misumi, S; Kim, T-S; Nishino, H

    2007-02-09

    Rats raised in an enriched environment (enriched rats) have been reported to show less motor dysfunction following brain lesions, but the neuronal correlates of this improvement have not been well clarified. The present study aimed to elucidate the effect of chemical brain lesions and environmental enrichment on motor function and lesion-induced neurogenesis. Three week-old, recently weaned rats were divided into two groups: one group was raised in an enriched environment and the other group was raised in a standard cage for 5 weeks. Striatal damage was induced at an age of 8 weeks by injection of the neuro-toxins 6-hydroxydopamine (6-OHDA) or quinolinic acid (QA) into the striatum, or by injection of 6-OHDA into the substantia nigra (SN), which depleted nigrostriatal dopaminergic innervation. Enriched rats showed better performance on beam walking compared with those raised in standard conditions, but both groups showed similar forelimb use asymmetry in a cylinder test. The number of bromodeoxyuridine-labeled proliferating cells in the subventricular zone was increased by a severe striatal lesion induced by QA injection 1 week after the lesion, but decreased by injection of 6-OHDA into the SN. Following induction of lesions by striatal injection of 6-OHDA or QA, the number of cells positive for doublecortin (DCX) was strongly increased in the striatum; however, there was no change in the number of DCX-positive cells following 6-OHDA injection into the SN. Environmental enrichment enhanced the increase of DCX-positive cells with migrating morphology in the dorsal striatum. In enriched rats, DCX-positive cells traversed the striatal parenchyma far from the corpus callosum and lateral ventricle. DCX-positive cells co-expressed an immature neuronal marker, polysialylated neural cell adhesion molecule, but were negative for a glial marker. These data suggest that environmental enrichment improves motor performance on beam walking and enhances neuronal migration toward

  8. Sensitivity to theta-burst timing permits LTP in dorsal striatal adult brain slice

    PubMed Central

    Hawes, Sarah L.; Gillani, Fawad; Evans, Rebekah C.; Benkert, Elizabeth A.

    2013-01-01

    Long-term potentiation (LTP) of excitatory afferents to the dorsal striatum likely occurs with learning to encode new skills and habits, yet corticostriatal LTP is challenging to evoke reliably in brain slice under physiological conditions. Here we test the hypothesis that stimulating striatal afferents with theta-burst timing, similar to recently reported in vivo temporal patterns corresponding to learning, evokes LTP. Recording from adult mouse brain slice extracellularly in 1 mM Mg2+, we find LTP in dorsomedial and dorsolateral striatum is preferentially evoked by certain theta-burst patterns. In particular, we demonstrate that greater LTP is produced using moderate intraburst and high theta-range frequencies, and that pauses separating bursts of stimuli are critical for LTP induction. By altering temporal pattern alone, we illustrate the importance of burst-patterning for LTP induction and demonstrate that corticostriatal long-term depression is evoked in the same preparation. In accord with prior studies, LTP is greatest in dorsomedial striatum and relies on N-methyl-d-aspartate receptors. We also demonstrate a requirement for both Gq- and Gs/olf-coupled pathways, as well as several kinases associated with memory storage: PKC, PKA, and ERK. Our data build on previous reports of activity-directed plasticity by identifying effective values for distinct temporal parameters in variants of theta-burst LTP induction paradigms. We conclude that those variants which best match reports of striatal activity during learning behavior are most successful in evoking dorsal striatal LTP in adult brain slice without altering artificial cerebrospinal fluid. Future application of this approach will enable diverse investigations of plasticity serving striatal-based learning. PMID:23926032

  9. Extrasynaptic Neurotransmission in the Modulation of Brain Function. Focus on the Striatal Neuronal–Glial Networks

    PubMed Central

    Fuxe, Kjell; Borroto-Escuela, Dasiel O.; Romero-Fernandez, Wilber; Diaz-Cabiale, Zaida; Rivera, Alicia; Ferraro, Luca; Tanganelli, Sergio; Tarakanov, Alexander O.; Garriga, Pere; Narváez, José Angel; Ciruela, Francisco; Guescini, Michele; Agnati, Luigi F.

    2012-01-01

    Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT) and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR) heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT) and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT) and histamine striatal afferents, the cholinergic interneurons, and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal cellular networks

  10. Long-term changes in striatal opioid systems after 6-hydroxydopamine lesion of rat substantia nigra.

    PubMed

    Smith, J A; Leslie, F M; Broide, R S; Loughlin, S E

    1993-08-01

    The effects of unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway on striatal opioid peptides and receptors were determined at different time-intervals, from three days up to 24 weeks, post-lesion. Mu, delta and kappa opioid binding site densities in the ipsilateral caudate-putamen were decreased by 25-50% in rats which exhibited a greater than 90% loss of dopamine uptake sites. Differentiation of radioligand binding to kappa1 and kappa2 subtypes demonstrated a selective loss of kappa2 sites post-lesion. The onset of significant 6-hydroxydopamine lesion-induced changes in striatal opioid binding sites was delayed with respect to the loss of dopamine uptake sites. Furthermore, maximal loss of dopamine uptake sites was apparent within seven days post-lesion, but not until two to four weeks for mu, delta and kappa sites. In animals which exhibited an incomplete loss of dopamine uptake sites (less than 80%) there was no significant change in opioid binding site density. Striatal proenkephalin and prodynorphin messenger RNA levels were increased and decreased, respectively, after complete 6-hydroxydopamine lesion. Modulation of peptide messenger RNA levels was apparent within seven days and was maintained up to 24 weeks post-lesion. In contrast, proenkephalin and prodynorphin messenger RNA levels were unchanged in animals which exhibited an incomplete loss of striatal dopamine uptake sites. Taken together, these observations suggest that the majority of mu, delta and kappa2 opioid binding sites are localized on non-dopaminergic elements in the caudate-putamen, but that substantia nigra innervation plays a role in the control of striatal opioid receptor expression. The 6-hydroxydopamine lesion-induced decreases in striatal opioid binding site density may, in part, be a function of agonist-induced receptor downregulation. Alternatively, both opioid receptor and peptide expression in the caudate-putamen may be directly, but independently, regulated by ventral

  11. Striatal blood-brain barrier permeability in Parkinson's disease.

    PubMed

    Gray, Madison T; Woulfe, John M

    2015-05-01

    In vivo studies have shown that blood-brain barrier (BBB) dysfunction is involved in the course of Parkinson's disease (PD). However, these have lacked either anatomic definition or the ability to recognize minute changes in BBB integrity. Here, using histologic markers of serum protein, iron, and erythrocyte extravasation, we have shown significantly increased permeability of the BBB in the postcommissural putamen of PD patients. The dense innervation of the striatum by PD-affected regions allows for exploitation of this permeability for therapeutic goals. These results are also discussed in the context of the retrograde trans-synaptic hypothesis of PD spread.

  12. Effects of recovery from immobilization stress on striatal preprodynorphin- and kappa opioid receptor-mRNA levels of the male rat.

    PubMed

    Lucas, Louis R; Dragisic, Tina; Duwaerts, Caroline C; Swiatkowski, Michael; Suzuki, Hideo

    2011-10-24

    Previously, we have reported that brain regions that are thought to be involved in motivated behavior are altered in animals undergoing repeated exposures to immobilization stress. The goal of the present study was to determine the effects of recovery from this type of stress on these same mesolimbic brain regions. For this purpose, adult male Sprague-Dawley rats were initially exposed to immobilization stress either once (2 h) or repeatedly (2 h×10 days). Rats were then either allowed to recover from the stressor for a shorter (2 days) or longer period of time (9 days) in their home cages. At the end of this recovery period, rats were euthanized and trunk blood and brains were processed for serum corticosterone (CORT) and neurochemistry, respectively. Brain mRNA levels were determined via in situ hybridization for the opioid preprodynorphin (DYN) and its cognate receptor (kappa, KOR), in striatal and accumbal subregions. A pattern of selective transcriptional activation emerged in the four resultant treatment conditions where a short recovery from either a single or repeated exposure to immobilization produced increases in KOR-mRNA levels in striatal and nucleus accumbens (Acb) subregions. Relative to controls, these differences were diminished after a longer recovery period. Interestingly, DYN-mRNA levels were unchanged after the shorter recovery period and after single or repeated immobilizations but appeared to be induced after a longer recovery period after repeated immobilizations. A relative amount of weight loss occurred after immobilization following repeated but not single exposure to stress. In addition, only those rats recovering from repeated stress exposures had higher CORT levels compared with non-immobilized controls. These results suggest that recovery from immobilization stress may alter the motivational system after as little as a single immobilization and that a possible dysphoric effect on appetitive behavior may be reflected by an altered

  13. Striatal activation by optogenetics induces dyskinesias in the 6-hydroxydopamine rat model of Parkinson disease.

    PubMed

    F Hernández, Ledia; Castela, Ivan; Ruiz-DeDiego, Irene; Obeso, Jose A; Moratalla, Rosario

    2017-04-01

    Long-term levodopa (l-dopa) treatment is associated with the development of l-dopa-induced dyskinesias in the majority of patients with Parkinson disease (PD). The etiopathogonesis and mechanisms underlying l-dopa-induced dyskinesias are not well understood. We used striatal optogenetic stimulation to induce dyskinesias in a hemiparkinsonian model of PD in rats. Striatal dopamine depletion was induced unilaterally by 6-hydroxydopamine injection into the medial forebrain bundle. For the optogenetic manipulation, we injected adeno-associated virus particles expressing channelrhodopsin to stimulate striatal medium spiny neurons with a laser source. Simultaneous optical activation of medium spiny neurons of the direct and indirect striatal pathways in the 6-hydroxydopamine lesion but l-dopa naïve rats induced involuntary movements similar to l-dopa-induced dyskinesias, labeled here as optodyskinesias. Noticeably, optodyskinesias were facilitated by l-dopa in animals that did not respond initially to the laser stimulation. In general, optodyskinesias lasted while the laser stimulus was applied, but in some instances remained ongoing for a few seconds after the laser was off. Postmortem tissue analysis revealed increased FosB expression, a molecular marker of l-dopa-induced dyskinesias, primarily in medium spiny neurons of the direct pathway in the dopamine-depleted hemisphere. Selective optogenetic activation of the dorsolateral striatum elicits dyskinesias in the 6-hydroxydopamine rat model of PD. This effect was associated with a preferential activation of the direct striato-nigral pathway. These results potentially open new avenues in the understanding of mechanisms involved in l-dopa-induced dyskinesias. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  14. Specific reactions of different striatal neuron types in morphology induced by quinolinic acid in rats.

    PubMed

    Feng, Qiqi; Ma, Yuxin; Mu, Shuhua; Wu, Jiajia; Chen, Si; Ouyang, Lisi; Lei, Wanlong

    2014-01-01

    Huntington's disease (HD) is a neurological degenerative disease and quinolinic acid (QA) has been used to establish HD model in animals through the mechanism of excitotoxicity. Yet the specific pathological changes and the underlying mechanisms are not fully elucidated. We aimed to reveal the specific morphological changes of different striatal neurons in the HD model. Sprague-Dawley (SD) rats were subjected to unilaterally intrastriatal injections of QA to mimic the HD model. Behavioral tests, histochemical and immunhistochemical stainings as well as Western blots were applied in the present study. The results showed that QA-treated rats had obvious motor and cognitive impairments when compared with the control group. Immunohistochemical detection showed a great loss of NeuN+ neurons and Darpp32+ projection neurons in the transition zone in the QA group when compared with the control group. The numbers of parvalbumin (Parv)+ and neuropeptide Y (NPY)+ interneurons were both significantly reduced while those of calretinin (Cr)+ and choline acetyltransferase (ChAT)+ were not changed notably in the transition zone in the QA group when compared to the controls. Parv+, NPY+ and ChAT+ interneurons were not significantly increased in fiber density while Cr+ neurons displayed an obvious increase in fiber density in the transition zone in QA-treated rats. The varicosity densities of Parv+, Cr+ and NPY+ interneurons were all raised in the transition zone after QA treatment. In conclusion, the present study revealed that QA induced obvious behavioral changes as well as a general loss of striatal projection neurons and specific morphological changes in different striatal interneurons, which may help further explain the underlying mechanisms and the specific functions of various striatal neurons in the pathological process of HD.

  15. Reduction in Subventricular Zone-Derived Olfactory Bulb Neurogenesis in a Rat Model of Huntington’s Disease Is Accompanied by Striatal Invasion of Neuroblasts

    PubMed Central

    Kandasamy, Mahesh; Rosskopf, Michael; Wagner, Katrin; Klein, Barbara; Couillard-Despres, Sebastien; Reitsamer, Herbert A.; Stephan, Michael; Nguyen, Huu Phuc; Riess, Olaf; Bogdahn, Ulrich; Winkler, Jürgen; von Hörsten, Stephan; Aigner, Ludwig

    2015-01-01

    Huntington’s disease (HD) is an inherited progressive neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the huntingtin gene (HTT). The primary neuropathology of HD has been attributed to the preferential degeneration of medium spiny neurons (MSN) in the striatum. Reports on striatal neurogenesis have been a subject of debate; nevertheless, it should be considered as an endogenous attempt to repair the brain. The subventricular zone (SVZ) might offer a close-by region to supply the degenerated striatum with new cells. Previously, we have demonstrated that R6/2 mice, a widely used preclinical model representing an early onset HD, showed reduced olfactory bulb (OB) neurogenesis but induced striatal migration of neuroblasts without affecting the proliferation of neural progenitor cell (NPCs) in the SVZ. The present study revisits these findings, using a clinically more relevant transgenic rat model of late onset HD (tgHD rats) carrying the human HTT gene with 51 CAG repeats and mimicking many of the neuropathological features of HD seen in patients. We demonstrate that cell proliferation is reduced in the SVZ and OB of tgHD rats compared to WT rats. In the OB of tgHD rats, although cell survival was reduced, the frequency of neuronal differentiation was not altered in the granule cell layer (GCL) compared to the WT rats. However, an increased frequency of dopamenergic neuronal differentiation was noticed in the glomerular layer (GLOM) of tgHD rats. Besides this, we observed a selective proliferation of neuroblasts in the adjacent striatum of tgHD rats. There was no evidence for neuronal maturation and survival of these striatal neuroblasts. Therefore, the functional role of these invading neuroblasts still needs to be determined, but they might offer an endogenous alternative for stem or neuronal cell transplantation strategies. PMID:25719447

  16. Striatal adenosine-cannabinoid receptor interactions in rats over-expressing adenosine A2A receptors.

    PubMed

    Chiodi, Valentina; Ferrante, Antonella; Ferraro, Luca; Potenza, Rosa Luisa; Armida, Monica; Beggiato, Sarah; Pèzzola, Antonella; Bader, Michael; Fuxe, Kjell; Popoli, Patrizia; Domenici, Maria Rosaria

    2016-03-01

    Adenosine A2A receptors (A2 A Rs) and cannabinoid CB1 receptors (CB1 Rs) are highly expressed in the striatum, where they functionally interact and form A2A /CB1 heteroreceptor complexes. We investigated the effects of CB1 R stimulation in a transgenic rat strain over-expressing A2 A Rs under the control of the neural-specific enolase promoter (NSEA2A rats) and in age-matched wild-type (WT) animals. The effects of the CB1 R agonist WIN 55,212-2 (WIN) were significantly lower in NSEA2A rats than in WT animals, as demonstrated by i) electrophysiological recordings of synaptic transmission in corticostriatal slices; ii) the measurement of glutamate outflow from striatal synaptosomes and iii) in vivo experiments on locomotor activity. Moreover, while the effects of WIN were modulated by both A2 A R agonist (CGS 21680) and antagonists (ZM 241385, KW-6002 and SCH-442416) in WT animals, the A2 A R antagonists failed to influence WIN-mediated effects in NSEA2A rats. The present results demonstrate that in rats with genetic neuronal over-expression of A2 A Rs, the effects mediated by CB1 R activation in the striatum are significantly reduced, suggesting a change in the stoichiometry of A2A and CB1 receptors and providing a strategy to dissect the involvement of A2 A R forming or not forming heteromers in the modulation of striatal functions. These findings add additional evidence for the existence of an interaction between striatal A2 A Rs and CB1 Rs, playing a fundamental role in the regulation of striatal functions. We studied A2A -CB1 receptor interaction in transgenic rats over-expressing adenosine A2A receptors under the control of the neuron-specific enolase promoter (NSEA2A ). In these rats, we demonstrated a reduced effect of the CB1 receptor agonist WIN 55,212-2 in the modulation of corticostriatal synaptic transmission and locomotor activity, while CB1 receptor expression level did not change with respect to WT rats. A reduction in the expression of A2A -CB1

  17. Spike-dependent intrinsic plasticity increases firing probability in rat striatal neurons in vivo.

    PubMed

    Mahon, Séverine; Casassus, Guillaume; Mulle, Christophe; Charpier, Stéphane

    2003-08-01

    The collision of pre- and postsynaptic activity is known to provide a trigger for controlling the gain of synaptic transmission between neurons. Here, using in vivo intracellular recordings of rat striatal output neurons, we analyse the effect of a single action potential, generated by ongoing synaptic activity, on subsequent excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of the cerebral cortex. This pairing induced a short-term increase in the probability that cortically evoked EPSPs caused striatal cells to fire. This enhanced EPSP-spike coupling was associated with a decrease in the voltage firing threshold with no apparent change in the synaptic strength itself. Antidromic action potentials in striatal cells were also able to induce the facilitation while subthreshold EPSPs were ineffective, indicating that the postsynaptic spike was necessary and sufficient for the induction of the plasticity. A prior spontaneous action potential also enhanced the probability with which directly applied current pulses elicited firing, suggesting that the facilitation originated from changes in the intrinsic electrical properties of the postsynaptic cell. Using whole-cell recordings in cortico-striatal slices, we found that the increase in membrane excitability as well as in EPSP-spike coupling was abolished by low concentration of 4-aminopyridine. This suggests that the intrinsic plasticity results from a time-dependent modulation of a striatal voltage-dependent potassium current available close to the firing threshold. Action potentials thus provide a postsynaptic signal, not only for associative synaptic plasticity but also for activity-dependent intrinsic plasticity, which directly controls the efficacy of coupling between pre- and postsynaptic neurons.

  18. Spike-Dependent Intrinsic Plasticity Increases Firing Probability in Rat Striatal Neurons In Vivo

    PubMed Central

    Mahon, Séverine; Casassus, Guillaume; Mulle, Christophe; Charpier, Stéphane

    2003-01-01

    The collision of pre- and postynaptic activity is known to provide a trigger for controlling the gain of synaptic transmission between neurons. Here, using in vivo intracellular recordings of rat striatal output neurons, we analyse the effect of a single action potential, generated by ongoing synaptic activity, on subsequent excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of the cerebral cortex. This pairing induced a short-term increase in the probability that cortically evoked EPSPs caused striatal cells to fire. This enhanced EPSP-spike coupling was associated with a decrease in the voltage firing threshold with no apparent change in the synaptic strength itself. Antidromic action potentials in striatal cells were also able to induce the facilitation while subthreshold EPSPs were ineffective, indicating that the postsynaptic spike was necessary and sufficient for the induction of the plasticity. A prior spontaneous action potential also enhanced the probability with which directly applied current pulses elicited firing, suggesting that the facilitation originated from changes in the intrinsic electrical properties of the postsynaptic cell. Using whole-cell recordings in cortico-striatal slices, we found that the increase in membrane excitability as well as in EPSP-spike coupling was abolished by low concentration of 4-aminopyridine. This suggests that the intrinsic plasticity results from a time-dependent modulation of a striatal voltage-dependent potassium current available close to the firing threshold. Action potentials thus provide a postsynaptic signal, not only for associative synaptic plasticity but also for activity-dependent intrinsic plasticity, which directly controls the efficacy of coupling between pre- and postsynaptic neurons. PMID:12844508

  19. Irrational choice under uncertainty correlates with lower striatal D(2/3) receptor binding in rats.

    PubMed

    Cocker, Paul J; Dinelle, Katherine; Kornelson, Rick; Sossi, Vesna; Winstanley, Catharine A

    2012-10-31

    Individual differences in dopamine (DA) signaling, including low striatal D(2/3) receptors, may increase vulnerability to substance abuse, although whether this phenotype confers susceptibility to nonchemical addictions is unclear. The degree to which people use "irrational" cognitive heuristics when choosing under uncertainty can determine whether they find gambling addictive. Given that dopaminergic projections to the striatum signal reward expectancy and modulate decision-making, individual differences in DA signaling could influence the extent of such biases. To test this hypothesis, we used a novel task to model biased, risk-averse decision-making in rats. Animals chose between a "safe" lever, which guaranteed delivery of the wager, or an "uncertain" lever, which delivered either double the wager or nothing with 50:50 odds. The bet size varied from one to three sugar pellets. Although the amount at stake did not alter the options' utility, a subgroup of "wager-sensitive" rats increased their preference for the safe lever as the bet size increased, akin to risk aversion. In contrast, wager-insensitive rats slightly preferred the uncertain option consistently. Amphetamine increased choice of the uncertain option in wager-sensitive, but not in wager-insensitive rats, whereas a D(2/3) receptor antagonist decreased uncertain lever choice in wager-insensitive rats alone. Micro-PET and autoradiography using [(11)C]raclopride confirmed a strong correlation between high wager sensitivity and low striatal D(2/3) receptor density. These data suggest that the propensity for biased decision-making under uncertainty is influenced by striatal D(2/3) receptor expression, and provide novel support for the hypothesis that susceptibility to chemical and behavioral addictions may share a common neurobiological basis.

  20. Region-specific depression of striatal activity in Wistar rat by modest ethanol consumption over a ten-month period.

    PubMed

    Adermark, L; Jonsson, S; Söderpalm, B; Ericson, M

    2013-06-01

    The nucleus accumbens (nAc) is the primary target for the mesolimbic dopamine system and a key brain region for the reinforcing effects displayed by drugs of abuse, including ethanol. During the transition from recreational to compulsive consumption of reinforcing drugs, however, the dorsal striatum seems to be recruited. Understanding how synaptic activity is altered in a sub-region specific manner in the striatum during the course of long-term drug consumption thus could be essential for understanding the long-lasting changes produced by addictive substances, including ethanol. Here we evaluated synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc) of single-housed Wistar rats consuming water, or water and ethanol, for up to 10 months. Even though ethanol intake was moderate, it was sufficient to decrease input/output function in response to stimulation intensity in the DLS, while recorded population spike (PS) amplitudes in the nAc were unaffected. Striatal disinhibition induced by the GABAA receptor antagonist bicuculline had a slower onset in rats that had consumed ethanol for 2 months, and was significantly depressed in slices from rats that had consumed ethanol for 4 months. Bicuculline-induced disinhibition in the nAc, on the other hand, was not significantly altered by long-term ethanol intake. Changes in PS amplitude induced by taurine or the glycine receptor antagonist strychnine were not significantly altered by ethanol in any brain region. Even though input/output function was not significantly affected by age, there was a significant decline in antagonist-induced disinhibition in brain slices from aged rats. The data presented here suggest that even modest consumption of ethanol is sufficient to alter neurotransmission in the striatum, while synaptic activity appears to be relatively well-preserved in the nAc during the course of long-term ethanol consumption. Copyright © 2013 Elsevier Inc. All rights

  1. Effects of perinatal asphyxia on rat striatal cytoskeleton.

    PubMed

    Saraceno, G E; Ayala, M V; Badorrey, M S; Holubiec, M; Romero, J I; Galeano, P; Barreto, G; Giraldez-Alvárez, L D; Kölliker-Fres, R; Coirini, H; Capani, F

    2012-01-01

    Perinatal asphyxia (PA) is a medical condition associated with a high short-term morbimortality and different long-term neurological diseases. In previous works, we have shown that neuronal and synaptic changes in rat striatum lead to ubi-protein accumulation in post-synaptic density (PSD) after six months of sub-severe PA. However, very little is known about the synaptic and related structural modifications induced by PA in young rats. In the present work, we studied neuronal cytoskeleton modifications in striatum induced by subsevere PA in 30-day-old rats. We observed a significant decrease in the number of neurons, in particular calbindin immunoreactive neurons after PA. In addition, it was also observed that actin cytoskeleton was highly modified in the PSD as well as an increment of F-actin staining by Phalloidin-alexa(488) in the striatum of PA rats. Using correlative fluorescence-electron microscopy photooxidation, we confirmed and extended confocal observations. F-actin staining augmentation was mostly related with an increment in the number of mushroom-shaped spines. Consistent with microscopic data, Western blot analysis revealed a β-actin increment in PSD in PA rats. On the other hand, MAP-2 immunostaining was decreased after PA, being NF-200 expression unmodified. Although neuronal death was observed, signs of generalized neurodegeneration were absent. Taken together these results showed early post-synaptic F-actin cytoskeleton changes induced by PA with slightly modifications in the other components of the neuronal cytoskeleton, suggesting that F-actin accumulation in the dendritic spines could be involved in the neuronal loss induced by PA. Copyright © 2011 Wiley Periodicals, Inc.

  2. Central Thalamic Deep-Brain Stimulation Alters Striatal-Thalamic Connectivity in Cognitive Neural Behavior.

    PubMed

    Lin, Hui-Ching; Pan, Han-Chi; Lin, Sheng-Huang; Lo, Yu-Chun; Shen, Elise Ting-Hsin; Liao, Lun-De; Liao, Pei-Han; Chien, Yi-Wei; Liao, Kuei-Da; Jaw, Fu-Shan; Chu, Kai-Wen; Lai, Hsin-Yi; Chen, You-Yin

    2015-01-01

    Central thalamic deep brain stimulation (CT-DBS) has been proposed as an experimental therapeutic approach to produce consistent sustained regulation of forebrain arousal for several neurological diseases. We investigated local field potentials (LFPs) induced by CT-DBS from the thalamic central lateral nuclei (CL) and the striatum as potential biomarkers for the enhancement of lever-pressing skill learning. LFPs were simultaneously recorded from multiple sites in the CL, ventral striatum (Vstr), and dorsal striatum (Dstr). LFP oscillation power and functional connectivity were assessed and compared between the CT-DBS and sham control groups. The theta and alpha LFP oscillations were significantly increased in the CL and striatum in the CT-DBS group. Furthermore, interhemispheric coherences between bilateral CL and striatum were increased in the theta band. Additionally, enhancement of c-Fos activity, dopamine D2 receptor (Drd2), and α4-nicotinic acetylcholine receptor (α4-nAChR) occurred after CT-DBS treatment in the striatum and hippocampus. CT-DBS strengthened thalamic-striatal functional connectivity, which demonstrates that the inter-regional connectivity enhancement might contribute to synaptic plasticity in the striatum. Altered dopaminergic and cholinergic receptors resulted in modulation of striatal synaptic plasticity's ability to regulate downstream signaling cascades for higher brain functions of lever-pressing skill learning.

  3. Central Thalamic Deep-Brain Stimulation Alters Striatal-Thalamic Connectivity in Cognitive Neural Behavior

    PubMed Central

    Lin, Hui-Ching; Pan, Han-Chi; Lin, Sheng-Huang; Lo, Yu-Chun; Shen, Elise Ting-Hsin; Liao, Lun-De; Liao, Pei-Han; Chien, Yi-Wei; Liao, Kuei-Da; Jaw, Fu-Shan; Chu, Kai-Wen; Lai, Hsin-Yi; Chen, You-Yin

    2016-01-01

    Central thalamic deep brain stimulation (CT-DBS) has been proposed as an experimental therapeutic approach to produce consistent sustained regulation of forebrain arousal for several neurological diseases. We investigated local field potentials (LFPs) induced by CT-DBS from the thalamic central lateral nuclei (CL) and the striatum as potential biomarkers for the enhancement of lever-pressing skill learning. LFPs were simultaneously recorded from multiple sites in the CL, ventral striatum (Vstr), and dorsal striatum (Dstr). LFP oscillation power and functional connectivity were assessed and compared between the CT-DBS and sham control groups. The theta and alpha LFP oscillations were significantly increased in the CL and striatum in the CT-DBS group. Furthermore, interhemispheric coherences between bilateral CL and striatum were increased in the theta band. Additionally, enhancement of c-Fos activity, dopamine D2 receptor (Drd2), and α4-nicotinic acetylcholine receptor (α4-nAChR) occurred after CT-DBS treatment in the striatum and hippocampus. CT-DBS strengthened thalamic-striatal functional connectivity, which demonstrates that the inter-regional connectivity enhancement might contribute to synaptic plasticity in the striatum. Altered dopaminergic and cholinergic receptors resulted in modulation of striatal synaptic plasticity's ability to regulate downstream signaling cascades for higher brain functions of lever-pressing skill learning. PMID:26793069

  4. Diminished hippocalcin expression in Huntington's disease brain does not account for increased striatal neuron vulnerability as assessed in primary neurons.

    PubMed

    Rudinskiy, Nikita; Kaneko, Yoshio A; Beesen, Ayshe Ana; Gokce, Ozgun; Régulier, Etienne; Déglon, Nicole; Luthi-Carter, Ruth

    2009-10-01

    Hippocalcin is a neuronal calcium sensor protein previously implicated in regulating neuronal viability and plasticity. Hippocalcin is the most highly expressed neuronal calcium sensor in the medium spiny striatal output neurons that degenerate selectively in Huntington's disease (HD). We have previously shown that decreased hippocalcin expression occurs in parallel with the onset of disease phenotype in mouse models of HD. Here we show by in situ hybridization histochemistry that hippocalcin RNA is also diminished by 63% in human HD brain. These findings lead us to hypothesize that diminished hippocalcin expression might contribute to striatal neurodegeneration in HD. We tested this hypothesis by assessing whether restoration of hippocalcin expression would decrease striatal neurodegeneration in cellular models of HD comprising primary striatal neurons exposed to mutant huntingtin, the mitochondrial toxin 3-nitropropionic acid or an excitotoxic concentration of glutamate. Counter to our hypothesis, hippocalcin expression did not improve the survival of striatal neurons under these conditions. Likewise, expression of hippocalcin together with interactor proteins including the neuronal apoptosis inhibitory protein did not increase the survival of striatal cells in cellular models of HD. These results indicate that diminished hippocalcin expression does not contribute to HD-related neurodegeneration.

  5. Release of taurine, GABA and dopamine from rat striatal slices: mutual interactions and developmental aspects.

    PubMed

    Kontro, P; Oja, S S

    1988-01-01

    The spontaneous and potassium-stimulated release of preloaded taurine and GABA from striatal slices of adult and 7-day-old rats were studied using a superfusion system. Particular attention was paid to mutual interactions of taurine and GABA with dopamine in the release processes. Potassium stimulation (50 mM) enhanced taurine release more in the immature than in the adult striatum, whereas the response was the opposite with GABA release. Spontaneous taurine efflux was increased by dopamine and apomorphine, whereas stimulated release was suppressed by these agents in both age groups. This dopamine effect was partially antagonized by haloperidol, suggesting that dopaminergic systems were able to modify taurine release, possibly via dopaminergic receptors. Dopamine and apomorphine had similar but more inconsistent effects on striatal GABA release, which were not, however, mediated through conventional dopamine receptors. Stimulation with 25 mM K+ caused an 11-fold increase in striatal dopamine release: this effect was potentiated by taurine, while the actions of GABA on dopamine release were variable.

  6. Prenatal neuroleptic exposure alters postnatal striatal cholinergic activity in the rat.

    PubMed

    Miller, J C; Friedhoff, A J

    1986-01-01

    Previous studies in our laboratory have shown that prenatal exposure to a neuroleptic during a critical period of gestation in the rat results in a marked deficit in the number of striatal dopamine-binding sites and in a diminution of dopamine agonist-induced stereotyped behavior. In the present studies, we examined the effect of prenatal neuroleptic exposure on biochemical parameters of cholinergic activity to determine whether the balance between striatal dopaminergic and cholinergic activity might be altered. The number of muscarinic cholinergic-binding sites and the specific activity of choline acetyltransferase were found to be significantly increased by prenatal treatment with the neuroleptics haloperidol or (+)-butaclamol. From the present studies and previous observations made in our laboratory, it is concluded that the ability of a neuroleptic to affect the number of muscarinic cholinergic receptors in postnatal life may be a result of the phenotypically undifferentiated state of the developing dopamine-binding site. Our findings of increased striatal cholinergic activity accompanied by a marked decrease in dopaminergic activity may have implications for an increased vulnerability to extrapyramidal motor disturbances during postnatal development.

  7. Diazepam blocks striatal lipid peroxidation and improves stereotyped activity in a rat model of acute stress.

    PubMed

    Méndez-Cuesta, Luis A; Márquez-Valadez, Berenice; Pérez-De La Cruz, Verónica; Escobar-Briones, Carolina; Galván-Arzate, Sonia; Alvarez-Ruiz, Yarummy; Maldonado, Perla D; Santana, Ricardo A; Santamaría, Abel; Carrillo-Mora, Paul

    2011-11-01

    In this work, the effect of a single dose of diazepam was tested on different markers of oxidative damage in the striatum of rats in an acute model of immobilization (restraint) stress. In addition, the locomotor activity was measured at the end of the restraint period. Immobilization was induced to animals for 24 hr, and then, lipid peroxidation, superoxide dismutase activity and content, and mitochondrial function were all estimated in striatal tissue samples. Corticosterone levels were measured in serum. Diazepam was given to rats as a pre-treatment (1 mg/kg, i.p.) 20 min. before the initiation of stress. Our results indicate that acute stress produced enhanced striatal levels of lipid peroxidation (73% above the control), decreased superoxide dismutase activity (54% below the control), reduced levels of mitochondrial function (35% below the control) and increased corticosterone serum levels (86% above the control). Pre-treatment of stressed rats with diazepam decreased the striatal lipid peroxidation levels (68% below the stress group) and improved mitochondrial function (18% above the stress group), but only mild preservation of superoxide dismutase activity was detected (17% above the stress group). In regard to the motor assessment, only the stereotyped activity was increased in the stress group with respect to control (46% above the control), and this effect was prevented by diazepam administration (30% below the stress group). The preventive actions of diazepam in this acute model of stress suggest that drugs exhibiting anxiolytic and antioxidant properties might be useful for the design of therapies against early acute phases of physic stress.

  8. Modulation of Corpus Striatal Neurochemistry by Astrocytes and Vasoactive Intestinal Peptide (VIP) in Parkinsonian Rats.

    PubMed

    Yelkenli, İbrahim Halil; Ulupinar, Emel; Korkmaz, Orhan Tansel; Şener, Erol; Kuş, Gökhan; Filiz, Zeynep; Tunçel, Neşe

    2016-06-01

    The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used in animal models of Parkinson's disease. In various neurodegenerative diseases, astrocytes play direct, active, and critical roles in mediating neuronal survival and functions. Vasoactive intestinal peptide (VIP) has neurotrophic actions and modulates a number of astrocytic activities. In this study, the effects of VIP on the striatal neurochemistry were investigated in parkinsonian rats. Adult Sprague-Dawley rats were divided into sham-operated, unilaterally 6-OHDA-lesioned, and lesioned + VIP-administered (25 ng/kg i.p.) groups. VIP was first injected 1 h after the intrastriatal 6-OHDA microinjection and then every 2 days throughout 15 days. Extracellular striatal concentration of glutathione (GSH), gamma-aminobutyric acid (GABA), glutamate (GLU), and lactate were measured in microdialysates by high-performance liquid chromatography (HPLC). Quantification of GABA and activity dependent neuroprotective protein (ADNP)-expressing cells were determined by glutamic acid decarboxylase (GAD)/ADNP + glial fibrillary acidic protein (GFAP) double immunohistochemistry. Our results demonstrated that a 6-OHDA lesion significantly increased the density of astrocytes in the striatum and VIP treatment slightly reduced the gliosis. Extracellular concentration of GABA, GLU, and lactate levels did not change, but GSH level significantly increased in the striatum of parkinsonian rats. VIP treatment reduced GSH level comparable to sham-operated groups, but enhanced GABA and GLU levels. Our double labeling results showed that VIP primarily acts on neurons to increase ADNP and GAD expression for protection. These results suggest that, in the 6-OHDA-induced neurodegeneration model, astrocytes were possibly activated for forefront defensiveness by modulating striatal neurochemistry.

  9. Striatal Molecular Signature of Subchronic Subthalamic Nucleus High Frequency Stimulation in Parkinsonian Rat

    PubMed Central

    Lortet, Sylviane; Lacombe, Emilie; Boulanger, Nicolas; Rihet, Pascal; Nguyen, Catherine; Goff, Lydia Kerkerian-Le; Salin, Pascal

    2013-01-01

    This study addresses the molecular mechanisms underlying the action of subthalamic nucleus high frequency stimulation (STN-HFS) in the treatment of Parkinson's disease and its interaction with levodopa (L-DOPA), focusing on the striatum. Striatal gene expression profile was assessed in rats with nigral dopamine neuron lesion, either treated or not, using agilent microarrays and qPCR verification. The treatments consisted in anti-akinetic STN-HFS (5 days), chronic L-DOPA treatment inducing dyskinesia (LIDs) or the combination of the two treatments that exacerbated LIDs. STN-HFS modulated 71 striatal genes. The main biological processes associated with the differentially expressed gene products include regulation of growth, of apoptosis and of synaptic transmission, and extracellular region is a major cellular component implicated. In particular, several of these genes have been shown to support survival or differentiation of striatal or of dopaminergic neurons. These results indicate that STN HFS may induce widespread anatomo-functional rearrangements in the striatum and create a molecular environment favorable for neuroprotection and neuroplasticity. STN-HFS and L-DOPA treatment share very few common gene regulation features indicating that the molecular substrates underlying their striatal action are mostly different; among the common effects is the down-regulation of Adrb1, which encodes the adrenergic beta-1- receptor, supporting a major role of this receptor in Parkinson's disease. In addition to genes already reported to be associated with LIDs (preprodynorphin, thyrotropin-releasing hormone, metabotropic glutamate receptor 4, cannabinoid receptor 1), the comparison between DOPA and DOPA/HFS identifies immunity-related genes as potential players in L-DOPA side effects. PMID:23593219

  10. Morphometric analysis of NADPH diaphorase reactive neurons in a rat model of focal excitotoxic striatal injury.

    PubMed

    Freire, Marco Aurelio M; Guimaraes, Joanilson S; Santos, Jose Ronaldo; Simplício, Hougelle; Gomes-Leal, Walace

    2016-12-01

    Excitotoxicity is the major component in neuropathological conditions, related to harmful action of imbalanced concentrations of glutamate and its agonists in the nervous tissue, ultimately resulting in cell death. In the present study, we evaluated the effects of an acute striatal lesion induced by a focal N-methyl-D-aspartate (NMDA) microinjection on the morphometry of NADPH diaphorase-reactive neurons (NADPH-d(+) ), a subset of cells which release nitric oxide (NO) in the brain and are known by its resistance in pathological conditions. Two hundred and forty NADPH-d neurons from NMDA-lesioned striatum and contralateral counterpart were tridimensionally reconstructed at 1, 3 and 7 post-lesion days (PLDs). Cell body and dendritic field areas, length of dendrites by order and fractal dimension were analyzed. There were no significant morphometric differences when NADPH-d(+) neurons from lesioned and control striatal regions were compared among PLDs evaluated. Conversely, a conspicuous pallor in striatal neuropil reactivity was evidenced, especially in latter survival time. In addition, we observed a noticeable inflammatory response induced by NMDA. Our results suggest that NADPH-d(+) neurons were spared from deleterious effects of acute NMDA excitotoxic damage in the striatum, reinforcing the notion that this cell group is selectively resistant to injury in the nervous system.

  11. An Intrastriatal Brain-Derived Neurotrophic Factor Infusion Restores Striatal Gene Expression in Bdnf Heterozygous Mice

    PubMed Central

    Saylor, Alicia J.; McGinty, Jacqueline F.

    2011-01-01

    Reduction in the amount of brain-derived neurotrophic factor (BDNF) in corticostriatal afferents is thought to contribute to the vulnerability of medium spiny striatal neurons in Huntington’s disease. In young Bdnf heterozygous (+/−) mice, striatal medium spiny neurons express less preprodynorphin, preproenkephalin, and D3 receptor mRNA than wildtype mice. Further, in aged Bdnf+/− mice, opioid, trkB receptor, and glutamic acid decarboxylase gene expression, and the number of dendritic spines on medium spiny neurons are more affected than in wildtype or younger Bdnf+/− mice. In this study, the possibility that intrastriatal infusions of BDNF would elevate gene expression in the striatum of Bdnf+/− mice was investigated. Wildtype and Bdnf+/− mice received a single, bilateral microinjection of BDNF or PBS into the dorsal striatum. Mice were sacrificed 24 hours later and semi-quantitative in situ hybridization histochemical analysis confirmed that preprodynorphin, preproenkephalin and D3 receptor mRNA was less in the caudate-putamen and nucleus accumbens core of Bdnf+/− mice than in wildtype mice. A BDNF infusion increased preprodynorphin mRNA in the caudate-putamen and NAc core of wildtype mice and restored preprodynorphin mRNA levels in the nucleus accumbens core of Bdnf+/− mice. BDNF also restored the gene expression of preproenkephalin in the caudate-putamen of Bdnf+/− mice to wildtype levels; however, preproenkephalin mRNA in the nucleus accumbens did not differ among groups. Furthermore, BDNF increased D3 receptor mRNA in the nucleus accumbens core of wildtype and Bdnf+/− mice. These results demonstrate that exogenous BDNF restores striatal opioid and D3R gene expression in mice with genetically reduced levels of endogenous BDNF. PMID:20938680

  12. Chronic Δ9-Tetrahydrocannabinol during Adolescence Differentially Modulates Striatal CB1 Receptor Expression and the Acute and Chronic Effects on Learning in Adult Rats.

    PubMed

    Weed, Peter F; Filipeanu, Catalin M; Ketchum, Myles J; Winsauer, Peter J

    2016-01-01

    The purpose of this study was to determine whether chronic administration of Δ(9)-tetrahydrocannabinol (THC) during adolescence would (1) modify any sex-specific effects of THC on learning and (2) affect the development of tolerance to THC as an adult. Male and female rats received daily injections of saline or 5.6 mg/kg of THC from postnatal day 35-75, yielding four groups (female/saline, female/THC, male/saline, and male/THC). Rats were then trained on a procedure that assayed both learning and performance behavior and administered 0.32-18 mg/kg of THC acutely as adults (experiment 1). THC produced rate-decreasing and error-increasing effects in both sexes; however, female rats were more sensitive than male rats were to the rate-decreasing effects. Rats were then chronically administered 10 mg/kg of THC (experiment 2). Rats that received THC during adolescence developed tolerance to the rate-decreasing effects more slowly and less completely than did rats that received saline; in addition, females developed tolerance to the error-increasing effects of THC slower than males did. Western blot analysis of brain tissue indicated long-term changes in hippocampal and striatal cannabinoid type-1 receptor (CB1R) levels despite levels that were indistinguishable immediately after chronic treatment during adolescence. Striatal CB1R levels were increased in adult rats that received THC during adolescence; hippocampal CB1R levels varied by sex. In summary, female rats were more sensitive than male rats were to the acute and chronic effects of THC, and chronic administration of THC during adolescence produced long-term changes in CB1R levels that correlated with decreased tolerance development to the rate-decreasing effects of THC.

  13. In vitro studies of striatal vesicles containing the vesicular monoamine transporter (VMAT2): rat versus mouse differences in sequestration of 1-methyl-4-phenylpyridinium.

    PubMed

    Staal, R G; Hogan, K A; Liang, C L; German, D C; Sonsalla, P K

    2000-05-01

    Significant differences exist in the sensitivity of mice and rats to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that cannot be explained by differences in exposure to or uptake of 1-methyl-4-phenylpyridinium (MPP(+)) into dopamine (DA) neurons. MPP(+) is also a substrate for the brain vesicular monoamine transporter (VMAT2), and sequestration into synaptic vesicles may be one mechanism of protection against MPP(+) toxicity. A greater sequestration of MPP(+) into vesicles of DA neurons in rats versus mice could explain the lower vulnerability of DA neurons in the rat to MPP(+) toxicity. To test this hypothesis, the kinetics of uptake for [(3)H]MPP(+) and [(3)H]DA as well as [(3)H]dihydrotetrabenazine binding to VMAT2 were compared in vesicles isolated from the striata of rats and mice. The K(m) value of [(3)H]MPP(+) transport was similar in the two species. In contrast, the maximal transport rate (V(max)) was 2-fold greater in vesicles from rats than in those from mice. Likewise, the K(m) value for [(3)H]DA transport was similar in both preparations, but the V(max) value was 2-fold greater in rat than in mouse vesicles. The B(max) value for [(3)H]dihydrotetrabenazine binding was also 2-fold greater in striatal vesicles from rats than in those from mice. Electron micrographs demonstrated that vesicles isolated from rats and mice were approximately the same size. Based on these observations, we propose that striatal vesicles from rats have more VMAT2 than vesicles from mice and that this species difference in VMAT2 density may help explain the reduced vulnerability of rat DA neurons to MPP(+) neurotoxicity.

  14. Anticipatory reward signals in ventral striatal neurons of behaving rats.

    PubMed

    Khamassi, Mehdi; Mulder, Antonius B; Tabuchi, Eiichi; Douchamps, Vincent; Wiener, Sidney I

    2008-11-01

    It has been proposed that the striatum plays a crucial role in learning to select appropriate actions, optimizing rewards according to the principles of 'Actor-Critic' models of trial-and-error learning. The ventral striatum (VS), as Critic, would employ a temporal difference (TD) learning algorithm to predict rewards and drive dopaminergic neurons. This study examined this model's adequacy for VS responses to multiple rewards in rats. The respective arms of a plus-maze provided rewards of varying magnitudes; multiple rewards were provided at 1-s intervals while the rat stood still. Neurons discharged phasically prior to each reward, during both initial approach and immobile waiting, demonstrating that this signal is predictive and not simply motor-related. In different neurons, responses could be greater for early, middle or late droplets in the sequence. Strikingly, this activity often reappeared after the final reward, as if in anticipation of yet another. In contrast, previous TD learning models show decremental reward-prediction profiles during reward consumption due to a temporal-order signal introduced to reproduce accurate timing in dopaminergic reward-prediction error signals. To resolve this inconsistency in a biologically plausible manner, we adapted the TD learning model such that input information is nonhomogeneously distributed among different neurons. By suppressing reward temporal-order signals and varying richness of spatial and visual input information, the model reproduced the experimental data. This validates the feasibility of a TD-learning architecture where different groups of neurons participate in solving the task based on varied input information.

  15. Extrinsic Sources of Cholinergic Innervation of the Striatal Complex: A Whole-Brain Mapping Analysis

    PubMed Central

    Dautan, Daniel; Hacioğlu Bay, Husniye; Bolam, J. Paul; Gerdjikov, Todor V.; Mena-Segovia, Juan

    2016-01-01

    Acetylcholine in the striatal complex plays an important role in normal behavior and is affected in a number of neurological disorders. Although early studies suggested that acetylcholine in the striatum (STR) is derived almost exclusively from cholinergic interneurons (CIN), recent axonal mapping studies using conditional anterograde tracing have revealed the existence of a prominent direct cholinergic pathway from the pedunculopontine and laterodorsal tegmental nuclei to the dorsal striatum and nucleus accumbens. The identification of the importance of this pathway is essential for creating a complete model of cholinergic modulation in the striatum, and it opens the question as to whether other populations of cholinergic neurons may also contribute to such modulation. Here, using novel viral tracing technologies based on phenotype-specific fluorescent reporter expression in combination with retrograde tracing, we aimed to define other sources of cholinergic innervation of the striatum. Systematic mapping of the projections of all cholinergic structures in the brain (Ch1 to Ch8) by means of conditional tracing of cholinergic axons, revealed that the only extrinsic source of cholinergic innervation arises in the brainstem pedunculopontine and laterodorsal tegmental nuclei. Our results thus place the pedunculopontine and laterodorsal nuclei in a key and exclusive position to provide extrinsic cholinergic modulation of the activity of the striatal systems. PMID:26834571

  16. Effect of chronic treatment with angiotensin type 1 receptor antagonists on striatal dopamine levels in normal rats and in a rat model of Parkinson's disease treated with L-DOPA.

    PubMed

    Dominguez-Meijide, Antonio; Villar-Cheda, Begoña; Garrido-Gil, Pablo; Sierrra-Paredes, German; Guerra, Maria J; Labandeira-Garcia, Jose L

    2014-01-01

    Beneficial effects of angiotensin type-1 receptor (AT1) inhibition have been observed in a number of brain processes mediated by oxidative stress and neuroinflammation, including Parkinson's disease. However, important counterregulatory interactions between dopamine and angiotensin systems have recently been demonstrated in several peripheral tissues, and it is possible that a decrease in dopamine levels due to AT1 inhibition may interfere with neuroprotective strategies. The present experiments involving rats with normal dopaminergic innervation indicate that chronic treatment with the AT1 antagonist candesartan does not significantly affect striatal levels of dopamine, serotonin or metabolites, as does not significantly affect motor behavior, as evaluated by the rotarod test. Interestingly, chronic administration of candesartan to normal rats induced a marked increase in dopamine D1 and a decrease in dopamine D2 receptor expression. In a rat model of Parkinson's disease treated with L-DOPA, no differences in striatal dopamine and serotonin levels were observed between candesartan-treated rats and untreated, which suggests that chronic treatment with candesartan does not significantly affect the process of L-DOPA decarboxylation and dopamine release in Parkinson's disease patients. Candesartan did not induce any differences in the striatal expression of dopamine D1 and D2 and serotonin 5-HT1B receptors in 6ydroxydopamine-lesioned rats treated with L-DOPA. The results suggest that chronic treatment with AT1 antagonists as a neuroprotective strategy does not significantly affect striatal dopamine release or motor behavior. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

  17. Modulation of acetylcholine release from rat striatal slices by the GABA/benzodiazepine receptor complex

    SciTech Connect

    Supavilai, P.; Karobath, M.

    1985-02-04

    GABA, THIP and muscimol enhance spontaneous and inhibit electrically induced release of tritium labelled compounds from rat striatal slices which have been pre-labelled with /sup 3/H-choline. Baclofen is inactive in this model. Muscimol can inhibit electrically induced release of tritiated material by approximately 75% with half maximal effects at 2 ..mu..M. The response to muscimol can be blocked by the GABA antagonists bicuculline methobromide, picrotoxin, anisatin, R 5135 and CPTBO (cyclopentylbicyclophosphate). Drugs which act on the benzodiazepine receptor (BR) require the presence of muscimol to be effective and they modulate the effects of muscimol in a bidirectional manner. Thus BR agonists enhance and inverse BR agonists attenuate the inhibitory effects of muscimol on electrically induced release. Ro15-1788, a BR antagonist, does not modulate the inhibitory effects of muscimol but antagonizes the actions of clonazepam, a BR agonist, and of DMCM, an inverse BR agonist. These results demonstrate that a GABA/benzodiazepine receptor complex can modulate acetylcholine release from rat striatal slices in vitro. 24 references, 3 figures, 5 table.

  18. 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.

  19. Increased dopamine uptake in striatal synaptosomes after treatment of rats with amantadine.

    PubMed

    Page, G; Peeters, M; Maloteaux, J M; Hermans, E

    2000-09-01

    The aim of the present study was to investigate the effect of short- and long-term treatments with amantadine on the activity of the neuronal dopamine transporter (DAT) in the rat striatum. For this purpose, the [3H]dopamine uptake was measured in striatal synaptosomes prepared from rats treated for 2, 7 and 14 days with amantadine (40 mg/kg; i.p.). After 7 days of treatment, amantadine increased the apparent V(max) by 30% without modification of the apparent K(m) of dopamine uptake whereas no change in these parameters was observed after 2 and 14 days treatment. Binding assays conducted with [3H]GBR-12935 on membranes prepared from animals treated with amantadine revealed no difference in the density and the affinity of striatal DAT binding sites as compared to control. This indicates that the increased dopamine uptake was not reflecting a modification at the level of the DAT expression. The activity of the DAT is regulated by phosphorylation and one may propose that ionotropic glutamate receptors present on presynaptic terminals directly modulate this phosphorylation. An indirect mechanism would involve presynaptic dopamine receptors that control the activity of the DAT in response to the increased dopamine concentration in the synaptic cleft.

  20. Postnatal functional inactivation of the entorhinal cortex or ventral subiculum has different consequences for latent inhibition-related striatal dopaminergic responses in adult rats.

    PubMed

    Meyer, F; Peterschmitt, Y; Louilot, A

    2009-05-01

    Latent inhibition has been found to be disrupted in patients with acute schizophrenia. Striatal dopaminergic dysregulation is commonly acknowledged in schizophrenia. This disease may be consecutive to a functional disconnection between integrative regions, stemming from neurodevelopmental failures. Various anomalies suggesting early abnormal brain development have been described in the entorhinal cortex (ENT) and ventral subiculum (SUB) of patients. This study examines the consequences of a neonatal transitory blockade of the left ENT or left SUB for latent inhibition-related dopamine responses in the anterior part of the dorsal striatum using in-vivo voltammetry in freely moving adult rats. Reversible inactivation of both structures in different animals was achieved by local microinjection of tetrodotoxin (TTX) at postnatal day 8. Results obtained during the retention session of a three-stage latent inhibition protocol showed that the functional neonatal disconnection of the ENT or SUB caused the behavioural latent inhibition expression in pre-exposed (PE)-TTX-conditioned adult rats to disappear. After postnatal inactivation of the SUB, PE-TTX-conditioned rats displayed a reversal of the latent inhibition-related striatal dopamine responses, whereas after neonatal blockade of the ENT, dopamine changes in PE-TTX-conditioned rats monitored in the anterior striatum were between those observed in PE-phosphate-buffered-saline-conditioned and non-PE-TTX-conditioned animals. These data suggest that neonatal functional inactivation of the SUB disrupts latent inhibition-related striatal dopamine responses in adult animals more than that of the ENT. They may help improve understanding of the pathophysiology of schizophrenia.

  1. Striatal damage and oxidative stress induced by the mitochondrial toxin malonate are reduced in clorgyline-treated rats and MAO-A deficient mice.

    PubMed

    Maragos, William F; Young, Kristie L; Altman, Chris S; Pocernich, Chava B; Drake, Jennifer; Butterfield, D Allan; Seif, Isabelle; Holschneider, Daniel P; Chen, Kevin; Shih, Jean C

    2004-04-01

    Intrastriatal administration of the succinate dehydrogenase (SDH) inhibitor malonate produces neuronal injury by a "secondary excitotoxic" mechanism involving the generation of reactive oxygen species (ROS). Recent evidence indicates dopamine may contribute to malonate-induced striatal neurodegeneration; infusion of malonate causes a pronounced increase in extracellular dopamine and dopamine deafferentation attenuates malonate toxicity. Inhibition of the catabolic enzyme monoamine oxidase (MAO) also attenuates striatal lesions induced by malonate. In addition to forming 3,4-dihydroxyphenylacetic acid, metabolism of dopamine by MAO generates H2O2, suggesting that dopamine metabolism may be a source of ROS in malonate toxicity. There are two isoforms of MAO, MAO-A and MAO-B. In this study, we have investigated the role of each isozyme in malonate-induced striatal injury using both pharmacological and genetic approaches. In rats treated with either of the specific MAO-A or -B inhibitors, clorgyline or deprenyl, respectively, malonate lesion volumes were reduced by 30% compared to controls. In knock-out mice lacking the MAO-A isoform, malonate-induced lesions were reduced by 50% and protein carbonyls, an index ROS formation, were reduced by 11%, compared to wild-type animals. In contrast, mice deficient in MAO-B showed highly variable susceptibility to malonate toxicity precluding us from determining the precise role of MAO-B in this form of brain damage. These findings indicate that normal levels of MAO-A participate in expression of malonate toxicity by a mechanism involving oxidative stress.

  2. Rats classified as low or high cocaine locomotor responders: A unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors

    PubMed Central

    Yamamoto, Dorothy J.; Nelson, Anna M.; Mandt, Bruce H.; Larson, Gaynor A.; Rorabaugh, Jacki M.; Ng, Christopher M.C.; Barcomb, Kelsey M.; Richards, Toni L.; Allen, Richard M.; Zahniser, Nancy R.

    2013-01-01

    Individual differences are a hallmark of drug addiction. Here, we describe a rat model based on differential initial responsiveness to low dose cocaine. Despite similar brain cocaine levels, individual outbred Sprague-Dawley rats exhibit markedly different magnitudes of acute cocaine-induced locomotor activity and, thereby, can be classified as low or high cocaine responders (LCRs or HCRs). LCRs and HCRs differ in drug-induced, but not novelty-associated, hyperactivity. LCRs have higher basal numbers of striatal dopamine transporters (DATs) than HCRs and exhibit marginal cocaine inhibition of in vivo DAT activity and cocaine-induced increases in extracellular DA. Importantly, lower initial cocaine response predicts greater locomotor sensitization, conditioned place preference and greater motivation to self-administer cocaine following low dose acquisition. Further, outbred Long-Evans rats classified as LCRs, versus HCRs, are more sensitive to cocaine’s discriminative stimulus effects. Overall, results to date with the LCR/HCR model underscore the contribution of striatal DATs to individual differences in initial cocaine responsiveness and the value of assessing the influence of initial drug response on subsequent expression of addiction-like behaviors. PMID:23850581

  3. Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia-ischemia.

    PubMed

    Cameron, Stella H; Alwakeel, Amr J; Goddard, Liping; Hobbs, Catherine E; Gowing, Emma K; Barnett, Elizabeth R; Kohe, Sarah E; Sizemore, Rachel J; Oorschot, Dorothy E

    2015-09-01

    Perinatal hypoxia-ischemia is a major cause of striatal injury and may lead to cerebral palsy. This study investigated whether delayed administration of bone marrow-derived mesenchymal stem cells (MSCs), at one week after neonatal rat hypoxia-ischemia, was neurorestorative of striatal medium-spiny projection neurons and improved motor function. The effect of a subcutaneous injection of a high-dose, or a low-dose, of MSCs was investigated in stereological studies. Postnatal day (PN) 7 pups were subjected to hypoxia-ischemia. At PN14, pups received treatment with either MSCs or diluent. A subset of high-dose pups, and their diluent control pups, were also injected intraperitoneally with bromodeoxyuridine (BrdU), every 24h, on PN15, PN16 and PN17. This permitted tracking of the migration and survival of neuroblasts originating from the subventricular zone into the adjacent injured striatum. Pups were euthanized on PN21 and the absolute number of striatal medium-spiny projection neurons was measured after immunostaining for DARPP-32 (dopamine- and cAMP-regulated phosphoprotein-32), double immunostaining for BrdU and DARPP-32, and after cresyl violet staining alone. The absolute number of striatal immunostained calretinin interneurons was also measured. There was a statistically significant increase in the absolute number of DARPP-32-positive, BrdU/DARPP-32-positive, and cresyl violet-stained striatal medium-spiny projection neurons, and fewer striatal calretinin interneurons, in the high-dose mesenchymal stem cell (MSC) group compared to their diluent counterparts. A high-dose of MSCs restored the absolute number of these neurons to normal uninjured levels, when compared with previous stereological data on the absolute number of cresyl violet-stained striatal medium-spiny projection neurons in the normal uninjured brain. For the low-dose experiment, in which cresyl violet-stained striatal medium-spiny neurons alone were measured, there was a lower statistically

  4. Intrastriatal taurine increases striatal extracellular dopamine in a tetrodotoxin-sensitive manner in rats.

    PubMed

    Ruotsalainen, M; Ahtee, L

    1996-07-19

    In vivo effects of locally administered taurine on striatal dopamine release and metabolism were studied by microdialysis in freely moving rats. Concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in striatal dialysates were quantified by high pressure liquid chromatography (HPLC) using electrochemical detection. Infusion of 150 mM taurine into the striatum for 2 h induced a 2.5-fold increase in the extracellular dopamine concentration. Extracellular DOPAC concentration increased nearly 2-fold. Taurine infusion initially decreased HVA to 70% but afterwards increased it to 140% of the control. When taurine was infused simultaneously with 1 microM tetrodotoxin starting 60 min after tetrodotoxin, the output of dopamine did not differ from that in the presence of tetrodotoxin alone. Tetrodotoxin abolished the effects of taurine on dopamine metabolites as well. Tetrodotoxin-sensitivity of the effects of taurine on dopamine and its metabolites suggests that intrastriatal taurine elevates extracellular dopamine by releasing it from neuronal pool.

  5. Paraxanthine displaces the binding of [3H]SCH 23390 from rat striatal membranes.

    PubMed

    Ferré, S; Guix, T; Sallés, J; Badia, A; Parra, P; Jané, F; Herrera-Marschitz, M; Ungerstedt, U; Casas, M

    1990-04-25

    We present evidence showing that paraxanthine (1,7-dimethylxanthine), the main metabolite of caffeine in man, displaces the binding of [3H]SCH 23390, a radioligand which selectively labels dopamine D-1 receptors when used at low concentrations, from striatal membranes of the rat. The displacement was competitive and indicated the existence of two affinity states (Hill coefficient = 0.49; K(high) = 0.15 microM; K(low) = 95.9 microM, %R(high) = 32.4). When the stable GTP analog Gpp(NH)p was included, the displacement curve indicated the presence of only the low-affinity state (Hill coefficient = 1.16; Ki = 72.1 microM). However, paraxanthine did not displace the specific binding of [3H]spiperone. After injection of 30 mg/kg s.c. of caffeine, a maximum of 10 microM of paraxanthine was found in striatal homogenates, which could be sufficient to occupy dopamine D-1 receptors. Our results suggest that a dopaminergic action of paraxanthine could be involved in the behavioural stimulation produced by caffeine.

  6. Somatostatin regulates dopamine release in rat striatal slices and cat caudate nuclei

    SciTech Connect

    Chesselet, M.F.; Reisine, T.D.

    1983-01-01

    The effects of somatostatin on the release of tritiated dopamine (DA) formed continuously from tritiated tyrosine were studied in vitro in superfused striatal slices and in vivo in both caudate nuclei and both substantiae nigrae of halothane-anesthetized cats using a push-pull cannula technique. Somatostatin (3 X 10(-10) to 3 X 10(-7) M) increased the spontaneous tritiated dopamine release from rat striatal slices. This effect was dose dependent and was completely prevented by tetrodotoxin (5 X 10(-7) M). When applied for 30 min in one cat caudate nucleus, somatostatin (10(-7) M) immediately increased the local release of tritiated DA, while a gradual inhibition of the tritiated amine's efflux was observed in the contralateral caudate nucleus. No changes in tritiated dopamine were seen in either substantia nigra during or after the peptide's application in the caudate nucleus. These results suggest that somatostatin in the striatum may play a role in the local and the distal control of dopamine release from the terminals of dopaminergic nigrostriatal neurons.

  7. Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat.

    PubMed

    Rupniak, N M; Mann, S; Hall, M D; Fleminger, S; Kilpatrick, G; Jenner, P; Marsden, C D

    1984-01-01

    Administration of haloperidol (1.4-1.6 mg/kg/day) for up to 12 months or sulpiride (102-109 mg/kg/day) for between 6 and 12 months increased the frequency of purposeless chewing jaw movements in rats. N,n-propylnorapomorphine (NPA) (0.25-2.0 mg/kg SC) did not induce hypoactivity in haloperidol-treated rats at any time; sulpiride treatment for 9 and 12 months caused a reduction in the ability of NPA to induce hypoactivity. Haloperidol, but not sulpiride, treatment enduringly inhibited low dose apomorphine effects (0.125 mg/kg SC). After 12 months, stereotypy induced by high doses of apomorphine (0.5-1.0 mg/kg) was exaggerated in haloperidol-, but not sulpiride-treated rats. Bmax for specific striatal 3H-spiperone binding was increased by haloperidol, but not sulpiride, treatment throughout the study. Bmax for 3H-piflutixol binding was not altered by chronic haloperidol or sulpiride treatment. Striatal dopamine-stimulated adenylate cyclase activity was inhibited for the 1st month of haloperidol treatment, thereafter returning to control levels; dopamine stimulation was increased after 12 months of sulpiride treatment. Striatal acetylcholine content was increased after 3 and 12 months of treatment with haloperidol, but was not affected by sulpiride. Chronic administration of sulpiride does not induce identical changes in striatal dopamine function to those caused by haloperidol.

  8. Functional connectivity in frontal-striatal brain networks and cocaine self-administration in female rhesus monkeys.

    PubMed

    Murnane, K S; Gopinath, K S; Maltbie, E; Daunais, J B; Telesford, Q K; Howell, L L

    2015-02-01

    Cocaine addiction is characterized by alternating cycles of abstinence and relapse and loss of control of drug use despite severe negative life consequences associated with its abuse. The objective of the present study was to elucidate critical neural circuits involved in individual vulnerabilities to resumption of cocaine self-administration following prolonged abstinence. The subjects were three female rhesus monkeys in prolonged abstinence following a long history of cocaine self-administration. Initial experiments examined the effects of acute cocaine administration (0.3 mg/kg, IV) on functional brain connectivity across the whole brain and in specific brain networks related to behavioral control using functional magnetic resonance imaging in fully conscious subjects. Subsequently, these subjects were allowed to resume cocaine self-administration to determine whether loss of basal connectivity within specific brain networks predicted the magnitude of resumption of cocaine intake following prolonged abstinence. Acute cocaine administration robustly decreased global functional connectivity and selectively impaired top-down prefrontal circuits that control behavior, while sparing connectivity of striatal areas within limbic circuits. Importantly, impaired connectivity between prefrontal and striatal areas during abstinence predicted cocaine intake when these subjects were provided renewed access to cocaine. Based on these findings, loss of prefrontal to striatal functional connectivity may be a critical mechanism underlying the negative downward spiral of cycles of abstinence and relapse that characterizes cocaine addiction.

  9. Neuroimaging Evidence of Altered Fronto-Cortical and Striatal Function after Prolonged Cocaine Self-Administration in the Rat

    PubMed Central

    Gozzi, Alessandro; Tessari, Michela; Dacome, Lisa; Agosta, Federica; Lepore, Stefano; Lanzoni, Anna; Cristofori, Patrizia; Pich, Emilio M; Corsi, Mauro; Bifone, Angelo

    2011-01-01

    Cocaine addiction is often modeled in experimental paradigms where rodents learn to self-administer (SA) the drug. However, the extent to which these models replicate the functional alterations observed in clinical neuroimaging studies of cocaine addiction remains unknown. We used magnetic resonance imaging (MRI) to assess basal and evoked brain function in rats subjected to a prolonged, extended-access cocaine SA scheme. Specifically, we measured basal cerebral blood volume (bCBV), an established correlate of basal metabolism, and assessed the reactivity of the dopaminergic system by mapping the pharmacological MRI (phMRI) response evoked by the dopamine-releaser amphetamine. Cocaine-exposed subjects exhibited reduced bCBV in fronto-cortical areas, nucleus accumbens, ventral hippocampus, and thalamus. The cocaine group also showed an attenuated functional response to amphetamine in ventrostriatal areas, an effect that was significantly correlated with total cocaine intake. An inverse relationship between bCBV in the reticular thalamus and the frontal response elicited by amphetamine was found in control subjects but not in the cocaine group, suggesting that the inhibitory interplay within this attentional circuit may be compromised by the drug. Importantly, histopathological analysis did not reveal significant alterations of the microvascular bed in the brain of cocaine-exposed subjects, suggesting that the imaging findings cannot be merely ascribed to cocaine-induced vascular damage. These results document that chronic, extended-access cocaine SA in the rat produces focal fronto-cortical and striatal alterations that serve as plausible neurobiological substrate for the behavioral expression of compulsive drug intake in laboratory animals. PMID:21775976

  10. Neuroimaging evidence of altered fronto-cortical and striatal function after prolonged cocaine self-administration in the rat.

    PubMed

    Gozzi, Alessandro; Tessari, Michela; Dacome, Lisa; Agosta, Federica; Lepore, Stefano; Lanzoni, Anna; Cristofori, Patrizia; Pich, Emilio M; Corsi, Mauro; Bifone, Angelo

    2011-11-01

    Cocaine addiction is often modeled in experimental paradigms where rodents learn to self-administer (SA) the drug. However, the extent to which these models replicate the functional alterations observed in clinical neuroimaging studies of cocaine addiction remains unknown. We used magnetic resonance imaging (MRI) to assess basal and evoked brain function in rats subjected to a prolonged, extended-access cocaine SA scheme. Specifically, we measured basal cerebral blood volume (bCBV), an established correlate of basal metabolism, and assessed the reactivity of the dopaminergic system by mapping the pharmacological MRI (phMRI) response evoked by the dopamine-releaser amphetamine. Cocaine-exposed subjects exhibited reduced bCBV in fronto-cortical areas, nucleus accumbens, ventral hippocampus, and thalamus. The cocaine group also showed an attenuated functional response to amphetamine in ventrostriatal areas, an effect that was significantly correlated with total cocaine intake. An inverse relationship between bCBV in the reticular thalamus and the frontal response elicited by amphetamine was found in control subjects but not in the cocaine group, suggesting that the inhibitory interplay within this attentional circuit may be compromised by the drug. Importantly, histopathological analysis did not reveal significant alterations of the microvascular bed in the brain of cocaine-exposed subjects, suggesting that the imaging findings cannot be merely ascribed to cocaine-induced vascular damage. These results document that chronic, extended-access cocaine SA in the rat produces focal fronto-cortical and striatal alterations that serve as plausible neurobiological substrate for the behavioral expression of compulsive drug intake in laboratory animals.

  11. The effect of venlafaxine on behaviour, body weight and striatal monoamine levels on sleep-deprived female rats.

    PubMed

    de Oliveira, Ricardo A; Cunha, Geanne M A; Borges, Karla Daisy M; de Bruin, Gabriela S; dos Santos-Filho, Emídio A; Viana, Glauce S B; de Bruin, Veralice M S

    2004-11-01

    Partial sleep deprivation is clinically associated with fatigue, depressive symptoms and reduced memory. Previously, it has been demonstrated that venlafaxine, an atypical antidepressant, increases the levels of noradrenaline and serotonin in rat hippocampus. The aim of this study was to evaluate the effects of venlafaxine on depression, anxiety, locomotor activity and memory in a model of REM sleep (REMs) deprivation in rats. We have also studied the influence of venlafaxine on monoamine levels in the striatum. Six groups of animals (N=20 each) were treated with saline or venlafaxine (1 or 10 mg/kg) during 10 days, submitted or not to REMs deprivation and studied with the forced swimming test of Porsolt (STP), plus-maze, passive avoidance and open-field tests right after sleep deprivation. Animals were also studied for passive avoidance 24 h later (rebound period). Brain samples for monoamine measurements were collected either immediately after REMs deprivation or after 24 h. Both REMs deprivation and venlafaxine showed an antidepressant effect. An anxiolytic effect was also observed after REMs deprivation. Previous treatment with venlafaxine blocked the antidepressant and anxiolytic effects of REMs deprivation. REMs deprivation alone and treatment with venlafaxine 10 mg/kg increased locomotor activity, and this effect was inhibited by venlafaxine in REMs deprived rats. Both venlafaxine treatment and REMs deprivation induced weight loss. Venlafaxine treatment, but not REMs deprivation, induced an increase in striatal dopamine (DA) levels. The combination of REMs deprivation and venlafaxine treatment was associated with an increase in serotonin turnover 24 h after rebound sleep. In this study, venlafaxine treatment hindered most behavioral effects of REMs deprivation and was associated with an interference on dopamine and serotonin systems in the striatum.

  12. Exercise improves motor deficits and alters striatal GFAP expression in a 6-OHDA-induced rat model of Parkinson's disease.

    PubMed

    Dutra, Márcio Ferreira; Jaeger, Mariane; Ilha, Jocemar; Kalil-Gaspar, Pedro Ivo; Marcuzzo, Simone; Achaval, Matilde

    2012-10-01

    Astrocytic changes have been demonstrated in several neurodegenerative diseases, showing that these cells play an important role in functional recovery/maintenance against brain damage. Physical exercise is known to contribute to this process; however, the cellular mechanisms involved are not fully understood. This study investigated the effects of physical exercise on motor deficits and the expression of glial fibrillary acidic protein (GFAP) in a model of Parkinson's disease (PD). Rats were divided into four groups: sham sedentary (SS) and sham trained (ST); lesioned sedentary (LS) and lesioned trained (LT). 6-OHDA was infused unilaterally into the medial forebrain bundle. Behavioral tasks were applied to evaluate motor abilities. Tyrosine hydroxylase (TH-in substantia nigra) and GFAP (in striatum) immunoreactivities (ir) were semi-quantified using optical density. The animals submitted to treadmill training completed fewer pharmacological-induced rotations when compared with sedentary animals and they also showed ameliorated motor impairments. Interestingly, although no change in TH-ir, the exercise led to restored striatal GFAP expression in the LT group while there was no effect in the ST group. This study is the first study to show data indicating the recovery of GFAP expression post-exercise in this model and further research is necessary to determine the precise action mechanisms of exercise on astrocytes in the PD.

  13. Effects of intranigral injection of taurine and GABA on striatal dopamine release monitored voltammetrically in the unanaesthetized rat.

    PubMed

    O'Neill, R D

    1986-09-10

    Linear sweep voltammetry with carbon-paste electrodes was used to detect changes in the extracellular concentration of homovanillic acid (HVA) in the striatum of unanaesthetized rats; under the present experimental conditions, changes in the HVA signal were used as an index of striatal dopamine release. The effects of unilateral intranigral infusion of saline, sucrose, taurine, GABA and the putative taurine-receptor antagonist, 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide (TAG), on the HVA signal were monitored in the striatum on the two sides of the brain. Both taurine and GABA caused an increase in the extracellular concentration of HVA which was significantly greater in the striatum on the side of the injection compared with the contralateral side. The effect of TAG varied between animals. The results are discussed in terms of the role of taurine as a possible neuromodulator in the substantia nigra and in the light of the suggestion that different pathways are involved in taurine- and GABA-induced contraversive circling.

  14. Number and type of synapses on the distal dendrite of a rat striatal cholinergic interneuron: a quantitative, ultrastructural study.

    PubMed

    Sizemore, Rachel J; Reynolds, John N J; Oorschot, Dorothy E

    2010-09-01

    Knowledge of the innervation of interneurons within the striatum is critical to determining their role in the functioning of the striatal network. To this end, the synaptic innervation of a distal dendrite of a rat striatal cholinergic interneuron was quantified for the first time. These synaptic data were compared to three other dendrites from rat striatal interneurons and to published data from dendrites in the mammalian cerebral cortex. To label the cholinergic interneurons and their distal dendrites, a male Wistar rat was perfused and the striatum was double-immunolabelled with an antibody to choline acetyltransferase (ChAT) and an antibody to m2 muscarinic receptor. After processing for transmission electron microscopy, a cholinergic interneuron was located and an m2-labelled distal dendrite identified by tracing it through serial ultrathin sections to this double-immunolabelled soma. Two interneuronal distal dendrites in the same tissue, and another from a second rat, were used for comparison. The widths and lengths of the four distal dendrites, the total number and type of synapses, and the number of synapses per mum for each distal dendrite were measured. Symmetric synapses were the most common type on all four dendrites. There were 0.73 synapses per mum on the distal dendrite of the identified striatal cholinergic interneuron. Two other interneuronal dendrites that were positive for the m2 muscarinic receptor antibody showed similar synaptic densities of 0.62 and 0.83 synapses per microm of distal dendrite, respectively. On a third unlabelled interneuronal distal dendrite located in the lateral striatum, there were 2.17 synapses per microm. This interneuron was thought to be a parvalbumin interneuron rather than a calretinin interneuron, which would more likely be medially located. These data suggest that the number of synapses per microm on the distal dendrite of the cholinergic interneuron, and possibly two other cholinergic interneurons, is three times

  15. The ionic mechanism of gamma resonance in rat striatal fast-spiking neurons.

    PubMed

    Sciamanna, Giuseppe; Wilson, Charles J

    2011-12-01

    Striatal fast-spiking (FS) cells in slices fire in the gamma frequency range and in vivo are often phase-locked to gamma oscillations in the field potential. We studied the firing patterns of these cells in slices from rats ages 16-23 days to determine the mechanism of their gamma resonance. The resonance of striatal FS cells was manifested as a minimum frequency for repetitive firing. At rheobase, cells fired a doublet of action potentials or doublets separated by pauses, with an instantaneous firing rate averaging 44 spikes/s. The minimum rate for sustained firing was also responsible for the stuttering firing pattern. Firing rate adapted during each episode of firing, and bursts were terminated when firing was reduced to the minimum sustainable rate. Resonance and stuttering continued after blockade of Kv3 current using tetraethylammonium (0.1-1 mM). Both gamma resonance and stuttering were strongly dependent on Kv1 current. Blockade of Kv1 channels with dendrotoxin-I (100 nM) completely abolished the stuttering firing pattern, greatly lowered the minimum firing rate, abolished gamma-band subthreshold oscillations, and slowed spike frequency adaptation. The loss of resonance could be accounted for by a reduction in potassium current near spike threshold and the emergence of a fixed spike threshold. Inactivation of the Kv1 channel combined with the minimum firing rate could account for the stuttering firing pattern. The resonant properties conferred by this channel were shown to be adequate to account for their phase-locking to gamma-frequency inputs as seen in vivo.

  16. Effect of ionizing radiation on in vivo striatal release of dopamine in the rat

    SciTech Connect

    Han-Tong Chen; Kandasamy, S.B.

    1996-07-01

    The time-course effect of ionizing radiation on the levels of basal and KCl-stimulated striatal release of dopamine (DA) was examined in vivo using microdialysis techniques. The basal level of extracellular DA in sham-irradiated controls was 0.172 {plus_minus} 0.042 pmol/sample (n = 9), and it increased 7.1-fold after the stimulation by 30 mM KCl (20 {mu}l). However, the release of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), two metabolites of DA, was reduced significantly by 30 mM KCl(P {le} 0.05). In the presence of 10 {mu}M forskolin, an activator of adenylate cyclase, a second stimulation by 30 mM KCl increased the release of DA 6.9-fold. Radiation exposure, at a dose of 10 Gyt at 10 Gy/min, had no significant effect on the levels of either basal or KCl-stimulated release of DA or on the release of DOPAC and HVA. Striatal DA releases increased in response to two consecutive challenges of KCl. However, the release of DA in response to the second challenge of KCl was significantly smaller than that after the first challenge (543 {plus_minus} 110% compared to 794 {plus_minus} 164%, P {le} 0.05; Student`s paired t test). Pretreatment with 10 {mu}M forskolin, which by itself had no significant effect on the level of basal release of DA, prevented the decreased response of DA to the second challenge of KCl. Our results suggest that radiation exposure at the dose we used has no significant effect on the level of the basal release of DA or the release of DA stimulated by 30 mM KCl in the rat striatum, and that a reduced release of DA in response to repeated KCl stimulation might involve the cAMP effector system. 22 refs., 5 figs., 1 tab.

  17. Copper reduces striatal protein nitration and tyrosine hydroxylase inactivation induced by MPP+ in rats.

    PubMed

    Rubio-Osornio, M; Montes, S; Pérez-Severiano, F; Aguilera, P; Floriano-Sánchez, E; Monroy-Noyola, A; Rubio, C; Ríos, C

    2009-06-01

    Striatal administration of 1-methyl-4-phenylpyridinium (MPP(+)), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes nigrostriatal dopaminergic pathway damage similar to that observed in Parkinson's disease. Copper acts as a prosthetic group of several antioxidant enzymes and recent data show that copper attenuated MPP(+)-evoked neurotoxicity. We evaluated the effect of copper (as a supplement) upon proteins nitration (60 kDa) and tyrosine hydroxylase (TH) inactivation induced by MPP(+) (10 microg/8 microL) injection into the rat striatum. Copper pretreatment (10 micromol/kg i.p.) prevented both MPP(+)-induced proteins nitration and TH inactivation. Copper treatment also prevented the dopamine-depleting effect of MPP(+) injection. Those results were accompanied by a significant reduction of enzymatic activity of the constitutive nitric oxide synthase (cNOS), whereas, the protein levels of the three isoforms of NOS remained unchanged. Results indicate that the effect of copper against MPP(+)-induced proteins nitration and TH inactivation in the striatum of rat may be mediated by a reduction of cNOS activity.

  18. 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.

  19. The effects of administration of monoamine oxidase-B inhibitors on rat striatal neurone responses to dopamine.

    PubMed Central

    Berry, M D; Scarr, E; Zhu, M Y; Paterson, I A; Juorio, A V

    1994-01-01

    1. (-)-Deprenyl has been shown to potentiate rat striatal neurone responses to dopamine agonists at doses not altering dopamine metabolism. Since there are a number of effects of (-)-deprenyl which could result in this phenomenon, we have investigated the effects of MDL 72,145 and Ro 19-6327, whose only common effect with (-)-deprenyl is an inhibition of monoamine oxidase-B (MAO-B), on rat striatal neurone responses to dopamine and on striatal dopamine metabolism. 2. Using in vivo electrophysiology, i.p. injection of either MDL 72,145 or Ro 19-6327 was found to produce a dose-dependent potentiation of striatal neurone responses to dopamine but not gamma-aminobutyric acid. 3. Neurochemical investigations revealed that this occurred at doses (0.25-1 mg kg-1) which, while not affecting levels of dopamine or its metabolites, 3,4-dihydroxyphenylacetic acid or homovanillic acid, did cause a significant, dose-dependent, elevation in striatal levels of the putative neuromodulator, 2-phenylethylamine (PE). 4. Inhibition of PE synthesis by i.p. injection of the aromatic L-amino acid decarboxylase inhibitor, NSD 1015, produced a reversal of the effects of MDL 72,145 and Ro 19-6327. 5. Neurochemical analysis revealed this to occur at a dose of NSD 1015 (10 mg kg-1) selective for reduction of elevated PE levels. 6. These results suggest that PE can act as a neuromodulator of dopaminergic responses and that MAO-B inhibitors may potentiate neuronal responses to dopamine via the indirect mechanism of elevation of PE following MAO-B inhibition. PMID:7889269

  20. Effect of neurotoxic lesion of pedunculopontine nucleus in nigral and striatal redox balance and motor performance in rats.

    PubMed

    Jimenez-Martin, J; Blanco-Lezcano, L; González-Fraguela, M E; Díaz-Hung, M-L; Serrano-Sánchez, T; Almenares, J L; Francis-Turner, L

    2015-03-19

    Early degeneration of pedunculopontine nucleus (PPN) is considered part of changes that characterize premotor stages of Parkinson's disease (PD). In this paper, the effects of unilateral neurotoxic lesion of the PPN in motor execution and in the development of oxidative stress events in striatal and nigral tissues in rats were evaluated. The motor performance was assessed using the beam test (BT) and the cylinder test (CT). Nigral and striatal redox balance, was studied by means of biochemical indicators such as malondialdehyde (MDA), nitric oxide (NO) and the catalase enzymatic activity (CAT EA). Lesioned rats showed fine motor dysfunction expressed both as an increase in the length (p<0.001) and deviation (p<0.001) of the traveled path and also in the time spent (p<0.01) in the circular small beam (CBS) (p<0.01) in comparison with control groups. In addition, the lesioned rats group presented a right asymmetry index greater than 0.5 which is consistent with a significant increase in the percentage of use of the right forelimb (ipsilateral to the lesion), compared with the control group (p<0.05). Biochemical studies revealed that after 48-h PPN neurotoxic injury, the CAT EA showed a significant increase in the subtantia nigra pars compacta (SNpc) (p<0.05). This significant increase of CAT EA persisted in the nigral tissue (p<0.001) and reached the striatal tissue (p<0.001) seven days after PPN injury. Also at seven days post-injury PPN, increased concentrations of MDA (p<0.01) and a tendency to decrease in the concentrations of NO in both structures (SNpc and striatum) were found. The events associated with the generation of free radicals at nigral and striatal levels, can be part of the physiological mechanisms underlying motor dysfunction in rats with unilateral PPN neurotoxic lesion.

  1. Development of specificity and stereoselectivity of rat brain dopamine receptors.

    PubMed

    Miller, J C; Friedhoff, A J

    1986-01-01

    Prenatal exposure to the neuroleptic haloperidol has been reported to produce an enduring decrement in the number of dopamine D2 receptors in rat striatum and a persistent diminution of a dopamine dependent behavior, stereotypy. The ontogeny of rat brain dopamine binding sites has been studied in terms of the kinetic properties and phenotypic specificity in rat fetal brain through early postnatal development. Sites showing some properties of the D2 binding site can be found prior to gestational day (GD) 18, can be labeled with [3H]dopamine or [3H]spiroperidol and can be displaced with dopaminergic agonists and antagonists. Saturation kinetics for specific [3H]spiroperidol has previously been found to occur on or about GD 18. It is of interest that the critical period for the prenatal effect of haloperidol to reduce striatal D2 binding sites, GD's 15-18, coincides with the period during which dopamine binding sites lack true specificity, but can be labeled with dopaminergic ligands. In these experiments the development of stereoselectivity of brain dopamine binding sites has been examined. When rat mothers were given either the neuroleptic (+)-butaclamol or its therapeutically inactive isomer (-)-butaclamol during the critical period GD's 15-18, the number of [3H]spiroperidol binding sites in striata of offspring was significantly reduced by both stereoisomers. This is in marked contrast to the postnatal treatment effect by a neuroleptic in which upregulation of striatal D2 binding sites occurs only by treatment with the therapeutically active isomer (+)-butaclamol. In vitro studies of the direct effect of the stereoisomers of butaclamol indicate that the recognition sites detected during fetal brain development with [3H]spiroperidol do not distinguish between the isomers of butaclamol.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Acute L: -DOPA effect on hydroxyl radical- and DOPAC-levels in striatal microdialysates of parkinsonian rats.

    PubMed

    Nowak, Przemysław; Kostrzewa, Rose Anna; Skaba, Dariusz; Kostrzewa, Richard M

    2010-04-01

    The object of the current study was to determine the effect of L: -3,4-dihydroxyphenylalanine (L: -DOPA) on the in vivo striatal microdialysate levels of the respective dopamine and serotonin metabolites 3,4-dihydroxyphenlalanine (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) and hydroxyl radical level (HO(*); 2,3- and 2,5-dihydroxybenzoic acid, 2,3- and 2,5-DHBA) in adult rats made parkinsonian by treatment at 3 days after birth with the neurotoxin 6-hydroxydopamine (6-OHDA; 66.7 microg, base form, on each side; desipramine pretreatment, 1 h). Using HPLC/ED we found that in 6-OHDA-lesioned rats the basal striatal extraneuronal level of DOPAC was dramatically reduced and constituted only approximately 4.5% of referenced value (intact rats). Conversely, the striatal microdialysate level of 5-HIAA was elevated 2-fold in 6-OHDA-lesioned rats. Acute L: -DOPA (60 mg/kg i.p.; S-carbidopa pretreatment, 12.5 mg/kg i.p., 30 min) produced a rapid rise in the extraneuronal DOPAC in both tested groups but to a much greater extent in intact rats (P < 0.05). Levels of HO(*) (spin-trap products of salicylate, 2,3- and 2,5-DHBA) were elevated 2-fold in 6-OHDA-lesioned rats. However, L: -DOPA did not enhance HO(*) production; acute 6-OHDOPA treatment (60 mg/kg i.p.) also did not alter HO(*) production. In summary, L: -DOPA, an effective drug in ameliorating PD symptoms, did not acutely pose a risk for HO(*) generation in parkinsonian rats. We conclude that L: -DOPA is not likely to generate reactive oxygen species in humans nor is L: -DOPA likely to accelerate PD in humans.

  3. Riluzole protects from motor deficits and striatal degeneration produced by systemic 3-nitropropionic acid intoxication in rats.

    PubMed

    Guyot, M C; Palfi, S; Stutzmann, J M; Mazière, M; Hantraye, P; Brouillet, E

    1997-11-01

    The putative neuroprotective effect of riluzole was investigated in a rat model of progressive striatal neurodegeneration induced by prolonged treatment (three weeks, intraperitoneal) with 3-nitropropionic acid, an irreversible inhibitor of succinate dehydrogenase. Quantitative analysis of motor behaviour indicated a significant protective effect (60%) of riluzole (8 mg/kg/day) on 3-nitropropionic acid-induced motor deficits as assessed using two independent motor tests. Furthermore, quantitative analysis of 3-nitropropionic acid-induced lesions indicated a significant 84% decrease in the volume of striatal damage produced by 3-nitropropionic acid, the neuroprotective effect apparently being more pronounced in the posterior striatum and pallidum. In addition, it was checked that this neuroprotective effect of riluzole against systemic 3-nitropropionic acid did not result from a decreased bioavailability of the neurotoxin or a direct action of riluzole on 3-nitropropionic acid-induced inhibition of succinate dehydrogenase. We found that riluzole significantly decreased by 48% the size of striatal lesions produced by stereotaxic intrastriatal injection of malonate, a reversible succinate dehydrogenase inhibitor. Furthermore, the inhibition of cortical and striatal succinate dehydrogenase activity induced by systemic 3-nitropropionic acid was left unchanged by riluzole administration. The present results, consistent with a beneficial effect of riluzole in amyotrophic lateral sclerosis, suggest that this compound may be useful in the treatment of chronic neurodegenerative diseases.

  4. Methamphetamine, morphine, and their combination: acute changes in striatal dopaminergic transmission evaluated by microdialysis in awake rats.

    PubMed

    Pereira, Frederico C; Lourenço, Elita; Milhazes, Nuno; Morgadinho, Teresa; Ribeiro, Carlos F; Ali, Syed F; Macedo, Tice R

    2006-08-01

    The co-administration of methamphetamine (METH) and MOR (MOR)-like compounds is becoming increasingly popular among drug abusers. Recently, it was demonstrated that rats would self-inject METH-heroin combination and that this combination produced a greater rewarding effect than the identical doses of METH alone and it was further suggested that enhanced reward might underlie the popularity of this combination. However, there is null information on the effects of the MOR-METH combination on striatal dopaminergic transmission. In the present article, in vivo brain microdialysis was used to examine the effects of two METH doses (1 and 5 mg/kg, i.p.; [METH1: hyperlocomotion-inducing] and [METH5: stereotypy-inducing], respectively) and MOR (10 mg/kg, i.p. [MOR10]) either alone or in combination on dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) release in caudate putamen (CPu) in freely moving rats. METH1 evoked a transient threefold increase in DA overflow in only one-third of dosed rats. On the contrary, METH5 elicited a 11-fold increase in the extracellular DA levels 30 min after dosing and stayed significantly (P < 0.05) above control levels up to 1.5 h. On the other hand, MOR10 did not significantly change DA extracellular levels. MOR10-METH1 combination prolonged DA outflow for 1 h in all rats dosed without changing peak effect compared to METH1. On the other hand, MOR10-METH5 combination did not change the peak effect nor the DA outflow profile compared to METH5 alone. Consistently, there is a concentration-dependent decrease in DOPAC efflux evoked by METH: METH1 evoked a smaller decrease in DOPAC outflow showing a tendency for returning to basal values whereas METH5 kept DOPAC extracellular levels reduced throughout the experiment. Again, MOR10 did not significantly change DOPAC extracellular levels. MOR delayed the onset without changing METH effect on the DOPAC output. These findings provide suggestive evidence that MOR potentiated the increase in

  5. Protective effect of L-kynurenine and probenecid on 6-hydroxydopamine-induced striatal toxicity in rats: implications of modulating kynurenate as a protective strategy.

    PubMed

    Silva-Adaya, Daniela; Pérez-De La Cruz, Verónica; Villeda-Hernández, Juana; Carrillo-Mora, Paul; González-Herrera, Irma Gabriela; García, Esperanza; Colín-Barenque, Laura; Pedraza-Chaverrí, José; Santamaría, Abel

    2011-01-01

    The neuroactive metabolite at the kynunerine pathway, kynurenic acid (KYNA), is a well-known competitive antagonist at the co-agonist glycine site of the N-methyl-D-aspartate receptor (NMDAr), and also decreases the extracellular levels of glutamate by blocking α7-nicotinic acetylcholine receptor (α7-nAchr) located on glutamatergic terminals. KYNA has been often reported to be neuroprotective in different neurotoxic models. The systemic administration of L-kynurenine (L-KYN)--the precursor of KYNA--together with probenecid (PROB)--an inhibitor of organic acids transport--to rodents increases KYNA levels in the brain in a dose-dependent manner. The striatal infusion of the toxin 6-hydroxydopamine (6-OHDA) to rodents is one of the common models used to simulate Parkinson's disease (PD). Different studies have linked PD alterations with excessive glutamatergic transmission in the striatum since NMDAr antagonists exert beneficial effects in PD models. In this work we investigated the effect that a systemic administration of L-KYN+PROB exerted on the toxic model induced by 6-OHDA in rats. PROB (50 mg/kg, i.p.) + L-KYN (75 mg/kg, i.p.) were given to rats for seven consecutive days. On day two of treatment, the animals were infused with a single injection of 6-OHDA (20 μg/2 μl) into the right striatum. Fourteen days post-lesion, rotation behavior was assessed as a marker of motor impairment. The total levels of dopamine (DA) were also estimated in striatal tissue samples of 6-OHDA-treated animals as a neurochemical marker of damage. In addition, twenty eight days post-lesion, the striatal damage was assessed by hematoxylin/eosin staining and immunohistochemistry against glial fibrillary acidic protein (GFAP) in the same animals. Neurodegeneration was also assessed by Fluoro Jade staining. 6-OHDA infusion increased rotation behavior, striatal reactive gliosis and neurodegeneration, while DA levels were decreased. For all markers evaluated, we observed protective

  6. Chronic Methamphetamine Effects on Brain Structure and Function in Rats

    PubMed Central

    Thanos, Panayotis K.; Kim, Ronald; Delis, Foteini; Ananth, Mala; Chachati, George; Rocco, Mark J.; Masad, Ihssan; Muniz, Jose A.; Grant, Samuel C.; Gold, Mark S.; Cadet, Jean Lud; Volkow, Nora D.

    2016-01-01

    Methamphetamine (MA) addiction is a growing epidemic worldwide. Chronic MA use has been shown to lead to neurotoxicity in rodents and humans. Magnetic resonance imaging (MRI) studies in MA users have shown enlarged striatal volumes and positron emission tomography (PET) studies have shown decreased brain glucose metabolism (BGluM) in the striatum of detoxified MA users. The present study examines structural changes of the brain, observes microglial activation, and assesses changes in brain function, in response to chronic MA treatment. Rats were randomly split into three distinct treatment groups and treated daily for four months, via i.p. injection, with saline (controls), or low dose (LD) MA (4 mg/kg), or high dose (HD) MA (8 mg/kg). Sixteen weeks into the treatment period, rats were injected with a glucose analog, [18F] fluorodeoxyglucose (FDG), and their brains were scanned with micro-PET to assess regional BGluM. At the end of MA treatment, magnetic resonance imaging at 21T was performed on perfused rats to determine regional brain volume and in vitro [3H]PK 11195 autoradiography was performed on fresh-frozen brain tissue to measure microglia activation. When compared with controls, chronic HD MA-treated rats had enlarged striatal volumes and increases in [3H]PK 11195 binding in striatum, the nucleus accumbens, frontal cortical areas, the rhinal cortices, and the cerebellar nuclei. FDG microPET imaging showed that LD MA-treated rats had higher BGluM in insular and somatosensory cortices, face sensory nucleus of the thalamus, and brainstem reticular formation, while HD MA-treated rats had higher BGluM in primary and higher order somatosensory and the retrosplenial cortices, compared with controls. HD and LD MA-treated rats had lower BGluM in the tail of the striatum, rhinal cortex, and subiculum and HD MA also had lower BGluM in hippocampus than controls. These results corroborate clinical findings and help further examine the mechanisms behind MA

  7. Chronic Methamphetamine Effects on Brain Structure and Function in Rats.

    PubMed

    Thanos, Panayotis K; Kim, Ronald; Delis, Foteini; Ananth, Mala; Chachati, George; Rocco, Mark J; Masad, Ihssan; Muniz, Jose A; Grant, Samuel C; Gold, Mark S; Cadet, Jean Lud; Volkow, Nora D

    2016-01-01

    Methamphetamine (MA) addiction is a growing epidemic worldwide. Chronic MA use has been shown to lead to neurotoxicity in rodents and humans. Magnetic resonance imaging (MRI) studies in MA users have shown enlarged striatal volumes and positron emission tomography (PET) studies have shown decreased brain glucose metabolism (BGluM) in the striatum of detoxified MA users. The present study examines structural changes of the brain, observes microglial activation, and assesses changes in brain function, in response to chronic MA treatment. Rats were randomly split into three distinct treatment groups and treated daily for four months, via i.p. injection, with saline (controls), or low dose (LD) MA (4 mg/kg), or high dose (HD) MA (8 mg/kg). Sixteen weeks into the treatment period, rats were injected with a glucose analog, [18F] fluorodeoxyglucose (FDG), and their brains were scanned with micro-PET to assess regional BGluM. At the end of MA treatment, magnetic resonance imaging at 21T was performed on perfused rats to determine regional brain volume and in vitro [3H]PK 11195 autoradiography was performed on fresh-frozen brain tissue to measure microglia activation. When compared with controls, chronic HD MA-treated rats had enlarged striatal volumes and increases in [3H]PK 11195 binding in striatum, the nucleus accumbens, frontal cortical areas, the rhinal cortices, and the cerebellar nuclei. FDG microPET imaging showed that LD MA-treated rats had higher BGluM in insular and somatosensory cortices, face sensory nucleus of the thalamus, and brainstem reticular formation, while HD MA-treated rats had higher BGluM in primary and higher order somatosensory and the retrosplenial cortices, compared with controls. HD and LD MA-treated rats had lower BGluM in the tail of the striatum, rhinal cortex, and subiculum and HD MA also had lower BGluM in hippocampus than controls. These results corroborate clinical findings and help further examine the mechanisms behind MA

  8. Longitudinal magnetic resonance imaging reveals striatal hypertrophy in a rat model of long-term stimulant treatment.

    PubMed

    Biezonski, D; Shah, R; Krivko, A; Cha, J; Guilfoyle, D N; Hrabe, J; Gerum, S; Xie, S; Duan, Y; Bansal, R; Leventhal, B L; Peterson, B S; Kellendonk, C; Posner, J

    2016-09-06

    Stimulant treatment is highly effective in mitigating symptoms associated with attention-deficit/hyperactivity disorder (ADHD), though the neurobiological underpinnings of this effect have not been established. Studies using anatomical magnetic resonance imaging (MRI) in children with ADHD have suggested that long-term stimulant treatment may improve symptoms of ADHD in part by stimulating striatal hypertrophy. This conclusion is limited, however, as these studies have either used cross-sectional sampling or did not assess the impact of treatment length on their dependent measures. We therefore used longitudinal anatomical MRI in a vehicle-controlled study design to confirm causality regarding stimulant effects on striatal morphology in a rodent model of clinically relevant long-term stimulant treatment. Sprague Dawley rats were orally administered either lisdexamfetamine (LDX, 'Vyvanse') or vehicle (N=12 per group) from postnatal day 25 (PD25, young juvenile) until PD95 (young adult), and imaged one day before and one day after the 70-day course of treatment. Our LDX dosing regimen yielded blood levels of dextroamphetamine comparable to those documented in patients. Longitudinal analysis of striatal volume revealed significant hypertrophy in LDX-treated animals when compared to vehicle-treated controls, with a significant treatment by time point interaction. These findings confirm a causal link between long-term stimulant treatment and striatal hypertrophy, and support utility of longitudinal MRI in rodents as a translational approach for bridging preclinical and clinical research. Having demonstrated comparable morphological effects in both humans and rodents using the same imaging technology, future studies may now use this rodent model to identify the underlying cellular mechanisms and behavioral consequences of stimulant-induced striatal hypertrophy.

  9. Mitochondrial impairment induced by 3-nitropropionic acid is enhanced by endogenous metalloprotease activity inhibition in cultured rat striatal neurons.

    PubMed

    de Oca Balderas, Pavel Montes; Ospina, Gabriel Gutiérrez; Del Ángel, Abel Santamaría

    2013-06-24

    Metalloproteases from the metzincin family mediate molecule processing at the cell membrane termed ectodomain shedding (ES). This mechanism enables the generation of intracellular and extracellular fragments from cell membrane molecules that exert additional functions involved in cell processes including cell death, beyond those of full length molecules. Micotoxin 3-nitropropionic acid (3-NP) induces striatal neuronal degeneration in vivo and in vitro through mitochondrial complex II inhibition. In this study, we hypothesized that metalloproteases regulate mitochondrial activity in cultured rat striatal neurons undergoing degeneration. To test this idea, striatal neuronal cultures characterized by NeuN and GAD-67 expression were treated with 3-NP together with the metalloprotease inhibitor GM6001 and their mitochondrial activity was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Our results showed that metalloprotease inhibition potentiated mitochondrial activity impairment induced by 3-NP whereas the inhibitor alone had no effect. These results indicate that metalloproteases regulate and promote mitochondrial functionality in striatal neurons undergoing degeneration induced by 3-NP. Since NMDA receptor is involved in the excitotoxic neuronal death triggered by 3-NP and is known to undergo ES, we analyzed NMDAR subunit NR1 phenotypic distribution by immunofluorescence. 3-NP and GM6001 induced abnormal perinuclear NR1 accumulation that was not observed with 3-NP or GM6001 alone. This observation suggests that metalloproteases are involved in NR1 cellular reorganization induced by 3-NP, and that their inhibition results in abnormal NR1 distribution. Together results indicate that endogenous metalloproteases are activated during striatal neurodegeneration induced by 3-NP eliciting an adaptative or compensatory response that protects mitochondrial functionality.

  10. Longitudinal magnetic resonance imaging reveals striatal hypertrophy in a rat model of long-term stimulant treatment

    PubMed Central

    Biezonski, D; Shah, R; Krivko, A; Cha, J; Guilfoyle, D N; Hrabe, J; Gerum, S; Xie, S; Duan, Y; Bansal, R; Leventhal, B L; Peterson, B S; Kellendonk, C; Posner, J

    2016-01-01

    Stimulant treatment is highly effective in mitigating symptoms associated with attention-deficit/hyperactivity disorder (ADHD), though the neurobiological underpinnings of this effect have not been established. Studies using anatomical magnetic resonance imaging (MRI) in children with ADHD have suggested that long-term stimulant treatment may improve symptoms of ADHD in part by stimulating striatal hypertrophy. This conclusion is limited, however, as these studies have either used cross-sectional sampling or did not assess the impact of treatment length on their dependent measures. We therefore used longitudinal anatomical MRI in a vehicle-controlled study design to confirm causality regarding stimulant effects on striatal morphology in a rodent model of clinically relevant long-term stimulant treatment. Sprague Dawley rats were orally administered either lisdexamfetamine (LDX, ‘Vyvanse') or vehicle (N=12 per group) from postnatal day 25 (PD25, young juvenile) until PD95 (young adult), and imaged one day before and one day after the 70-day course of treatment. Our LDX dosing regimen yielded blood levels of dextroamphetamine comparable to those documented in patients. Longitudinal analysis of striatal volume revealed significant hypertrophy in LDX-treated animals when compared to vehicle-treated controls, with a significant treatment by time point interaction. These findings confirm a causal link between long-term stimulant treatment and striatal hypertrophy, and support utility of longitudinal MRI in rodents as a translational approach for bridging preclinical and clinical research. Having demonstrated comparable morphological effects in both humans and rodents using the same imaging technology, future studies may now use this rodent model to identify the underlying cellular mechanisms and behavioral consequences of stimulant-induced striatal hypertrophy. PMID:27598968

  11. Effects of delayed treatment with nebracetam on neurotransmitters in brain regions after microsphere embolism in rats

    PubMed Central

    Takeo, Satoshi; Hayashi, Hideki; Miyake, Keiko; Takagi, Kaori; Tadokoro, Mina; Takagi, Norio; Oshikawa, Sayuri

    1997-01-01

    The effects of delayed treatment with nebracetam, a novel nootropic drug, on neurotransmitters of brain regions were examined in rats with microsphere embolism-induced cerebral ischaemia. Cerebral ischaemia was induced by administration of 900 microspheres (48 μm) into the internal carotid artery. The rats with stroke-like symptoms were treated p.o. with 30 mg kg−1 nebracetam twice daily. The levels of acetylcholine, dopamine, noradrenaline, 5-hydroxytryptamine (5-HT) and their metabolites in the cerebral cortex, striatum and hippocampus of animals with microsphere embolism were determined by high performance liquid chromatography (h.p.l.c.) on the 3rd and 7th days after the operation. Although the microsphere embolism induced significant changes in most of the neurotransmitters and some of their metabolites in the brain regions, the delayed treatment with nebracetam partially restored only the hippocampal 5-HT and the striatal dopamine metabolite contents on the 3rd day. The hippocampal in vivo 5-HT synthesis, but not the striatal dopamine synthesis, was attenuated in rats with microsphere embolism on the 3rd day, but was restored by treatment with nebracetam. In vivo striatal dopamine turnover rate of the rats with microsphere embolism was inhibited on the 3rd day irrespective of treatment with nebracetam. The present study provides evidence for a possible action of nebracetam on 5-HT metabolism in the ischaemic brain. PMID:9179389

  12. 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.

  13. Striatal cholinergic functional alterations in hypoxic neonatal rats: role of glucose, oxygen, and epinephrine resuscitation.

    PubMed

    Anju, T R; Paulose, C S

    2013-10-01

    Molecular processes regulating cholinergic functions play an important role in the control of respiration under hypoxia. Cholinergic alterations and its further complications in respiration due to hypoxic insult in neonatal rats and the effect of glucose, oxygen, and epinephrine resuscitation was evaluated in the present study. Receptor binding and gene expression studies were done in the corpus striatum to analyse the changes in total muscarinic receptors, muscarinic M1, M2, M3 receptors, and the enzymes involved in acetylcholine metabolism, choline acetyltransferase and acetylcholinesterase. Neonatal hypoxia decreased total muscarinic receptors with reduced expression of muscarinic M1, M2, and M3 receptor genes. The reduction in acetylcholine metabolism is indicated by the downregulated choline acetyltransferase and upregulated acetyl cholinesterase expression. These cholinergic disturbances were reversed to near control in glucose-resuscitated hypoxic neonates. The adverse effects of immediate oxygenation and epinephrine administration are also reported. The present findings points to the cholinergic alterations due to neonatal hypoxic shock and suggests a proper resuscitation method to ameliorate these striatal changes.

  14. Release of (/sup 3/H)-monoamines from superfused rat striatal slices by methylenedioxymethamphetamine (MDMA)

    SciTech Connect

    Levin, J.A.; Schmidt, C.J.; Lovenberg, W.

    1986-03-05

    MDMA is a phenylisopropylamine which is reported to have unique behavioral effects in man. Because of its structural similarities to the amphetamines the authors have compared the effects of MDMA and two related amphetamines on the spontaneous release of tritiated dopamine (DA) and serotonin (5HT) from superfused rat striatal slices. At concentrations of 10/sup -7/ - 10/sup -5/M MDMA and the serotonergic neurotoxin, p-chloroamphetamine, were equipotent releasers of (/sup 3/H)5HT being approximately 10x more potent than methamphetamine. However, methamphetamine was the more potent releaser of (/sup 3/H)DA by a factor of approximately 10x. MDMA-induced release of both (/sup 5/H)5HT and (/sup 3/H)DA was Ca/sup 2 +/-independent and inhibited by selective monoamine uptake blockers suggesting a carrier-dependent release mechanism. Synaptosomal uptake experiments with (+)(/sup 3/H)MDMA indicated no specific uptake of the drug further suggesting the effect of uptake blockers may be to inhibit the carrier-mediated export of amines displaced by MDMA.

  15. 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.

  16. Neural differentiation of transplanted neural stem cells in a rat model of striatal lacunar infarction: light and electron microscopic observations

    PubMed Central

    Muñetón-Gómez, Vilma C.; Doncel-Pérez, Ernesto; Fernandez, Ana P.; Serrano, Julia; Pozo-Rodrigálvarez, Andrea; Vellosillo-Huerta, Lara; Taylor, Julian S.; Cardona-Gómez, Gloria P.; Nieto-Sampedro, Manuel; Martínez-Murillo, Ricardo

    2012-01-01

    The increased risk and prevalence of lacunar stroke and Parkinson's disease (PD) makes the search for better experimental models an important requirement for translational research. In this study we assess ischemic damage of the nigrostriatal pathway in a model of lacunar stroke evoked by damaging the perforating arteries in the territory of the substantia nigra (SN) of the rat after stereotaxic administration of endothelin-1 (ET-1), a potent vasoconstrictor peptide. We hypothesized that transplantation of neural stem cells (NSCs) with the capacity of differentiating into diverse cell types such as neurons and glia, but with limited proliferation potential, would constitute an alternative and/or adjuvant therapy for lacunar stroke. These cells showed neuritogenic activity in vitro and a high potential for neural differentiation. Light and electron microscopy immunocytochemistry was used to characterize GFP-positive neurons derived from the transplants. 48 h after ET-1 injection, we characterized an area of selective degeneration of dopaminergic neurons within the nigrostriatal pathway characterized with tissue necrosis and glial scar formation, with subsequent behavioral signs of Parkinsonism. Light microscopy showed that grafted cells within the striatal infarction zone differentiated with a high yield into mature glial cells (GFAP-positive) and neuron types present in the normal striatum. Electron microscopy revealed that NSCs-derived neurons integrated into the host circuitry establishing synaptic contacts, mostly of the asymmetric type. Astrocytes were closely associated with normal small-sized blood vessels in the area of infarct, suggesting a possible role in the regulation of the blood brain barrier and angiogenesis. Our results encourage the use of NSCs as a cell-replacement therapy for the treatment of human vascular Parkinsonism. PMID:22876219

  17. An age-related decline in striatal taurine is correlated with a loss of dopaminergic markers.

    PubMed

    Dawson, R; Pelleymounter, M A; Cullen, M J; Gollub, M; Liu, S

    1999-02-01

    Taurine is present in high concentration in the mammalian brain and is known to decline with aging. The present studies examined the relationship between the loss of striatal neurotransmitters and spatial learning ability in aged male Long-Evans rats. The effects of intrahippocampal infusions of neurotrophic factors-nerve growth factor (NGF) and brain-derived neurotrophic factor-were also examined for their ability to ameliorate the age-related decline in brain amino acid content. Taurine content was found to be significantly reduced in the striatum of aged rats (26 months old) that were impaired in spatial learning performance when compared to young unimpaired rats (5 months old). Aged rats that were behaviorally unimpaired had more modest reductions in taurine. Striatal dopamine content was also significantly reduced in aged learning-impaired rats. There was a significant (p < 0.001) correlation (r=0.61) between the striatal content of taurine and dopamine, but no such correlation was found for other striatal transmitters (glutamate, serotonin, norepinephrine). Treatment with neurotrophins had little effect on the age-related decline in striatal amino acids, although NGF treatment did improve spatial learning. These studies suggest (1) a link between age-related declines in striatal dopamine and taurine and (2) that NGF-induced improvement in spatial learning is not related to mechanisms involving changes in taurine or glutamate content.

  18. Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to coordination defects in mice

    PubMed Central

    Seeher, Sandra; Carlson, Bradley A.; Miniard, Angela C.; Wirth, Eva K.; Mahdi, Yassin; Hatfield, Dolph L.; Driscoll, Donna M.; Schweizer, Ulrich

    2014-01-01

    Selenocysteine Insertion Sequence (SECIS)-Binding Protein 2 (Secisbp2) binds to SECIS elements located in the 3′-untranslated region of eukaryotic selenoprotein mRNAs. It facilitates incorporation of the rare amino acid selenocysteine in response to UGA codons. Inactivation of Secisbp2 in hepatocytes greatly reduced selenoprotein levels. Neuron-specific inactivation of Secisbp2 (CamK-Cre; Secisbp2fl/fl) reduced cerebral expression of selenoproteins to a lesser extent than inactivation of tRNA[Ser]Sec. This allowed us to study the development of cortical parvalbumin-positive (PV+) interneurons, which are completely lost in tRNA[Ser]Sec mutants. PV+ interneuron density was reduced in the somatosensory cortex, hippocampus, and striatum. In situ-hybridization for Gad67 confirmed the reduction of GABAergic interneurons. Because of the obvious movement phenotype involving a broad, dystonic gait, we suspected basal ganglia dysfunction. Tyrosine hydroxylase expression was normal in substantia nigra neurons and their striatal terminals. However the densities of striatal PV+ and Gad67+ neurons were decreased by 65% and 49%, respectively. Likewise, the density of striatal cholinergic neurons was reduced by 68%. Our observations demonstrate that several classes of striatal interneurons depend on selenoprotein expression. These findings may offer an explanation for the movement phenotype of selenoprotein P-deficient mice and the movement disorder and mental retardation described in a patient carrying SECISBP2 mutations. PMID:24844465

  19. Western Diet Chow Consumption in Rats Induces Striatal Neuronal Activation While Reducing Dopamine Levels without Affecting Spatial Memory in the Radial Arm Maze

    PubMed Central

    Nguyen, Jason C. D.; Ali, Saher F.; Kosari, Sepideh; Woodman, Owen L.; Spencer, Sarah J.; Killcross, A. Simon; Jenkins, Trisha A.

    2017-01-01

    Rats fed high fat diets have been shown to be impaired in hippocampal-dependent behavioral tasks, such as spatial recognition in the Y-maze and reference memory in the Morris water maze (MWM). It is clear from previous studies, however, that motivation and reward factor into the memory deficits associated with obesity and high-fat diet consumption, and that the prefrontal cortex and striatum and neurotransmitter dopamine play important roles in cognitive performance. In this series of studies we extend our research to investigate the effect of a high fat diet on striatal neurochemistry and performance in the delayed spatial win-shift radial arm maze task, a paradigm highly reliant on dopamine-rich brain regions, such as the striatum after high fat diet consumption. Memory performance, neuronal activation and brain dopaminergic levels were compared in rats fed a “Western” (21% fat, 0.15% cholesterol) chow diet compared to normal diet (6% fat, 0.15% cholesterol)-fed controls. Twelve weeks of dietary manipulation produced an increase in weight in western diet-fed rats, but did not affect learning and performance in the delayed spatial win-shift radial arm maze task. Concurrently, there was an observed decrease in dopamine levels in the striatum and a reduction of dopamine turnover in the hippocampus in western diet-fed rats. In a separate cohort of rats Fos levels were measured after rats had been placed in a novel arena and allowed to explore freely. In normal rats, this exposure to a unique environment did not affect neuronal activation. In contrast, rats fed a western diet were found to have significantly increased Fos expression in the striatum, but not prefrontal cortex or hippocampus. Our study demonstrates that while western diet consumption in rats produces weight gain and brain neuronal and neurotransmitter changes, it did not affect performance in the delayed spatial win-shift paradigm in the radial arm maze. We conclude that modeling the cognitive

  20. Western Diet Chow Consumption in Rats Induces Striatal Neuronal Activation While Reducing Dopamine Levels without Affecting Spatial Memory in the Radial Arm Maze.

    PubMed

    Nguyen, Jason C D; Ali, Saher F; Kosari, Sepideh; Woodman, Owen L; Spencer, Sarah J; Killcross, A Simon; Jenkins, Trisha A

    2017-01-01

    Rats fed high fat diets have been shown to be impaired in hippocampal-dependent behavioral tasks, such as spatial recognition in the Y-maze and reference memory in the Morris water maze (MWM). It is clear from previous studies, however, that motivation and reward factor into the memory deficits associated with obesity and high-fat diet consumption, and that the prefrontal cortex and striatum and neurotransmitter dopamine play important roles in cognitive performance. In this series of studies we extend our research to investigate the effect of a high fat diet on striatal neurochemistry and performance in the delayed spatial win-shift radial arm maze task, a paradigm highly reliant on dopamine-rich brain regions, such as the striatum after high fat diet consumption. Memory performance, neuronal activation and brain dopaminergic levels were compared in rats fed a "Western" (21% fat, 0.15% cholesterol) chow diet compared to normal diet (6% fat, 0.15% cholesterol)-fed controls. Twelve weeks of dietary manipulation produced an increase in weight in western diet-fed rats, but did not affect learning and performance in the delayed spatial win-shift radial arm maze task. Concurrently, there was an observed decrease in dopamine levels in the striatum and a reduction of dopamine turnover in the hippocampus in western diet-fed rats. In a separate cohort of rats Fos levels were measured after rats had been placed in a novel arena and allowed to explore freely. In normal rats, this exposure to a unique environment did not affect neuronal activation. In contrast, rats fed a western diet were found to have significantly increased Fos expression in the striatum, but not prefrontal cortex or hippocampus. Our study demonstrates that while western diet consumption in rats produces weight gain and brain neuronal and neurotransmitter changes, it did not affect performance in the delayed spatial win-shift paradigm in the radial arm maze. We conclude that modeling the cognitive decline

  1. Marked differences in the number and type of synapses innervating the somata and primary dendrites of midbrain dopaminergic neurons, striatal cholinergic interneurons, and striatal spiny projection neurons in the rat.

    PubMed

    Sizemore, Rachel J; Zhang, Rong; Lin, Naili; Goddard, Liping; Wastney, Timothy; Parr-Brownlie, Louise C; Reynolds, John N J; Oorschot, Dorothy E

    2016-04-01

    Elucidating the link between cellular activity and goal-directed behavior requires a fuller understanding of the mechanisms underlying burst firing in midbrain dopaminergic neurons and those that suppress activity during aversive or non-rewarding events. We have characterized the afferent synaptic connections onto these neurons in the rat substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA), and compared these findings with cholinergic interneurons and spiny projection neurons in the striatum. We found that the average absolute number of synapses was three to three and one-half times greater onto the somata of dorsal striatal spiny projection neurons than onto the somata of dopaminergic neurons in the SNpc or dorsal striatal cholinergic interneurons. A similar comparison between populations of dopamine neurons revealed a two times greater number of somatic synapses on VTA dopaminergic neurons than SNpc dopaminergic neurons. The percentage of symmetrical, presumably inhibitory, synaptic inputs on somata was significantly higher on spiny projection neurons and cholinergic interneurons compared with SNpc dopaminergic neurons. Synaptic data on the primary dendrites yielded similar significant differences for the percentage of symmetrical synapses for VTA dopaminergic vs. striatal neurons. No differences in the absolute number or type of somatic synapses were evident for dopaminergic neurons in the SNpc of Wistar vs. Sprague-Dawley rat strains. These data from identified neurons are pivotal for interpreting their electrophysiological responses to afferent activity and for generating realistic computer models of neuronal networks of striatal and midbrain dopaminergic function.

  2. 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.

  3. 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.

  4. Prenatal ethanol enhances rotational behavior to apomorphine in the 24-month-old rat offspring with small striatal lesion.

    PubMed

    Gomide, Vânia C; Chadi, Gerson

    2004-01-01

    Pregnant Wistar rats received a hyperproteic liquid diet containing 37.5% ethanol-derived calories during gestation. Isocaloric amount of liquid diet, with maltose-dextrin substituted for ethanol, was given to control pair-fed dams. Offsprings were allowed to survive until 24 months of age. A set of aged female offsprings of both control diet and ethanol diet groups was registered for spontaneous motor activity, by means of an infrared motion sensor activity monitor, or for apomorphine-induced rotational behavior, while another lot of male offsprings was submitted to an unilateral striatal small mechanical lesion by a needle, 6 days before rotational recordings. Prenatal ethanol did not alter spontaneous motor parameters like resting time as well as the events of small and large movements in the aged offsprings. Bilateral circling behavior was already increased 5 min after apomorphine in the unlesioned offsprings of both the control and ethanol diet groups. However, it lasted more elevated for 45- to 75-min time intervals in the gestational ethanol-exposed offsprings, while decreasing faster in the control offsprings. Apomorphine triggered a strong and sustained elevation of contraversive turns in the striatal-lesioned 24-month-old offsprings of the ethanol group, but only a small and transient elevation was seen in the offsprings of the control diet group. Astroglial and microglial reactions were seen surrounding the striatal needle track lesion. Microdensitometric image analysis demonstrated no differences in the levels of tyrosine hydroxylase immunoreactivity in the striatum of 24-month-old unlesioned and lesioned offsprings of control and alcohol diet groups. The results suggest that ethanol exposure during gestation may alter the sensitivity of dopamine receptor in aged offsprings, which is augmented by even a small striatal lesion.

  5. Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.

    PubMed

    Colle, Dirleise; Santos, Danúbia Bonfanti; Moreira, Eduardo Luiz Gasnhar; Hartwig, Juliana Montagna; dos Santos, Alessandra Antunes; Zimmermann, Luciana Teixeira; Hort, Mariana Appel; Farina, Marcelo

    2013-01-01

    Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD involve oxidative stress and mitochondrial dysfunction. Administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, in rodents has been proposed as a useful experimental model of HD. This study evaluated the effects of probucol, a lipid-lowering agent with anti-inflammatory and antioxidant properties, on the biochemical parameters related to oxidative stress, as well as on the behavioral parameters related to motor function in an in vivo HD model based on 3-NP intoxication in rats. Animals were treated with 3.5 mg/kg of probucol in drinking water daily for 2 months and, subsequently, received 3-NP (25 mg/kg i.p.) once a day for 6 days. At the end of the treatments, 3-NP-treated animals showed a significant decrease in body weight, which corresponded with impairment on motor ability, inhibition of mitochondrial complex II activity and oxidative stress in the striatum. Probucol, which did not rescue complex II inhibition, protected against behavioral and striatal biochemical changes induced by 3-NP, attenuating 3-NP-induced motor impairments and striatal oxidative stress. Importantly, probucol was able to increase activity of glutathione peroxidase (GPx), an enzyme important in mediating the detoxification of peroxides in the central nervous system. The major finding of this study was that probucol protected against 3-NP-induced behavioral and striatal biochemical changes without affecting 3-NP-induced mitochondrial complex II inhibition, indicating that long-term probucol treatment resulted in an increased resistance against neurotoxic events (i.e., increased oxidative damage) secondary to mitochondrial dysfunction. These data appeared to be of great relevance when

  6. Essential fatty acid-rich diets protect against striatal oxidative damage induced by quinolinic acid in rats.

    PubMed

    Morales-Martínez, Adriana; Sánchez-Mendoza, Alicia; Martínez-Lazcano, Juan Carlos; Pineda-Farías, Jorge Baruch; Montes, Sergio; El-Hafidi, Mohammed; Martínez-Gopar, Pablo Eliasib; Tristán-López, Luis; Pérez-Neri, Iván; Zamorano-Carrillo, Absalom; Castro, Nelly; Ríos, Camilo; Pérez-Severiano, Francisca

    2017-09-01

    Essential fatty acids have an important effect on oxidative stress-related diseases. The Huntington's disease (HD) is a hereditary neurologic disorder in which oxidative stress caused by free radicals is an important damage mechanism. The HD experimental model induced by quinolinic acid (QUIN) has been widely used to evaluate therapeutic effects of antioxidant compounds. The aim of this study was to test whether the fatty acid content in olive- or fish-oil-rich diet prevents against QUIN-related oxidative damage in rats. Rats were fed during 20 days with an olive- or a fish-oil-rich diet (15% w/w). Posterior to diet period, rats were striatally microinjected with QUIN (240 nmol/µl) or saline solution. Then, we evaluated the neurological damage, oxidative status, and gamma isoform of the peroxisome proliferator-activated receptor (PPARγ) expression. Results showed that fatty acid-rich diet, mainly by fish oil, reduced circling behavior, prevented the fall in GABA levels, increased PPARγ expression, and prevented oxidative damage in striatal tissue. In addition none of the enriched diets exerted changes neither on triglycerides or cholesterol blood levels, nor or hepatic function. This study suggests that olive- and fish-oil-rich diets exert neuroprotective effects.

  7. Association between striatal dopamine D2/D3 receptors and brain activation during visual attention: effects of sleep deprivation.

    PubMed

    Tomasi, D; Wang, G-J; Volkow, N D

    2016-05-31

    Sleep deprivation (SD) disrupts dopamine (DA) signaling and impairs attention. However, the interpretation of these concomitant effects requires a better understanding of dopamine's role in attention processing. Here we test the hypotheses that D2/D3 receptors (D2/D3R) in dorsal and ventral striatum would distinctly regulate the activation of attention regions and that, by decreasing D2/D3, SD would disrupt these associations. We measured striatal D2/D3R using positron emission tomography with [(11)C]raclopride and brain activation to a visual attention (VA) task using 4-Tesla functional magnetic resonance imaging. Fourteen healthy men were studied during rested wakefulness and also during SD. Increased D2/D3R in striatum (caudate, putamen and ventral striatum) were linearly associated with higher thalamic activation. Subjects with higher D2/D3R in caudate relative to ventral striatum had higher activation in superior parietal cortex and ventral precuneus, and those with higher D2/D3R in putamen relative to ventral striatum had higher activation in anterior cingulate. SD impaired the association between striatal D2/D3R and VA-induced thalamic activation, which is essential for alertness. Findings suggest a robust DAergic modulation of cortical activation during the VA task, such that D2/D3R in dorsal striatum counterbalanced the stimulatory influence of D2/D3R in ventral striatum, which was not significantly disrupted by SD. In contrast, SD disrupted thalamic activation, which did not show counterbalanced DAergic modulation but a positive association with D2/D3R in both dorsal and ventral striatum. The counterbalanced dorsal versus ventral striatal DAergic modulation of VA activation mirrors similar findings during sensorimotor processing (Tomasi et al., 2015) suggesting a bidirectional influence in signaling between the dorsal caudate and putamen and the ventral striatum.

  8. Association between striatal dopamine D2/D3 receptors and brain activation during visual attention: effects of sleep deprivation

    PubMed Central

    Tomasi, D; Wang, G-J; Volkow, N D

    2016-01-01

    Sleep deprivation (SD) disrupts dopamine (DA) signaling and impairs attention. However, the interpretation of these concomitant effects requires a better understanding of dopamine's role in attention processing. Here we test the hypotheses that D2/D3 receptors (D2/D3R) in dorsal and ventral striatum would distinctly regulate the activation of attention regions and that, by decreasing D2/D3, SD would disrupt these associations. We measured striatal D2/D3R using positron emission tomography with [11C]raclopride and brain activation to a visual attention (VA) task using 4-Tesla functional magnetic resonance imaging. Fourteen healthy men were studied during rested wakefulness and also during SD. Increased D2/D3R in striatum (caudate, putamen and ventral striatum) were linearly associated with higher thalamic activation. Subjects with higher D2/D3R in caudate relative to ventral striatum had higher activation in superior parietal cortex and ventral precuneus, and those with higher D2/D3R in putamen relative to ventral striatum had higher activation in anterior cingulate. SD impaired the association between striatal D2/D3R and VA-induced thalamic activation, which is essential for alertness. Findings suggest a robust DAergic modulation of cortical activation during the VA task, such that D2/D3R in dorsal striatum counterbalanced the stimulatory influence of D2/D3R in ventral striatum, which was not significantly disrupted by SD. In contrast, SD disrupted thalamic activation, which did not show counterbalanced DAergic modulation but a positive association with D2/D3R in both dorsal and ventral striatum. The counterbalanced dorsal versus ventral striatal DAergic modulation of VA activation mirrors similar findings during sensorimotor processing (Tomasi et al., 2015) suggesting a bidirectional influence in signaling between the dorsal caudate and putamen and the ventral striatum. PMID:27219347

  9. 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

  10. Behavioural inflexibility in a comorbid rat model of striatal ischemic injury and mutant hAPP overexpression.

    PubMed

    Levit, Alexander; Regis, Aaron M; Garabon, Jessica R; Oh, Seung-Hun; Desai, Sagar J; Rajakumar, Nagalingam; Hachinski, Vladimir; Agca, Yuksel; Agca, Cansu; Whitehead, Shawn N; Allman, Brian L

    2017-08-30

    Alzheimer disease (AD) and stroke coexist and interact; yet how they interact is not sufficiently understood. Both AD and basal ganglia stroke can impair behavioural flexibility, which can be reliably modeled in rats using an established operant based set-shifting test. Transgenic Fischer 344-APP21 rats (TgF344) overexpress pathogenic human amyloid precursor protein (hAPP) but do not spontaneously develop overt pathology, hence TgF344 rats can be used to model the effect of vascular injury in the prodromal stages of Alzheimer disease. We demonstrate that the injection of endothelin-1 (ET1) into the dorsal striatum of TgF344 rats (Tg-ET1) produced an exacerbation of behavioural inflexibility with a behavioural phenotype that was distinct from saline-injected wildtype & TgF344 rats as well as ET1-injected wildtype rats (Wt-ET1). In addition to profiling the types of errors made, interpolative modeling using logistic exposure-response regression provided an informative analysis of the timing and efficiency of behavioural flexibility. During set-shifting, Tg-ET1 committed fewer perseverative errors than Wt-ET1. However, Tg-ET1 committed significantly more regressive errors and had a less efficient strategy change than all other groups. Thus, behavioural flexibility was more vulnerable to striatal ischemic injury in TgF344 rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. 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.

  12. Effect of cocaine on striatal dopamine clearance in a rat model of developmental stress and attention-deficit/hyperactivity disorder.

    PubMed

    Womersley, Jacqueline S; Kellaway, Lauriston A; Stein, Dan J; Gerhardt, Greg A; Russell, Vivienne A

    2016-01-01

    Attention-deficit/hyperactivity disorder (ADHD) and developmental stress are considered risk factors for the development of drug abuse. Though the physiological mechanisms underlying this risk are not yet clear, ADHD, developmental stress and drug abuse are known to share underlying disturbances in dopaminergic neurotransmission. Thus, we hypothesized that clearance of cocaine-induced elevations in striatal dopamine would be prolonged in a rat model of ADHD and that this would be further increased by exposure to developmental stress. In the current study, male spontaneously hypertensive rats (SHRs), a well-validated model of ADHD, and control Wistar-Kyoto (WKY) rats were exposed to either standard rearing (nMS) or a maternal separation (MS) paradigm involving removal of the pups from the dam for 180 min/day over 13 days. This produced a 2 × 2 factorial design (SHR/WKY × nMS/MS) with 5-6 rats/group. Striatal clearance of exogenously applied dopamine was measured via in vivo chronoamperometry, and the difference in dopamine uptake parameters before and after cocaine administration was compared between experimental groups. Cocaine, a potent dopamine transporter inhibitor, reliably increased the clearance time of dopamine though no difference in this parameter was found between SHR and WKY strains. However, developmental stress elevated the cocaine-induced increase in time to clear 50% of exogenously applied dopamine (T50) in SHR but had no effect in WKY rats. These findings suggest that a strain × environment interaction prolongs elevated levels of dopamine thereby potentially increasing the rewarding properties of this drug in SHR.

  13. Stereological assessment of vulnerability of immunocytochemically identified striatal and hippocampal neurons after global cerebral ischemia in rats.

    PubMed

    Larsson, E; Lindvall, O; Kokaia, Z

    2001-09-21

    Detailed quantitative analysis of the vulnerability of different hippocampal and striatal neurons to global forebrain ischemia has not previously been performed. Here we have studied the survival of immunocytochemically identified neurons using an unbiased stereological method in rats subjected to global forebrain ischemia for 30 min and sacrificed 48 h, 1 week or 4 weeks thereafter. Within the hippocampal formation, there was extensive, progressive loss of CA1 pyramidal neurons and dentate hilar neuropeptide Y (NPY)-positive interneurons. In contrast, no reduction of the number of CA3 and CA4 pyramidal neurons or hilar parvalbumin-positive interneurons was detected. In the dorsolateral striatum, the insult caused a major loss of projection neurons immunoreactive to dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein with a molecular weight of 32 kilodalton (DARPP-32). The number of parvalbumin-positive striatal interneurons was significantly reduced, while NPY-positive interneurons were resistant. All striatal cholinergic interneurons survived the ischemic insult. At 48 h following the ischemia, the cholinergic interneurons within the lesioned striatum transiently expressed the p75 neurotrophin receptor (p75(NTR)), as shown by double-label immunocytochemistry. Furthermore, there was a significant increase in the number of choline acetyltransferase (ChAT)- and TrkA-immunoreactive interneurons at 4 weeks after the insult. Injections with the cell mitotic division marker BrdU provided no evidence that the elevated cholinergic cell number was due to neurogenesis. Probably, the higher number of ChAT- and TrkA-positive interneurons reflected increased intracellular levels of the corresponding proteins leading to more cells detectable with immunocytochemistry. This study gives the first quantitative description of the vulnerability of defined hippocampal and striatal neurons after global forebrain ischemia. The ischemia-induced increases of p75(NTR), Trk

  14. The effects of apomorphine and D-amphetamine on striatal c-Fos expression in Sprague-Dawley and Long Evans rats and their F1 progeny.

    PubMed

    Saint Marie, Richard L; Neary, Alaina C; Shoemaker, Jody M; Swerdlow, Neal R

    2006-11-13

    We previously reported that Sprague-Dawley (SD) rats are significantly more sensitive than Long Evans (LE) rats to disruption of prepulse inhibition (PPI) of the startle reflex by the dopamine agonists, apomorphine (APO) and D-amphetamine (AMPH). This susceptibility is inherited through F1 (SD x LE) and N2 backcross (F1 x SD) generations via an orderly pattern (SD>N2>F1>LE). Here we examined systemic APO (0.5 mg/kg) and AMPH (4.5 mg/kg) modulation of neural activity in four regions of the striatum suspected to be involved in the dopaminergic regulation of PPI - dorsolateral (dlCPu) and medial (mCPu) caudate/putamen and core (NACc) and medial shell (NACms) regions of nucleus accumbens - under conditions that mimicked those used to assess PPI. Immunohistochemical quantification of c-Fos protein expression was used as the surrogate measure of neural activity in SD and LE rats and their F1 crosses. Vehicle-treatment showed significant regional differences in Fos expression, particularly between the dlCPu and the other three areas, but no strain-related differences were observed. Three of four brain areas examined (dlCPu, mCPu and NACc) exhibited drug-induced changes in Fos expression--APO decreased and AMPH increased Fos expression in each region. The aggregate effect across these three regions revealed Fos expression to be significantly greater in LE compared to SD rats for both drugs, with F1 rats intermediate. This pattern of inheritance (LE>F1>SD) reveals an inverse relationship between striatal Fos expression and PPI sensitivity for these drugs; and a positive relationship with reported heritable differences in D2-linked G-protein binding in the CPu and NACc, and with locomotor activation/suppression by AMPH and APO.

  15. Dissecting striatal adenosine-cannabinoid receptor interactions. New clues from rats over-expressing adenosine A2A receptors.

    PubMed

    Ferré, Sergi; Sebastião, Ana Maria

    2016-03-01

    This Editorial highlights a study by Chiodi et al. () showing that the effects mediated by cannabinoid CB1 receptor (CB1R) activation in the striatum are significantly reduced in rats with neuronal over-expression of adenosine A2A receptors (A2AR). Two hypotheses are derived from that study. Hypothesis A: two subpopulations of pre-synaptic CB1R in corticostriatal glutamatergic terminals exist, one forming and another not forming heteromers with A2AR. Hypothesis B: CB1R are predominantly forming heteromers with A2AR. In the case of hypothesis A, the A2AR might be required for CB1R-A2AR heteromeric signaling, whereas non-heteromeric CB1R activity is inhibited by A2ARs. In the case of hypothesis B, up-regulation of A2ARs may perturb heteromeric stoichiometry, thus reducing CB1R functioning. In any case, pre-synaptic striatal A2AR-CB1R heteromers emerge as important targets of the effects of cannabinoids demonstrated at the neuronal and behavioral level. Read the highlighted article 'Striatal adenosine-cannabinoid receptor interactions in rats over-expressing adenosine A2A receptors' on page 907. © 2016 International Society for Neurochemistry.

  16. Osteopontin: correlation with phagocytosis by brain macrophages in a rat model of stroke.

    PubMed

    Shin, Yoo-Jin; Kim, Hong Lim; Choi, Jeong-Sun; Choi, Jae-Youn; Cha, Jung-Ho; Lee, Mun-Yong

    2011-03-01

    Osteopontin (OPN) is an adhesive glycoprotein linked to a variety of pathophysiological processes. We investigated whether OPN might act as an opsonin in the diseased brain by studying the postischemic expression and localization of OPN mRNA and protein in a rat model of ischemic stroke. In addition, we characterized the subcellular localization of OPN protein in the ischemic brain core. Induction of OPN mRNA occurred in activated microglia/macrophages in the ischemic core on days 3-7 after reperfusion and this was sustained up to day 28, at least. OPN protein was synthesized and secreted by brain macrophages, which first surrounded damaged striatal white matter tracts and then infiltrated into them. Punctate OPN-immunoreactive profiles were scattered throughout the infarction core except in white matter bundles. Electron microscopy showed the localization of OPN protein along the membranes lining what appeared to be the debris of dead neurons. These were located in the extracellular space and within the cytoplasm of brain macrophages, indicating that the OPN protein accumulated selectively on the surface of dead cells, most of which were phagocytosed subsequently by brain macrophages. However, no significant induction of OPN occurred in degenerating striatal white matter tracts or in brain macrophage-engulfed axonic or myelin debris. These data suggest that OPN secreted by brain macrophages in this rat model of stroke might be involved in the phagocytosis of fragmented cell debris and possibly not in the phagocytosis of axonic or myelin debris. Copyright © 2010 Wiley-Liss, Inc.

  17. Amelioration of hypoxia-induced striatal 5-HT(2A) receptor, 5-HT transporter and HIF1 alterations by glucose, oxygen and epinephrine in neonatal rats.

    PubMed

    Anju, T R; Paulose, C S

    2011-09-20

    Alterations in neurotransmitters and its receptors expression induce brain injury during neonatal hypoxic insult. Molecular processes regulating the serotonergic receptors play an important role in the control of respiration under hypoxic insult. The present study focused on the serotonergic regulation of neonatal hypoxia and its resuscitation methods. Receptor binding assays and gene expression studies were done to evaluate the changes in 5HT(2A) receptors and its transporter in the corpus striatum of hypoxic neonatal rats and hypoxic rats resuscitated with glucose, oxygen and epinephrine. Total 5HT and 5HT(2A) receptor number was increased in hypoxic neonates along with an up regulation of 5HT(2A) receptor and 5HT transporter gene. The enhanced striatal 5HT(2A) receptors modulate the ventilatory response to hypoxia. Immediate glucose resuscitation was found to ameliorate the receptor and transporter alterations. Hypoxia induced ATP depletion mediated reduction in blood glucose levels can be encountered by glucose administration and oxygenation helps in overcoming the anaerobic condition. The adverse effect of immediate oxygenation and epinephrine supplementation was also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia.

  18. Large-Scale, Ion-Current-Based Proteomic Investigation of the Rat Striatal Proteome in a Model of Short- and Long-Term Cocaine Withdrawal.

    PubMed

    Shen, Shichen; Jiang, Xiaosheng; Li, Jun; Straubinger, Robert M; Suarez, Mauricio; Tu, Chengjian; Duan, Xiaotao; Thompson, Alexis C; Qu, Jun

    2016-05-06

    Given the tremendous detriments of cocaine dependence, effective diagnosis and patient stratification are critical for successful intervention yet difficult to achieve due to the largely unknown molecular mechanisms involved. To obtain new insights into cocaine dependence and withdrawal, we employed a reproducible, reliable, and large-scale proteomics approach to investigate the striatal proteomes of rats (n = 40, 10 per group) subjected to chronic cocaine exposure, followed by either short- (WD1) or long- (WD22) term withdrawal. By implementing a surfactant-aided precipitation/on-pellet digestion procedure, a reproducible and sensitive nanoLC-Orbitrap MS analysis, and an optimized ion-current-based MS1 quantification pipeline, >2000 nonredundant proteins were quantified confidently without missing data in any replicate. Although cocaine was cleared from the body, 129/37 altered proteins were observed in WD1/WD22 that are implicated in several biological processes related closely to drug-induced neuroplasticity. Although many of these changes recapitulate the findings from independent studies reported over the last two decades, some novel insights were obtained and further validated by immunoassays. For example, significantly elevated striatal protein kinase C activity persisted over the 22 day cocaine withdrawal. Cofilin-1 activity was up-regulated in WD1 and down-regulated in WD22. These discoveries suggest potentially distinct structural plasticity after short- and long-term cocaine withdrawal. In addition, this study provides compelling evidence that blood vessel narrowing, a long-known effect of cocaine use, occurred after long-term but not short-term withdrawal. In summary, this work developed a well-optimized paradigm for ion-current-based quantitative proteomics in brain tissues and obtained novel insights into molecular alterations in the striatum following cocaine exposure and withdrawal.

  19. Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

    PubMed Central

    Izquierdo, Alicia; Pozos, Hilda; De La Torre, Adrianna; DeShields, Simone; Cevallos, James; Rodriguez, Jonathan; Stolyarova, Alexandra

    2016-01-01

    Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner. PMID:27091300

  20. Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats.

    PubMed

    Izquierdo, Alicia; Pozos, Hilda; Torre, Adrianna De La; DeShields, Simone; Cevallos, James; Rodriguez, Jonathan; Stolyarova, Alexandra

    2016-07-15

    Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Functional circuit mapping of striatal output nuclei using simultaneous deep brain stimulation and fMRI.

    PubMed

    Van Den Berge, Nathalie; Albaugh, Daniel L; Salzwedel, Andrew; Vanhove, Christian; Van Holen, Roel; Gao, Wei; Stuber, Garret D; Ian Shih, Yen-Yu

    2017-02-01

    The substantia nigra pars reticulata (SNr) and external globus pallidus (GPe) constitute the two major output targets of the rodent striatum. Both the SNr and GPe converge upon thalamic relay nuclei (directly or indirectly, respectively), and are traditionally modeled as functionally antagonistic relay inputs. However, recent anatomical and functional studies have identified unanticipated circuit connectivity in both the SNr and GPe, demonstrating their potential as far more than relay nuclei. In the present study, we employed simultaneous deep brain stimulation and functional magnetic resonance imaging (DBS-fMRI) with cerebral blood volume (CBV) measurements to functionally and unbiasedly map the circuit- and network level connectivity of the SNr and GPe. Sprague-Dawley rats were implanted with a custom-made MR-compatible stimulating electrode in the right SNr (n=6) or GPe (n=7). SNr- and GPe-DBS, conducted across a wide range of stimulation frequencies, revealed a number of surprising evoked responses, including unexpected CBV decreases within the striatum during DBS at either target, as well as GPe-DBS-evoked positive modulation of frontal cortex. Functional connectivity MRI revealed global modulation of neural networks during DBS at either target, sensitive to stimulation frequency and readily reversed following cessation of stimulation. This work thus contributes to a growing literature demonstrating extensive and unanticipated functional connectivity among basal ganglia nuclei.

  2. Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata.

    PubMed

    Staal, R G; Sonsalla, P K

    2000-05-01

    Dopamine neurons from various animal species differ in sensitivity to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP(+)). Compared with striatal vesicles isolated from mice, those from rats have a higher density of the brain vesicular monoamine transporter (VMAT2) and a greater ability to sequester MPP(+), suggesting a larger storage capacity for MPP(+) in rat vesicles. In the present study, we examined whether striatal VMAT2-containing vesicles might provide protection against the neurotoxic effects of MPP(+) in vivo. Dose-response curves for striatally infused MPP(+) were determined in animals pretreated with or without a VMAT2 inhibitor. Ro 4-1284 administration (10 mg/kg i.p.; VMAT2 inhibitor) produced a 5-fold leftward shift in the MPP(+) dose-response curve and a significant lowering of the EC(50) concentration for MPP(+)-induced damage. These findings provide evidence for a substantial accumulation of MPP(+) in VMAT2-containing vesicles in vivo in the rat striatum and support the hypothesis that MPP(+) sequestration in vesicles can provide protection against its toxic actions. In mice, VMAT2 inhibition did not reliably enhance toxicity produced by a striatal infusion of MPP(+) or by systemic administration of MPTP. These data suggest that vesicular sequestration of MPP(+) may be of less importance in mice than in rats as relates to protection from the toxin. The present results also reveal that although VMAT2 inhibition enhanced striatal MPP(+) toxicity in the rat, the potency of MPP(+) in the rat striatum was less than that in mouse striatum. This implies that there are other factors that either exacerbate MPP(+) toxicity in the mouse or attenuate MPP(+) toxicity in rats.

  3. Striatal 5-HT1A receptor stimulation reduces D1 receptor-induced dyskinesia and improves movement in the hemiparkinsonian rat

    PubMed Central

    Dupre, Kristin B.; Eskow, Karen L.; Barnum, Christopher J.; Bishop, Christopher

    2008-01-01

    Summary Convergent evidence suggests that serotonin 5-HT1A receptor (5-HT1AR) agonists reduce L-DOPA-induced dyskinesia by auto-regulating aberrant release of L-DOPA-derived dopamine (DA) from raphestriatal neurons. However, recent findings indicate that 5-HT1AR stimulation also modifies D1 receptor (D1R)-mediated dyskinesia and rotations implicating a previously unexplored extra-raphe mechanism. In order to characterize the contribution of the striatum to these effects, rats with medial forebrain bundle DA lesions were tested for abnormal involuntary movements (AIMs) and rotations following striatal microinfusions of the 5-HT1AR agonist ±8-OH-DPAT and systemic D1R agonist treatment with SKF81297. Additional rats with multi-site striatal DA lesions were tested for motor disability following systemic or intrastriatal ±8-OH-DPAT with or without systemic SKF81297. In rats with medial forebrain bundle lesions, striatal infusions of ±8-OH-DPAT dose-dependently reduced AIMs while conversely increasing rotations. In rats with striatal lesions, ±8-OH-DPAT alone, both systemic and intrastriatal administration, optimally reversed motor disability. Collectively, these results support an important functional interaction between 5-HT1AR and D1R in the striatum with implications for the improved treatment of Parkinson’s disease. PMID:18824001

  4. Brain neuronal chromatin responses in acute soman intoxicated rats.

    PubMed

    Martin, L J; Doebler, J A; Wall, T J; Shih, T M; Anthony, A

    1986-08-01

    Male Sprague-Dawley rats (200 g) were injected subcutaneously with soman, a potent neuronal acetylcholinesterase (AChE) inhibitor, at doses of 0.5, 0.8 and 1.0 LD50 (1 LD50 = 135 micrograms/kg) before decapitation at 1 and 24 h post-exposure. Correlative data were obtained on the severity of brain AChE inactivation and physicochemical changes in nuclear chromatin of cerebrocortical (layer V) and striatal neurons using Feulgen-DNA (F-DNA) cytophotometry and ocular filar micrometry. Decreased lability of neurons to F-DNA acid hydrolysis (reduced F-DNA yield), nuclear shrinkage and chromatin aggregation (decreased chromophore area) were used as indices of suppression of genomic template activity; conversely, increases in F-DNA yield and chromophore area signify enhanced neuroexcitation. At 1 hr post-soman there was a dose-dependent inactivation of AChE with a moderate increase in chromatin activation, i.e., nuclear hypertrophy and chromatin dispersion. At 24 hr post-soman there was a partial restoration of AChE activity, notably in striatal neurons, with a suppression in chromatin template activity. These data indicate that actions of soman on neuronal functioning are time-dependent. The absence of any dose-related neuronal chromatin changes may signify existence of non-cholinergic mediated events.

  5. Individual Differences in Cue-Induced Motivation and Striatal Systems in Rats Susceptible to Diet-Induced Obesity.

    PubMed

    Robinson, Mike J F; Burghardt, Paul R; Patterson, Christa M; Nobile, Cameron W; Akil, Huda; Watson, Stanley J; Berridge, Kent C; Ferrario, Carrie R

    2015-08-01

    Pavlovian cues associated with junk-foods (caloric, highly sweet, and/or fatty foods), like the smell of brownies, can elicit craving to eat and increase the amount of food consumed. People who are more susceptible to these motivational effects of food cues may have a higher risk for becoming obese. Further, overconsumption of junk-foods leading to the development of obesity may itself heighten attraction to food cues. Here, we used a model of individual susceptibility to junk-foods diet-induced obesity to determine whether there are pre-existing and/or diet-induced increases in attraction to and motivation for sucrose-paired cues (ie, incentive salience or 'wanting'). We also assessed diet- vs obesity-associated alterations in mesolimbic function and receptor expression. We found that rats susceptible to diet-induced obesity displayed heightened conditioned approach prior to the development of obesity. In addition, after junk-food diet exposure, those rats that developed obesity also showed increased willingness to gain access to a sucrose cue. Heightened 'wanting' was not due to individual differences in the hedonic impact ('liking') of sucrose. Neurobiologically, Mu opioid receptor mRNA expression was lower in striatal 'hot-spots' that generate eating or hedonic impact only in those rats that became obese. In contrast, prolonged exposure to junk-food resulted in cross-sensitization to amphetamine-induced locomotion and downregulation of striatal D2R mRNA regardless of the development of obesity. Together these data shed light on individual differences in behavioral and neurobiological consequences of exposure to junk-food diets and the potential contribution of incentive sensitization in susceptible individuals to greater food cue-triggered motivation.

  6. Individual Differences in Cue-Induced Motivation and Striatal Systems in Rats Susceptible to Diet-Induced Obesity

    PubMed Central

    Robinson, Mike JF; Burghardt, Paul R; Patterson, Christa M; Nobile, Cameron W; Akil, Huda; Watson, Stanley J; Berridge, Kent C; Ferrario, Carrie R

    2015-01-01

    Pavlovian cues associated with junk-foods (caloric, highly sweet, and/or fatty foods), like the smell of brownies, can elicit craving to eat and increase the amount of food consumed. People who are more susceptible to these motivational effects of food cues may have a higher risk for becoming obese. Further, overconsumption of junk-foods leading to the development of obesity may itself heighten attraction to food cues. Here, we used a model of individual susceptibility to junk-foods diet-induced obesity to determine whether there are pre-existing and/or diet-induced increases in attraction to and motivation for sucrose-paired cues (ie, incentive salience or ‘wanting’). We also assessed diet- vs obesity-associated alterations in mesolimbic function and receptor expression. We found that rats susceptible to diet-induced obesity displayed heightened conditioned approach prior to the development of obesity. In addition, after junk-food diet exposure, those rats that developed obesity also showed increased willingness to gain access to a sucrose cue. Heightened ‘wanting’ was not due to individual differences in the hedonic impact (‘liking’) of sucrose. Neurobiologically, Mu opioid receptor mRNA expression was lower in striatal ‘hot-spots’ that generate eating or hedonic impact only in those rats that became obese. In contrast, prolonged exposure to junk-food resulted in cross-sensitization to amphetamine-induced locomotion and downregulation of striatal D2R mRNA regardless of the development of obesity. Together these data shed light on individual differences in behavioral and neurobiological consequences of exposure to junk-food diets and the potential contribution of incentive sensitization in susceptible individuals to greater food cue-triggered motivation. PMID:25761571

  7. STRIATAL NEUROPROTECTION WITH METHYLENE BLUE

    PubMed Central

    Rojas, Julio C.; Simola, Nicola; Kermath, Bailey A.; Kane, Jacqueline R.; Schallert, Timothy; Gonzalez-Lima, F.

    2009-01-01

    Recent literature indicates that low-dose methylene blue (MB), an autoxidizable dye with powerful antioxidant and metabolic enhancing properties, might prevent neurotoxin-induced neural damage and associated functional deficits. This study evaluated whether local MB may counteract the anatomical and functional effects of the intrastriatal infusion of the neurotoxin rotenone in the rat. To this end, stereological analyses of striatal lesion volumes were performed and changes in oxidative energy metabolism in the striatum and related motor regions were mapped using cytochrome oxidase histochemistry. The influence of MB on striatal levels of oxidative stress induced by rotenone was determined, and behavioral tests were used to investigate the effect of unilateral MB co-administration on motor asymmetry. Rotenone induced large anatomical lesions resembling “metabolic strokes”, whose size was greatly reduced in MB-treated rats. Moreover, MB prevented the decrease in cytochrome oxidase activity and the perilesional increase in oxidative stress associated with rotenone infusion in the striatum. MB also prevented the indirect effects of the rotenone-induced lesion on cytochrome oxidase activity in related motor regions, such as the striatal regions rostral and caudal to the lesion, the substantia nigra compacta and reticulata, and the pedunculopontine nucleus. At a network level, MB maintained a global strengthening of functional connectivity in basal ganglia-thalamocortical motor circuits, as opposed to the functional decoupling observed in rotenone-alone subjects. Finally, MB partially prevented the behavioral sensorimotor asymmetries elicited by rotenone. These results are consistent with protective effects of MB against neurotoxic damage in the brain parenchyma. This study provides the first demonstration of the anatomical, metabolic and behavioral neuroprotective effects of MB in the striatum in vivo, and supports the notion that MB could be a valuable

  8. Neuroblast proliferation on the surface of the adult rat striatal wall after focal ependymal loss by intracerebroventricular injection of neuraminidase.

    PubMed

    Del Carmen Gómez-Roldán, María; Pérez-Martín, Margarita; Capilla-González, Vivian; Cifuentes, Manuel; Pérez, Juan; García-Verdugo, Jose Manuel; Fernández-Llebrez, Pedro

    2008-04-01

    The subventricular zone of the striatal wall of adult rodents is an active neurogenic region for life. Cubic multiciliated ependyma separates the subventricular zone from the cerebrospinal fluid (CSF) and is involved in the control of adult neurogenesis. By injecting neuraminidase from Clostridium perfringens into the right lateral ventricle of the rat, we provoked a partial detachment of the ependyma in the striatal wall. The contralateral ventricle was never affected and was used as the experimental control. Neuraminidase caused widening of the intercellular spaces among some ependymal cells and their subsequent detachment and disintegration in the CSF. Partial ependymal denudation was followed by infiltration of the CSF with macrophages and neutrophils from the local choroid plexus, which ependymal cells never detached after neuraminidase administration. Inflammation extended toward the periventricular parenchyma. The ependymal cells that did not detach and remained in the ventricle wall never proliferated. The lost ependyma was never recovered, and ependymal cells never behaved as neural stem cells. Instead, a scar formed by overlapping astrocytic processes sealed those regions devoid of ependyma. Some ependymal cells at the border of the denudated areas lost contact with the ventricle and became located under the glial layer. Concomitantly with scar formation, some subependymal cells protruded toward the ventricle through the ependymal breaks, proliferated, and formed clusters of rounded ventricular cells that expressed the phenotype of neuroblasts. Ventricular clusters of neuroblasts remained in the ventricle up to 90 days after injection. In the subventricular zone, adult neurogenesis persisted.

  9. Quantitative gait analysis of long-term locomotion deficits in classical unilateral striatal intracerebral hemorrhage rat model.

    PubMed

    Liu, Yao; Ao, Li Juan; Lu, Gang; Leong, Elizabeth; Liu, Qiang; Wang, Xiao Hong; Zhu, Xian Lun; Sun, Tin Fung David; Fei, Zhou; Jiu, Tian; Hu, Xiang; Poon, Wai Sang

    2013-11-15

    Gait analysis is a systematic collection of quantitative information on bodily movements during locomotion. Gait analysis has been employed clinically in stroke patients for their rehabilitation planning. In animal studies, gait analysis has been employed for the assessment of their locomotive disturbances in ischemic stroke, spinal cord injury and Parkinson's disease. The aims of the work reported here were to identify the gait parameters, collected from the computer-generated CatWalk System, that change after unilateral intracerebral hemorrhage (ICH) in the acute stage and long term up to 56 days post-ICH. The results showed that with the collagenase-induced unilateral striatal lesion, the rats displayed a significant contralateral decrease in print and maximum contact area and paw intensity, a diagonal increase in the stance duration of the left front and right hind paws, a significant decrease in the stride length of all four limbs, and foot pattern instability as reflected by the base of support, support on styles, and cadence. These deficits, including those in print area, stance and pressure, were demonstrated throughout the long-term period following ICH. The correlations between the gait parameters, lesion volume and asymmetrical forelimb use were also reported in this paper. This work has provided a systematic description on gait parameters in the classical striatal ICH model, which might become an essential assessment tool in future studies of pathophysiology and the development of novel treatments for experimental unilateral intracerebral hemorrhage with gait deficits.

  10. Effect of ethanol on (/sup 3/H)dopamine release in rat nucleus accumbens and striatal slices

    SciTech Connect

    Russell, V.A.; Lamm, M.C.; Taljaard, J.J.

    1988-05-01

    Ethanol (10-200 mM) transiently increased tritium overflow from superfused rat nucleus accumbens slices previously incubated with (/sup 3/H)dopamine (DA) and (/sup 14/C)choline. The effect was greater in striatal tissue and did not appear to be a non-specific membrane effect since (/sup 14/C)acetylcholine (ACh) release was not affected. Lack of antagonism by picrotoxin suggested that gamma-aminobutyric acid (GABA) receptors were not involved. Calcium was not a requirement and the DA uptake blocker, nomifensine, was without effect. Ethanol appeared to be causing (/sup 3/H)DA release into the cytoplasm. K+ -stimulated release of (/sup 3/H)DA and (/sup 14/C)ACh from nucleus accumbens and striatal slices was not affected. Clonidine-mediated inhibition of the K+-evoked release of (/sup 3/H)DA remained unaltered. Ethanol attenuated the isoproterenol-induced enhancement of (/sup 3/H)DA release. Ethanol therefore appeared to interact with components of the DA terminal causing a transient increase in the release of neurotransmitter without impairing K+-evoked release but apparently interfering with the isoproterenol-induced effect.

  11. Inhibition of ( sup 3 H)dopamine uptake into rat striatal slices by quaternary N-methylated nicotine metabolites

    SciTech Connect

    Dwoskin, L.P.; Leibee, L.L.; Jewell, A.L.; Fang, Zhaoxia; Crooks, P.A. )

    1992-01-01

    The effects of quaternary N-methylated nicotine derivatives were examined on in vitro uptake of ({sup 3}H)dopamine (({sup 3}H)DA) in rat striatal slices. Striatal slices were incubated with a 10 {mu}M concentration of the following compounds: N-methylnicotinium, N-methylnornicotinium, N-methylcotininium, N,N{prime}-dimethylnicotinium and N{prime}-methylnicotinium salts. The results clearly indicated that significant inhibition of ({sup 3}H)DA uptake occurred with those compounds possessing a N-methylpyridinium group; whereas, compounds that were methylated at the N{prime}-pyrrolidinium position were less effective or exhibited no inhibition of ({sup 3}H)DA uptake. The results suggest that high concentrations of quaternary N-methylated nicotine metabolites which are structurally related to the neurotoxin MPP{sup +}, and which may be formed in the CNS, may protect against Parkinson's Disease and explain the inverse relationship between smoking and Parkinsonism reported in epidemiologic studies.

  12. Obesity and frontal-striatal brain structures in offspring of individuals with bipolar disorder: Results from the global mood and brain science initiative.

    PubMed

    Mansur, Rodrigo B; McIntyre, Roger S; Cao, Bo; Lee, Yena; Japiassú, Letícia; Chen, Kun; Lu, Rui; Lu, Weicong; Chen, Xiaodong; Li, Ting; Xu, Guiyun; Lin, Kangguang

    2017-09-25

    To compare frontal-striatal brain volumes between offspring of individuals with bipolar disorder (BD) and healthy controls; to investigate the associations of body mass index (BMI) and age with brain volumes; and to assess the moderating effects of BMI and age on the relationship between risk status and structural brain differences. We cross-sectionally assessed structural regional and global brain volumes using magnetic resonance imaging and BMI among 53 BD offspring subjects, stratified by risk status, and 23 non-BD offspring controls (aged 8-28 years). Analyses of variance and covariance and linear regression analyses were conducted to investigate the associations between BMI and measures of brain volume, as well as the interaction effects between age, BMI, and risk status on brain volumes. After adjusting for age, sex, and intracranial volume, higher BD risk status was associated with lower bilateral cerebellar cortical and right pars orbitalis volumes. Higher BMI was significantly associated with greater brain volumes in frontal and subcortical structures. A significant interaction effect between BMI and risk status was observed in right middle frontal volume. The moderating effect of BMI on brain volume was most robustly observed among subjects aged 14-19 years and less robustly observed among those aged 20-28 years; BMI and brain volumes were negatively correlated among subjects aged 8-13 years. Alterations in brain structures in individuals at risk for BD may be moderated by BMI. Obesity among individuals with a family history of BD may confer additional risk, particularly in mid-adolescence. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains

    PubMed Central

    Bai, Guang; Cheung, Iris; Shulha, Hennady P.; Coelho, Joana E.; Li, Ping; Dong, Xianjun; Jakovcevski, Mira; Wang, Yumei; Grigorenko, Anastasia; Jiang, Yan; Hoss, Andrew; Patel, Krupal; Zheng, Ming; Rogaev, Evgeny; Myers, Richard H.; Weng, Zhiping; Akbarian, Schahram; Chen, Jiang-Fan

    2015-01-01

    To investigate epigenetic contributions to Huntington's disease (HD) pathogenesis, we carried out genome-wide mapping of the transcriptional mark, trimethyl-histone H3-lysine 4 (H3K4me3) in neuronal nuclei extracted from prefrontal cortex of HD cases and controls using chromatin immunoprecipitation followed by deep-sequencing. Neuron-specific mapping of the genome-wide distribution of H3K4me3 revealed 136 differentially enriched loci associated with genes implicated in neuronal development and neurodegeneration, including GPR3, TMEM106B, PDIA6 and the Notch signaling genes hairy and enhancer of split 4 (HES4) and JAGGED2, supporting the view that the neuronal epigenome is affected in HD. Importantly, loss of H3K4me3 at CpG-rich sequences on the HES4 promoter was associated with excessive DNA methylation, reduced binding of nuclear proteins to the methylated region and altered expression of HES4 and HES4 targeted genes MASH1 and P21 involved in striatal development. Moreover, hypermethylation of HES4 promoter sequences was strikingly correlated with measures of striatal degeneration and age-of-onset in a cohort of 25 HD brains (r = 0.56, P = 0.006). Lastly, shRNA knockdown of HES4 in human neuroblastoma cells altered MASH1 and P21 mRNA expression and markedly increased mutated HTT-induced aggregates and cell death. These findings, taken together, suggest that epigenetic dysregulation of HES4 could play a critical role in modifying HD disease pathogenesis and severity. PMID:25480889

  14. An operant serial implicit learning task (SILT) in rats: task acquisition, performance and the effects of striatal lesions.

    PubMed

    Jay, Julia R; Dunnett, Stephen B

    2007-07-30

    We describe the serial implicit learning task (SILT), a novel test for assessing implicit and procedural learning in rodents, and have used the task to test whether striatal lesions disrupt the speed and accuracy of responding to stimulus-response (S-R) sequences that may be either predictable or unpredictable. In this task, the rats must learn to respond to two consecutive stimulus lights, S1 and S2, which may occur on each trial in any of five alternative response locations, for food reward. For two of the S1 locations, the location of the subsequent S2 is predictable, whereas for the other three S1 locations, the location of S2 is unpredictable and can appear with equal probability in any of the other four locations (i.e. any open hole other than S1 itself). All rats learned to make the serial responses rapidly and accurately. Effective implicit learning was demonstrated by there being a significant advantage in both speed and accuracy in responding to predictable than to unpredictable S2 stimuli. Following quinolinic acid lesions of the medial or lateral striatum, the lesioned rats showed significantly reduced accuracy and increased latencies in responding to both S1 and S2, although (contrary to initial hypothesis) the benefits of predictability of S2 were retained. These data establish a novel and efficient operant test for implicit learning in the rat.

  15. The effects of gestational and chronic atrazine exposure on motor behaviors and striatal dopamine in male Sprague-Dawley rats

    PubMed Central

    Walters, Jennifer L.; Lansdell, Theresa A.; Lookingland, Keith J.; Baker, Lisa E.

    2016-01-01

    This study sought to investigate the effects of environmentally relevant gestational followed by continued chronic exposure to the herbicide, atrazine, on motor function, cognition, and neurochemical indices of nigrostriatal dopamine (DA) activity in male rats. Dams were treated with 100 µg/kg atrazine, 10 mg/kg atrazine, or vehicle on gestational day 1 through postnatal day 21. Upon weaning, male offspring continued daily vehicle or atrazine gavage treatments for an additional six months. Subjects were tested in a series of behavioral assays, and 24 h after the last treatment, tissue samples from the striatum were analyzed for DA and 3,4-dihydroxyphenylacetic acid (DOPAC). At 10 mg/kg, this herbicide was found to produce modest disruptions in motor functioning, and at both dose levels it significantly lowered striatal DA and DOPAC concentrations. These results suggest exposures to atrazine have the potential to disrupt nigrostriatal DA neurons and behaviors associated with motor functioning. PMID:26440580

  16. /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.

  17. 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.

  18. The rat brain hippocampus proteome.

    PubMed

    Fountoulakis, Michael; Tsangaris, George T; Maris, Antony; Lubec, Gert

    2005-05-05

    The hippocampus is crucial in memory storage and retrieval and plays an important role in stress response. In humans, the CA1 area of hippocampus is one of the first brain areas to display pathology in Alzheimer's disease. A comprehensive analysis of the hippocampus proteome has not been accomplished yet. We applied proteomics technologies to construct a two-dimensional database for rat brain hippocampus proteins. Hippocampus samples from eight months old animals were analyzed by two-dimensional electrophoresis and the proteins were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The database comprises 148 different gene products, which are in the majority enzymes, structural proteins and heat shock proteins. It also includes 39 neuron specific gene products. The database may be useful in animal model studies of neurological disorders.

  19. Evaluation of the effects and mechanisms of action of glufosinate, an organophosphate insecticide, on striatal dopamine release by using in vivo microdialysis in freely moving rats.

    PubMed

    Ferreira Nunes, Brenda V; Durán, Rafael; Alfonso, Miguel; de Oliveira, Iris Machado; Ferreira Faro, Lilian R

    2010-10-01

    The purpose of the present work was to assess the effects of glufosinate ammonium (GLA), an aminoacid structurally related to glutamate, on in vivo dopamine (DA) release from rat striatum, using brain microdialysis coupled to HPLC-EC. Intrastriatal administration of GLA produced significant concentration-dependent increases in DA levels. At least two mechanisms can be proposed to explain these increases: GLA could be inducing DA release from synaptic vesicles or producing an inhibition of DA transporter (DAT). Thus, we investigated the effects of GLA under Ca(++)-free condition, and after pretreatment with reserpine and TTX. It was observed that the pretreatment with Ca(++)-free Ringer, reserpine or TTX significantly reduced the DA release induced by GLA. Coinfusion of GLA and nomifensine shows that the GLA-induced DA release did not involve the DAT. These results show that GLA-induced striatal DA release is probably mediated by an exocytotic-, Ca(++)-, action potential-dependent mechanism, being independent of DAT.

  20. Effect of gonadectomy of biochemical indices of striatal dopamine D/sub 1/ and D/sub 2/ receptors, their activity and adaptive response to antipsychotic drug treatment in rat

    SciTech Connect

    Jastrow, T.L.R.

    1987-01-01

    Endogenous gonadal steroids in male and female rats were removed by gonadectomy (Gnx). Striatal D/sub 1/ receptors and their activity were characterized by (/sup 3/H)SCH23390 binding parameters and D/sub 1/ receptor-stimulated adenylate cyclase activity in striatal membranes. Striatal D/sub 2/ receptors and their activity were characterized by (/sup 3/H)sulpiride binding parameters in striatal slices and D/sub 2/ receptor-mediated inhibition of forskolin-activated adenylate cyclase activity in striatal membranes. Sub-chronic D/sub 2/ receptor blockade consisted of the administration of the D/sub 2/ specific antagonist sulpiride (20 mg/kg) or vehicle i.p., 2x daily for 21 days followed by a 3 day drug withdrawal period. Gnx of female rats had no affect on striatal D/sub 1/-stimulated adenylate cyclase activity nor on the striatal D/sub 2/ receptor-mediated inhibition of forskolin-activated adenylate cyclase activity. Sub-chronic sulpiride treatment produced no adaptive changes in D/sub 1/-stimulated adenylate cyclase activity in sham-operated or Gnx female rats. Gnx of male rats produced a statistically significant 10% decrease in striatal (/sup 3/H)SCH23390 binding sites with no change in D/sub 1/-stimulated adenylate cyclase activity and no change in striatal(/sup 3/H)sulpiride binding parameters. Sub-chronic sulpiride treatment of sham-operated male rats produced a desensitization of the striatal D/sub 1/-stimulated adenylate cyclase activity with no change in the number of (/sup 3/H)SCH23390 binding sites and no change in (/sup 3/H)sulpiride binding parameters. Gnx of male rats blocked the development of the striatal D/sub 1/ receptor desensitization response elicited by sub-chronic sulpiride treatment, without affecting striatal (/sup 3/H)SCH23390 or (/sup 3/H)sulpiride binding parameters. We have demonstrated that sub-chronic D/sub 2/ receptor blockade in sham-operated male rats results in the desensitization of striatal D/sub 1/ receptor activity.

  1. Striatal Glutamate and GABA after High Frequency Subthalamic Stimulation in Parkinsonian Rat

    PubMed Central

    Lee, Kyung Jin; Shim, Insop; Sung, Jae Hoon; Hong, Jae Taek; Kim, Il sup; Cho, Chul Bum

    2017-01-01

    Objective High frequency stimulation (HFS) of the subthalamic nucleus (STN) is recognized as an effective treatment of advanced Parkinson’s disease. However, the neurochemical basis of its effects remains unknown. The aim of this study is to investigate the effects of STN HFS in intact and 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rat model on changes of principal neurotransmitters, glutamate, and gamma-aminobutyric acid (GABA) in the striatum. Methods The authors examined extracellular glutamate and GABA change in the striatum on sham group, 6-OHDA group, and 6-OHDA plus deep brain stimulation (DBS) group using microdialysis methods. Results High-pressure liquid chromatography was used to quantify glutamate and GABA. The results show that HFS-STN induces a significant increase of extracellular glutamate and GABA in the striatum of 6-OHDA plus DBS group compared with sham and 6-OHDA group. Conclusion Therefore, the clinical results of STN-HFS are not restricted to the direct STN targets but involve widespread adaptive changes within the basal ganglia. PMID:28264233

  2. Selective A2A receptor antagonist SCH 58261 modulates striatal oxidative stress and alleviates toxicity induced by 3-Nitropropionic acid in male Wistar rats.

    PubMed

    Bortolatto, Cristiani F; Reis, Angélica S; Pinz, Mikaela P; Voss, Guilherme T; Oliveira, Renata L; Vogt, Ane G; Roman, Silvane; Jesse, Cristiano R; Luchese, Cristiane; Wilhelm, Ethel A

    2017-08-09

    The aim of the present study was to investigate the effects of SCH58261, a selective adenosine A2A receptor antagonist, on striatal toxicity induced by 3-nitropropionic acid (3-NP) in rats. The experimental protocol consisted of 10 administrations (once a day) of SCH58261 (0.01 or 0.05 mg/kg/day, intraperitoneal, i.p.). From 7th to 10th day, 3-NP (20 mg/kg/day, i.p.) was injected 1 h after SCH58261 administration. Twenty-four hours after the last 3-NP injection, the body weight gain, locomotor activity (open-field test), motor coordination (rotarod test), striatal succinate dehydrogenase (SDH) activity and parameters linked to striatal oxidative status were evaluated in rats. The marked body weight loss resulting from 3-NP injections in rats was partially protected by SCH 58261 at both doses. SCH 58261 at the highest dose was effective against impairments on motor coordination and locomotor activity induced by 3-NP. SCH 58261 was unable to restore the inhibition of SDH activity caused by 3-NP. In addition, the increase in striatal reactive species (RS) levels, depletion of reduced glutathione (GSH) content and stimulation of glutathione reductase (GR) activity provoked by 3-NP injections were alleviated by both doses of SCH 58261. The highest dose of SCH 58261 was also effective in attenuating the increase of protein carbonyl levels as well as the inhibition of glutathione peroxidase (GPx) activity in rats exposed to 3-NP. Our results revealed that reduction of oxidative stress in rat striatum by adenosine A2A receptor antagonism contributes for alleviating 3-NP-induced toxicity.

  3. Methamphetamine-induced dopamine-independent alterations in striatal gene expression in the 6-hydroxydopamine hemiparkinsonian rats.

    PubMed

    Cadet, Jean Lud; Brannock, Christie; Krasnova, Irina N; Ladenheim, Bruce; McCoy, Michael T; Chou, Jenny; Lehrmann, Elin; Wood, William H; Becker, Kevin G; Wang, Yun

    2010-12-13

    Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle are used extensively as a model of Parkinson's disease. The present experiments sought to identify genes that were affected in the dopamine (DA)-denervated striatum after 6-hydroxydopamine-induced destruction of the nigrostriatal dopaminergic pathway in the rat. We also examined whether a single injection of methamphetamine (METH) (2.5 mg/kg) known to cause changes in gene expression in the normally DA-innervated striatum could still influence striatal gene expression in the absence of DA. Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle resulted in METH-induced rotational behaviors ipsilateral to the lesioned side and total striatal DA depletion on the lesioned side. This injection also caused decrease in striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels. DA depletion was associated with increases in 5-HIAA/5-HT ratios that were potentiated by the METH injection. Microarray analyses revealed changes (±1.7-fold, p<0.025) in the expression of 67 genes on the lesioned side in comparison to the intact side of the saline-treated hemiparkinsonian animals. These include follistatin, neuromedin U, and tachykinin 2 which were up-regulated. METH administration caused increases in the expression of c-fos, Egr1, and Nor-1 on the intact side. On the DA-depleted side, METH administration also increased the expression of 61 genes including Pdgf-d and Cox-2. There were METH-induced changes in 16 genes that were common in the DA-innervated and DA-depleted sides. These include c-fos and Nor-1 which show greater changes on the normal DA side. Thus, the present study documents, for the first time, that METH mediated DA-independent changes in the levels of transcripts of several genes in the DA-denervated striatum. Our results also implicate 5-HT as a potential player in these METH-induced alterations in gene expression because the METH injection also caused

  4. Methamphetamine-Induced Dopamine-Independent Alterations in Striatal Gene Expression in the 6-Hydroxydopamine Hemiparkinsonian Rats

    PubMed Central

    Cadet, Jean Lud; Brannock, Christie; Krasnova, Irina N.; Ladenheim, Bruce; McCoy, Michael T.; Chou, Jenny; Lehrmann, Elin; Wood, William H.; Becker, Kevin G.; Wang, Yun

    2010-01-01

    Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle are used extensively as a model of Parkinson's disease. The present experiments sought to identify genes that were affected in the dopamine (DA)–denervated striatum after 6-hydroxydopamine-induced destruction of the nigrostriatal dopaminergic pathway in the rat. We also examined whether a single injection of methamphetamine (METH) (2.5 mg/kg) known to cause changes in gene expression in the normally DA-innervated striatum could still influence striatal gene expression in the absence of DA. Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle resulted in METH-induced rotational behaviors ipsilateral to the lesioned side and total striatal DA depletion on the lesioned side. This injection also caused decrease in striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels. DA depletion was associated with increases in 5-HIAA/5-HT ratios that were potentiated by the METH injection. Microarray analyses revealed changes (± 1.7-fold, p<0.025) in the expression of 67 genes on the lesioned side in comparison to the intact side of the saline-treated hemiparkinsonian animals. These include follistatin, neuromedin U, and tachykinin 2 which were up-regulated. METH administration caused increases in the expression of c-fos, Egr1, and Nor-1 on the intact side. On the DA-depleted side, METH administration also increased the expression of 61 genes including Pdgf-d and Cox-2. There were METH-induced changes in 16 genes that were common in the DA-innervated and DA-depleted sides. These include c-fos and Nor-1 which show greater changes on the normal DA side. Thus, the present study documents, for the first time, that METH mediated DA-independent changes in the levels of transcripts of several genes in the DA-denervated striatum. Our results also implicate 5-HT as a potential player in these METH-induced alterations in gene expression because the METH injection also

  5. Methylphenidate administration to adolescent rats determines plastic changes on reward-related behavior and striatal gene expression.

    PubMed

    Adriani, Walter; Leo, Damiana; Greco, Dario; Rea, Monica; di Porzio, Umberto; Laviola, Giovanni; Perrone-Capano, Carla

    2006-09-01

    Administration of methylphenidate (MPH, Ritalin) to children with attention deficit hyperactivity disorder (ADHD) is an elective therapy, but raises concerns for public health, due to possible persistent neurobehavioral alterations. Wistar adolescent rats (30 to 46 day old) were administered MPH or saline (SAL) for 16 days, and tested for reward-related and motivational-choice behaviors. When tested in adulthood in a drug-free state, MPH-pretreated animals showed increased choice flexibility and economical efficiency, as well as a dissociation between dampened place conditioning and more marked locomotor sensitization induced by cocaine, compared to SAL-pretreated controls. The striatal complex, a core component of the natural reward system, was collected both at the end of the MPH treatment and in adulthood. Genome-wide expression profiling, followed by RT-PCR validation on independent samples, showed that three members of the postsynaptic-density family and five neurotransmitter receptors were upregulated in the adolescent striatum after subchronic MPH administration. Interestingly, only genes for the kainate 2 subunit of ionotropic glutamate receptor (Grik2, also known as KA2) and the 5-hydroxytryptamine (serotonin) receptor 7 (Htr7) (but not GABA(A) subunits and adrenergic receptor alpha1b) were still upregulated in adulthood. cAMP responsive element-binding protein and Homer 1a transcripts were modulated only as a long-term effect. In summary, our data indicate short-term changes in neural plasticity, suggested by modulation of expression of key genes, and functional changes in striatal circuits. These modifications might in turn trigger enduring changes responsible for the adult neurobehavioral profile, that is, altered processing of incentive values and a modified flexibility/habit balance.

  6. Effects of taurine, homotaurine and GABA on hypothalamic and striatal dopamine metabolism.

    PubMed

    Panula-Lehto, E; Mäkinen, M; Ahtee, L

    1992-07-01

    To elucidate the effects of taurine on hypothalamic and striatal dopaminergic neurotransmission we compared its effects to those of gamma-aminobutyric acid (GABA) and homotaurine (a GABAA-receptor agonist) on hypothalamic and striatal concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and, in the case of striatum, 3-methoxytyramine (3-MT) in rats. In addition, hypothalamic and striatal 5-hydroxytryptamine (5-HT) und 5-hydroxyindoleacetic acid, hypothalamic noradrenaline (NA) and 3-methoxy-4-hydroxyphenylglycol sulfate, and pituitary DA concentrations were also measured. The amino acids were injected into the lateral brain ventricles of conscious male rats in doses of 10 and 36 mumol/rat, and rat were sacrificed 15 and 60 min later, respectively. Homotaurine (by 11%) but not the other two amino acids elevated striatal DA, whereas hypothalamic DA was increased by both taurine (36%) and homotaurine (31%). All three amino acids at 36 mumol elevated striatal DOPAC, homotaurine (51%) more than taurine (31%) or GABA (30%), and hypothalamic DOPAC, both taurine (102%) and homotaurine (82%) clearly more than GABA (34%). Neither striatal nor hypothalamic HVA was altered by any of the amino acids. At 10 mumol the amino acids decreased striatal 3-MT by about 40%. At 36 mumol taurine and homotaurine reduced 3-MT by about 70%, whereas increasing the dose of GABA did not further reduce 3-MT. Both taurine and homotaurine at 36 mumol decreased hypothalamic NA content. Neither hypothalamic nor striatal 5-HT metabolism was altered. In the neurointermediate lobe of the pituitary gland taurine at 10 mumol but not at 36 mumol slightly (20%) increased DA.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Reversal-specific learning impairments after a binge regimen of methamphetamine in rats: possible involvement of striatal dopamine.

    PubMed

    Izquierdo, Alicia; Belcher, Annabelle M; Scott, Lori; Cazares, Victor A; Chen, Jack; O'Dell, Steven J; Malvaez, Melissa; Wu, Tiffany; Marshall, John F

    2010-01-01

    A growing body of evidence indicates that protracted use of methamphetamine (mAMPH) causes long-term impairments in cognitive function in humans. Aside from the widely reported problems with attention, mAMPH users exhibit learning and memory deficits, particularly on tasks requiring response control. Although binge mAMPH administration to animals results in cognitive deficits, few studies have attempted to test behavioral flexibility in animals after mAMPH exposure. The aim of this study was to evaluate whether mAMPH would produce impairments in two tasks assessing flexible responding in rats: a touchscreen-based discrimination-reversal learning task and an attentional set shift task (ASST) based on a hallmark test of executive function in humans, the Wisconsin Card Sort. We treated male Long-Evans rats with a regimen of four injections of 2 mg/kg mAMPH (or vehicle) within a single day, a dosing regimen shown earlier to produce object recognition impairments. We then tested them on (1) reversal learning after pretreatment discrimination learning or (2) the ASST. Early reversal learning accuracy was impaired in mAMPH-treated rats. MAMPH pretreatment also selectively impaired reversal performance during ASST testing, leaving set-shifting performance intact. Postmortem analysis of [(125)I]RTI-55 binding revealed small (10-20%) but significant reductions in striatal dopamine transporters produced by this mAMPH regimen. Together, these results lend new information to the growing field documenting impaired cognition after mAMPH exposure, and constitute a rat model of the widely reported decision-making deficits resulting from mAMPH abuse seen in humans.

  8. P2Y1 receptor modulation of Ca2+-activated K+ currents in medium-sized neurons from neonatal rat striatal slices

    PubMed Central

    Coppi, E.; Pedata, F.

    2012-01-01

    ATP signaling to neurons and glia in the nervous system occurs via activation of both P2Y and P2X receptors. Here, we investigated the effects of P2Y1 receptor stimulation in developing striatal medium-sized neurons using patch-clamp recordings from acute brain slices of 7- and 28-day-old rats. Application of the selective P2Y1 receptor agonist 2-(Methylthio) ADP trisodium salt (2-MeSADP; 250 nM) increased outward K+ currents evoked by a ramp depolarization protocol in voltage-clamp recordings. This effect was observed in 59 out of 82 cells (72%) and was blocked completely by the P2Y1 antagonist, 2′-deoxy-N6-methyl adenosine 3′,5′-diphosphate. The averaged 2-MeSADP-sensitive conductance was fitted by the sum of a linear conductance and a Boltzmann relation, giving one-half activation voltage of −14.2 mV and an equivalent charge of 2.91. The 2MeSADP-mediated effect was sensitive to submillimolar concentrations of tetraethylammonium (TEA; 200 μM), to 200 nM iberiotoxin and to 100 nM apamin, suggesting the involvement of both big and small potassium (BK and SK, respectively) calcium-activated channels. In current-clamp experiments, 2-MeSADP decreased depolarization-evoked action potential (AP) firing in all 26 cells investigated, and this effect was reversed by TEA and by apamin but not by iberiotoxin. We conclude that the stimulation of P2Y1 receptors in developing striatal neurons leads to activation of calcium-activated potassium channels [IK(Ca)] of both BK and SK subtypes, the latter responsible for decreasing the frequency of AP firing in response to current injection. Therefore, P2Y1 signaling leading to activation of IK(Ca) may be important in regulating the activity of medium-sized neurons in the striatum. PMID:22131374

  9. 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

  10. Triple monoamine inhibitor tesofensine decreases food intake, body weight, and striatal dopamine D2/D3 receptor availability in diet-induced obese rats.

    PubMed

    van de Giessen, Elsmarieke; de Bruin, Kora; la Fleur, Susanne E; van den Brink, Wim; Booij, Jan

    2012-04-01

    The novel triple monoamine inhibitor tesofensine blocks dopamine, serotonin and norepinephrine re-uptake and is a promising candidate for the treatment of obesity. Obesity is associated with lower striatal dopamine D2 receptor availability, which may be related to disturbed regulation of food intake. This study assesses the effects of chronic tesofensine treatment on food intake and body weight in association with changes in striatal dopamine D2/D3 receptor (D2/3R) availability of diet-induced obese (DIO) rats. Four groups of 15 DIO rats were randomized to one of the following treatments for 28 days: 1. tesofensine (2.0 mg/kg), 2. vehicle, 3. vehicle+restricted diet isocaloric to caloric intake of group 1, and 4. tesofensine (2.0 mg/kg)+ a treatment-free period of 28 days. Caloric intake and weight gain decreased significantly more in the tesofensine-treated rats compared to vehicle-treated rats, which confirms previous findings. After treatment discontinuation, caloric intake and body weight gain gradually increased again. Tesofensine-treated rats showed significantly lower D2/3R availability in nucleus accumbens and dorsal striatum than both vehicle-treated rats and vehicle-treated rats on restricted isocaloric diet. No correlations were observed between food intake or body weight and D2/3R availability. Thus, chronic tesofensine treatment leads to decreased food intake and weight gain. However, this appears not to be directly related to the decreased striatal D2/3R availability, which is mainly a pharmacological effect.

  11. Phase II antioxidant enzyme activities in brain of male and female ACI rats treated chronically with estradiol.

    PubMed

    Stakhiv, Timothy M; Mesia-Vela, Sonia; Kauffman, Frederick C

    2006-08-09

    Activities of Phase II antioxidant enzymes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), UDP-glucuronosyltransferase (UGT), and phenol sulfotransferase 1A1 (SULT1A1) were measured in brain of August-Copenhagen Irish (ACI) rats exposed chronically to low doses of estradiol (E(2)). ACI rats were selected for study because this strain is highly responsive to treatment with low doses of E(2) as indexed by a high incidence of E(2)-induced mammary tumors compared to other strains. Rats were exposed chronically to 3 mg E(2) contained in cholesterol pellets implanted subcutaneously for 6 weeks. This treatment increased activities of all four enzymes in the striatum of male but not female ACI rats. Blood E(2) levels at time of sacrifice correlated closely with activities of striatal NQO1, GST, and SULT1A1, but not with striatal UGT. NQO1, GST, and SULT1A1 activities in other brain regions including the cortex, cerebellum, and hippocampus were less sensitive to chronic E(2) treatment. NQO1 was primarily localized in vascular elements and neurons and SULT1A1 primarily in neurons and neuropil of control and E(2)-treated rats. Collectively, these results suggest that enhanced expression of NQO1, GST, and SULT1A1 may contribute to the antioxidant effects of E(2) in the striatum, an area of the brain that may be particularly prone to oxidative stress because of its high content of catecholamines.

  12. The BACHD Rat Model of Huntington Disease Shows Signs of Fronto-Striatal Dysfunction in Two Operant Conditioning Tests of Short-Term Memory

    PubMed Central

    Clemensson, Laura Emily; Riess, Olaf; Nguyen, Huu Phuc

    2017-01-01

    The BACHD rat is a recently developed transgenic animal model of Huntington disease, a progressive neurodegenerative disorder characterized by extensive loss of striatal neurons. Cognitive impairments are common among patients, and characterization of similar deficits in animal models of the disease is therefore of interest. The present study assessed the BACHD rats' performance in the delayed alternation and the delayed non-matching to position test, two Skinner box-based tests of short-term memory function. The transgenic rats showed impaired performance in both tests, indicating general problems with handling basic aspects of the tests, while short-term memory appeared to be intact. Similar phenotypes have been found in rats with fronto-striatal lesions, suggesting that Huntington disease-related neuropathology might be present in the BACHD rats. Further analyses indicated that the performance deficit in the delayed alternation test might be due to impaired inhibitory control, which has also been implicated in Huntington disease patients. The study ultimately suggests that the BACHD rats might suffer from neuropathology and cognitive impairments reminiscent of those of Huntington disease patients. PMID:28045968

  13. The BACHD Rat Model of Huntington Disease Shows Signs of Fronto-Striatal Dysfunction in Two Operant Conditioning Tests of Short-Term Memory.

    PubMed

    Clemensson, Erik Karl Håkan; Clemensson, Laura Emily; Riess, Olaf; Nguyen, Huu Phuc

    2017-01-01

    The BACHD rat is a recently developed transgenic animal model of Huntington disease, a progressive neurodegenerative disorder characterized by extensive loss of striatal neurons. Cognitive impairments are common among patients, and characterization of similar deficits in animal models of the disease is therefore of interest. The present study assessed the BACHD rats' performance in the delayed alternation and the delayed non-matching to position test, two Skinner box-based tests of short-term memory function. The transgenic rats showed impaired performance in both tests, indicating general problems with handling basic aspects of the tests, while short-term memory appeared to be intact. Similar phenotypes have been found in rats with fronto-striatal lesions, suggesting that Huntington disease-related neuropathology might be present in the BACHD rats. Further analyses indicated that the performance deficit in the delayed alternation test might be due to impaired inhibitory control, which has also been implicated in Huntington disease patients. The study ultimately suggests that the BACHD rats might suffer from neuropathology and cognitive impairments reminiscent of those of Huntington disease patients.

  14. Development of dopamine and N-methyl-D-aspartate systems in rat brain: the effect of prenatal phencyclidine exposure.

    PubMed

    Ali, S F; Holson, R R; Newport, G D; Slikker, W; Bowyer, J F

    1993-05-21

    Phencyclidine (PCP) inhibits the uptake of the neurotransmitter dopamine (DA), and blocks N-methyl-D-aspartate (NMDA) receptor-regulated ion channels. PCP also binds to sigma receptors in vivo and in vitro in rat brain. Prolonged exposure to PCP in adults has been observed to reduce the number of PCP binding sites in brain. We designed these experiments to evaluate whether prolonged prenatal exposure to PCP produces alterations in the development of DA and NMDA systems in brain. To do so, we characterized the normal course of development of basal and stimulated DA release in striatal slices, the ontogeny of striatal DA concentrations, and the development of NMDA receptor channels and associated glutamate binding sites in frontal cortex. We compared these developmental profiles to those in rats exposed to prenatal PCP, in an attempt to characterize the effect of prenatal PCP exposure on the pattern of brain development. Pregnant CD rats were injected s.c. with either 0, 10 or 20 mg/kg PCP daily on gestational days 8 through 20. On postnatal days (PND) 8, 21, 45, or 100, rats were sacrificed and brain tissues isolated for in vitro assessment. In vitro [3H]DA release from striatal slices evoked by either 40 microM glutamate or 15 mM K+ increased over 250% from PND 8 to PND 45, and glutamate-stimulated release was still significantly below adult levels at PND 45. In contrast, D-methamphetamine (D-METH)-evoked [3H]DA release, frontal cortical glutamate binding sites and NMDA channels developed early, reaching adult levels on or before PND 21.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Nonequilibrium Calcium Dynamics Regulate the Autonomous Firing Pattern of Rat Striatal Cholinergic Interneurons

    PubMed Central

    Goldberg, Joshua A.; Teagarden, Mark A.; Foehring, Robert C.; Wilson, Charles J.

    2009-01-01

    Striatal cholinergic interneurons discharge rhythmically in two patterns associated with different afterhyperpolarization timescales, each dictated by a different calcium-dependent potassium current. Single spiking depends on a medium-duration afterhyperpolarization (mAHP) generated by rapid SK currents that are associated with N-type calcium channels. Periodic bursting is driven by a delayed and slowly decaying afterhyperpolarization (sAHP) current associated with L-type channels. Using calcium imaging we show that the calcium transients underlying these currents exhibit two corresponding timescales throughout the somatodendritic tree. This result is not consistent with spatial compartmentalization of calcium entering through the two calcium channels and acting on the two potassium currents, or with differences in channel gating kinetics of the calcium dependent potassium currents. Instead, we show that nonequilibrium dynamics of calcium redistribution among cytoplasmic binding sites with different calcium binding kinetics can give rise to multiple timescales within the same cytoplasmic volume. The resulting independence of mAHP and sAHP currents allows cytoplasmic calcium to control two different and incompatible firing patterns (single spiking or bursting and pausing), depending on whether calcium influx is pulsatile or sustained. During irregular firing, calcium entry at both timescales can be detected, suggesting that an interaction between the medium and slow calcium-dependent afterhyperpolarizations may underlie this firing pattern. PMID:19571130

  16. Nonequilibrium calcium dynamics regulate the autonomous firing pattern of rat striatal cholinergic interneurons.

    PubMed

    Goldberg, Joshua A; Teagarden, Mark A; Foehring, Robert C; Wilson, Charles J

    2009-07-01

    Striatal cholinergic interneurons discharge rhythmically in two patterns associated with different afterhyperpolarization timescales, each dictated by a different calcium-dependent potassium current. Single spiking depends on a medium-duration afterhyperpolarization (mAHP) generated by rapid SK currents that are associated with N-type calcium channels. Periodic bursting is driven by a delayed and slowly decaying afterhyperpolarization (sAHP) current associated with L-type channels. Using calcium imaging we show that the calcium transients underlying these currents exhibit two corresponding timescales throughout the somatodendritic tree. This result is not consistent with spatial compartmentalization of calcium entering through the two calcium channels and acting on the two potassium currents, or with differences in channel gating kinetics of the calcium dependent potassium currents. Instead, we show that nonequilibrium dynamics of calcium redistribution among cytoplasmic binding sites with different calcium binding kinetics can give rise to multiple timescales within the same cytoplasmic volume. The resulting independence of mAHP and sAHP currents allows cytoplasmic calcium to control two different and incompatible firing patterns (single spiking or bursting and pausing), depending on whether calcium influx is pulsatile or sustained. During irregular firing, calcium entry at both timescales can be detected, suggesting that an interaction between the medium and slow calcium-dependent afterhyperpolarizations may underlie this firing pattern.

  17. Modified brain death model for rats.

    PubMed

    Zhang, Shuijun; Cao, Shengli; Wang, Tao; Yan, Bing; Lu, Yantao; Zhao, Yongfu

    2014-10-01

    Experimental animal models of brain death that mimic human conditions may be useful for investigating novel strategies that increase quality and quantity of organs for transplant. Brain death was induced by increasing intracranial pressure by inflating an intracranial placed balloon catheter. Brain death was confirmed by flatline electroencephalogram, physical signs of apnea, and absence of brain stem reflexes. Donor management was done after brain death. Intracranial pressure and physiologic variables were continually monitored during 9 hours' follow-up. Ninety percent of brain dead animals showed typical signs of brain death such as diabetes insipidus, hypertensive, and hypotensive periods. Donor care was performed for 9 hours after brain death, and the mean arterial pressure was maintained above 60 mm Hg. We conclude that the rat model of brain death can be performed in a standardized, reproducible, and successful way.

  18. Lithium normalizes amphetamine-induced changes in striatal FoxO1 phosphorylation and behaviors in rats.

    PubMed

    Zheng, Wenhua; Zeng, Zhiwen; Bhardwaj, Sanjeev K; Jamali, Sara; Srivastava, Lalit K

    2013-07-10

    Administration of the psychostimulant drug amphetamine (AMPH) to animals causes hyperactivity and deficit in prepulse inhibition (PPI) of startle, behaviors that are often observed in neuropsychiatric disorders such as schizophrenia and bipolar disorder. Enhanced central dopamine (DA) transmission is believed to mediate AMPH-induced behavioral alterations. Lithium, a drug used primarily in the treatment of bipolar disorder, is reported to interact with the DA system and antagonize some DA-related behaviors. Here, we provide evidence that AMPH and lithium reciprocally regulate the activity of the transcription factor forkhead box, class O1 (FoxO1), a downstream target of Akt. Administration of d-AMPH (3 mg/kg, intraperitoneally) to Sprague-Dawley rats resulted in a concomitant decrease in levels of phosphorylated (p) Akt as well as p-FoxO1 in the striatum, whereas lithium chloride (LiCl,100 mg/kg, intraperitoneally) exerted the opposite effect, that is, it increased levels of p-Akt and p-FoxO1. Pretreatment of animals with lithium prevented an AMPH-induced decrease in striatal p-Akt and p-FoxO1 levels. Pretreatment of animals with lithium also attenuated AMPH-induced locomotor activity and decreased prepulse inhibition. These in-vivo data suggest that the Akt-FoxO1 pathway may be a common target for the action of dopaminergic and antidopaminergic drugs, and its modulation may be relevant to the treatment of neuropsychiatric disorders.

  19. Modulation of catecholamine release from rat striatal slices by the fixed combination of aspirin, paracetamol and caffeine.

    PubMed

    Fiebich, Bernd L; Candelario-Jalil, Eduardo; Mantovani, Michela; Heinzmann, Marcus; Akundi, Ravi Shankar; Hüll, Michael; Knörle, Rainer; Schnierle, Peter; Finkenzeller, Günter; Aicher, Bernhard

    2006-04-01

    The fixed combination of aspirin, paracetamol (acetaminophen) and caffeine has been used successfully to treat different kinds of pain including migraine attacks. Even when this formulation has been marketed for a long time, the exact molecular mechanisms underlying its therapeutic effectiveness have not been completely elucidated. In the present investigation, we have studied the effects of the fixed combination of aspirin, paracetamol and caffeine (APC) on the release of dopamine and noradrenaline from rat striatal slices in an attempt to find potential new mechanisms of action of this widely used analgesic combination. We found that APC produced a significant reduction in extracellular dopamine and a dramatic increase in norepinephrine release from the slices incubated with different concentrations of APC (dose relationship 1:1:0.2, corresponding to the dose-relationship of Thomapyrin). These findings suggest that the modulation of catecholaminergic neurotransmission is a new pharmacological effect of APC which could explain the mechanism of action of this formulation, considering that the independent effect of either compound alone does not explain the potent antinociceptive properties when observed in combination.

  20. The effects of gestational and chronic atrazine exposure on motor behaviors and striatal dopamine in male Sprague-Dawley rats.

    PubMed

    Walters, Jennifer L; Lansdell, Theresa A; Lookingland, Keith J; Baker, Lisa E

    2015-12-01

    This study sought to investigate the effects of environmentally relevant gestational followed by continued chronic exposure to the herbicide, atrazine, on motor function, cognition, and neurochemical indices of nigrostriatal dopamine (DA) activity in male rats. Dams were treated with 100 μg/kg atrazine, 10mg/kg atrazine, or vehicle on gestational day 1 through postnatal day 21. Upon weaning, male offspring continued daily vehicle or atrazine gavage treatments for an additional six months. Subjects were tested in a series of behavioral assays, and 24h after the last treatment, tissue samples from the striatum were analyzed for DA and 3,4-dihydroxyphenylacetic acid (DOPAC). At 10mg/kg, this herbicide was found to produce modest disruptions in motor functioning, and at both dose levels it significantly lowered striatal DA and DOPAC concentrations. These results suggest that exposures to atrazine have the potential to disrupt nigrostriatal DA neurons and behaviors associated with motor functioning. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Preserving cortico-striatal function: deep brain stimulation in Huntington's disease.

    PubMed

    Nagel, Sean J; Machado, Andre G; Gale, John T; Lobel, Darlene A; Pandya, Mayur

    2015-01-01

    Huntington's disease (HD) is an incurable neurodegenerative disease characterized by the triad of chorea, cognitive dysfunction and psychiatric disturbances. Since the discovery of the HD gene, the pathogenesis has been outlined, but to date a cure has not been found. Disease modifying therapies are needed desperately to improve function, alleviate suffering, and provide hope for symptomatic patients. Deep brain stimulation (DBS), a proven therapy for managing the symptoms of some neurodegenerative movement disorders, including Parkinson's disease, has been reported as a palliative treatment in select cases of HD with debilitating chorea with variable success. New insights into the mechanism of action of DBS suggest it may have the potential to circumvent other manifestations of HD including cognitive deterioration. Furthermore, because DBS is already widely used, reversible, and has a risk profile that is relatively low, new studies can be initiated. In this article we contend that new clinical trials be considered to test the effects of DBS for HD.

  2. Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain.

    PubMed

    Volkow, N D; Wang, G-J; Logan, J; Alexoff, D; Fowler, J S; Thanos, P K; Wong, C; Casado, V; Ferre, S; Tomasi, D

    2015-04-14

    Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [(11)C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors.

  3. Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain

    PubMed Central

    Volkow, N D; Wang, G-J; Logan, J; Alexoff, D; Fowler, J S; Thanos, P K; Wong, C; Casado, V; Ferre, S; Tomasi, D

    2015-01-01

    Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [11C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors. PMID:25871974

  4. Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain

    DOE PAGES

    Volkow, N. D.; Wang, G. -J.; Logan, J.; ...

    2015-04-14

    Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [11C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release inmore » striatum in 20 healthy controls. Caffeine (300mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). Furthermore, the association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors.« less

  5. The effects of endomorphins and diprotin A on striatal dopamine release induced by electrical stimulation-an in vitro superfusion study in rats.

    PubMed

    Bagosi, Zsolt; Jászberényi, Miklós; Bujdosó, Erika; Szabó, Gyula; Telegdy, Gyula

    2006-12-01

    The endomorphins (EM1: Tyr-Pro-Trp-Phe-NH2, and EM2: Tyr-Pro-Phe-Phe-NH2) are recently discovered endogenous ligands for mu-opioid receptors (MORs) with role of neurotransmitters or neuromodulators in mammals. Cessation of their physiological action may be effected through rapid enzymatic degradation by the dipeptidyl-peptidase IV (DPPIV) found in the brain synaptic membranes. An in vitro superfusion system was utilized to investigate the actions of EM1, EM2 and specific DPPIV inhibitor diprotin A on the striatal release of dopamine (DA) induced by electrical stimulation in rats. The involvement of the different MORs (MOR1 and MOR2) in this process was studied by pretreatment with MOR antagonists beta-funaltrexamine (a MOR1 and MOR2 antagonist) and naloxonazine (a MOR1 antagonist). EM1 significantly increased the tritium-labelled dopamine DA release induced by electrical stimulation. EM2 was effective only when the slices were pretreated with diprotin A. beta-Funaltrexamine antagonized the stimulatory effects of both EM1 and EM2. The administration of naloxonazine did not appreciably influence the action of EM1, but blocked the action of EM2, at least when the slices were pretreated with diprotin A. These data suggest that both EM1 and EM2 increase DA release from the striatum and, though diprotin A does not affect the action of EM1, it inhibits the enzymatic degradation of EM2. The DA-stimulating action induced by EM1 seems to be mediated by MOR2, while that evoked by EM2 appears to be transmitted by MOR1.

  6. Reductions in calcium uptake induced in rat brain synaptosomes by ionizing radiation

    SciTech Connect

    Kandasamy, S.B.; Howerton, T.C.; Hunt, W.A. )

    1991-02-01

    Gamma irradiation (60Co) reduced KCl-stimulated voltage-dependent 45Ca2+ uptake in whole-brain, cortical, and striatal synaptosomes. The time course (3, 10, 30, and 60 s) of calcium uptake by irradiated (3 Gy) and nonirradiated synaptosomes, as well as the effect of KCl (15-65 mM), was measured in whole-brain synaptosomes. The fastest and highest rate of depolarization-dependent calcium uptake occurred at 3 s with 65 mM KCl. Irradiation reduced calcium uptake at all incubation times and KCl concentrations. Bay K 8644 enhancement of KCl-stimulated calcium influx was also reduced by radiation exposure. Nimodipine binding to dihydropyridine (DHP) L-type calcium channel receptors was not altered following radiation exposure. These results demonstrate an inhibitory effect of ionizing radiation on the voltage-sensitive calcium channels in rat brain synaptosomes that are not mediated by DHP receptors.

  7. Sr2+-dependent asynchronous evoked transmission at rat striatal inhibitory synapses in vitro

    PubMed Central

    Rumpel, Eva; Behrends, Jan C

    1999-01-01

    At striatal inhibitory synapses in cell culture, replacement of extracellular Ca2+ with Sr2+ desynchronized inhibitory postynaptic currents (IPSCs), reducing their peak amplitude and producing a succession of late, asynchronous synaptic events (late release). In the averaged IPSC waveform this resulted in an increase in both the fast and the slow decay time constant as well as in the time to peak.Rapid removal of extracellular Sr2+ during late release was without effect on the time course of the averaged IPSC. Thus, late release is not dependent on continuous Sr2+ influx, but must be related to the way in which Sr2+, as opposed to Ca2+, interacts with constituents of the intracellular space.After application of the membrane-permeant acetoxymethyl ester (AM) form of the Ca2+-chelator BAPTA, Sr2+-induced late release was greatly reduced and the kinetics of the Sr2+-dependent IPSC approached those of the Ca2+-dependent response. EGTA AM had a similar but less pronounced effect.Using rapid solution exchange, we stimulated synapses first in Sr2+- or Ca2+- and 100–300 ms afterwards in Ca2+-containing solution. Paired-pulse facilitation of late release was the same whether the conditioning pulse induced a presynaptic influx of Sr2+ or of Ca2+.It is concluded that Sr2+-mediated asynchrony is probably due to a less efficient intraterminal buffering of Sr2+ as opposed to Ca2+, allowing for Sr2+ ions to activate release in an area less confined to the immediate vicinity of the presynaptic Ca2+ channel. This hypothesis explains both the action of endogenous buffers and the apparent lack of specific facilitatory interaction between Ca2+-mediated and Sr2+-induced late release. PMID:9852326

  8. Sr2+-dependent asynchronous evoked transmission at rat striatal inhibitory synapses in vitro.

    PubMed

    Rumpel, E; Behrends, J C

    1999-01-15

    1. At striatal inhibitory synapses in cell culture, replacement of extracellular Ca2+ with Sr2+ desynchronized inhibitory postynaptic currents (IPSCs), reducing their peak amplitude and producing a succession of late, asynchronous synaptic events (late release). In the averaged IPSC waveform this resulted in an increase in both the fast and the slow decay time constant as well as in the time to peak. 2. Rapid removal of extracellular Sr2+ during late release was without effect on the time course of the averaged IPSC. Thus, late release is not dependent on continuous Sr2+ influx, but must be related to the way in which Sr2+, as opposed to Ca2+, interacts with constituents of the intracellular space. 3. After application of the membrane-permeant acetoxymethyl ester (AM) form of the Ca2+-chelator BAPTA, Sr2+-induced late release was greatly reduced and the kinetics of the Sr2+-dependent IPSC approached those of the Ca2+-dependent response. EGTA AM had a similar but less pronounced effect. 4. Using rapid solution exchange, we stimulated synapses first in Sr2+- or Ca2+- and 100-300 ms afterwards in Ca2+-containing solution. Paired-pulse facilitation of late release was the same whether the conditioning pulse induced a presynaptic influx of Sr2+ or of Ca2+. 5. It is concluded that Sr2+-mediated asynchrony is probably due to a less efficient intraterminal buffering of Sr2+ as opposed to Ca2+, allowing for Sr2+ ions to activate release in an area less confined to the immediate vicinity of the presynaptic Ca2+ channel. This hypothesis explains both the action of endogenous buffers and the apparent lack of specific facilitatory interaction between Ca2+-mediated and Sr2+-induced late release.

  9. Voltage-dependent membrane potential oscillations of rat striatal fast-spiking interneurons

    PubMed Central

    Bracci, Enrico; Centonze, Diego; Bernardi, Giorgio; Calabresi, Paolo

    2003-01-01

    We used whole-cell recordings to investigate subthreshold membrane potential oscillations and their relationship with intermittent firing in striatal fast-spiking interneurons. During current injections (100–500 pA, 1 s), these cells displayed a highly variable pattern of spike bursts (comprising 1–30 action potentials) interspersed with membrane potential oscillations. The oscillation threshold was −42 ± 10 mV, and coincided with that for action potentials. The oscillation frequency was voltage dependent and ranged between 20 and 100 Hz. Oscillations were unaffected by the calcium channel blockers cadmium and nickel and by blockers of ionotropic glutamate and GABA receptors. Conversely, the sodium channel blocker tetrodotoxin fully abolished the oscillations and the spike bursts. The first spike of a burst appeared to be triggered by an oscillation, since the timing and rate of rise of the membrane potential in the subthreshold voltage region was similar for the two events. Conversely, the second spike (and the subsequent ones) displayed much faster depolarisations in the subthreshold voltage range, indicating that they were generated by a different mechanism. Consistent with these notions, a small pulse of intracellular current delivered during the oscillation was effective in triggering a burst of action potentials that largely outlasted the pulse. We conclude that fast-spiking interneuron oscillations are generated by an intrinsic membrane mechanism that does not require fast synaptic transmission, and which depends on sodium conductance but not calcium conductance, and that such oscillations are responsible for triggering the intermittent spike bursts that are typical of these neurons. PMID:12665602

  10. A link between the hippocampal and the striatal memory systems of the brain.

    PubMed

    Rossato, Janine I; Zinn, Carolina G; Furini, Cristiane; Bevilaqua, Lia R M; Medina, Jorge H; Cammarota, Martín; Izquierdo, Iván

    2006-09-01

    Two major memory systems have been recognized over the years (Squire 1987): the declarative memory system, which is under the control of the hippocampus and related temporal lobe structures, and the procedural or habit memory system, which is under the control of the striatum and its connections. Most if not all learning tasks studied in animals, however, involve either the performance or the suppression of movement; this, if learned well, may be viewed as having become a habit. It is agreed that memory rules change from their first association to those that take place when the task is mastered. Does this change of rules involve a switch from one memory system to another? Here we will comment on: 1) reversal learning in the Morris water maze (MWM), in which the declarative or spatial component of a task is changed but the procedural component (to swim to safety) persists and needs to be re-linked with a different set of spatial cues; and 2) a series of observations on an inhibitory avoidance task that indicate that the brain systems involved change with further learning.

  11. Antagonism of quercetin against tremor induced by unilateral striatal lesion of 6-OHDA in rats.

    PubMed

    Mu, Xin; Yuan, Xia; Du, Li-Da; He, Guo-Rong; Du, Guan-Hua

    2016-01-01

    Quercetin, a flavonoid present in many plants, is reported to be effective in models of neurodegenerative diseases. The aim of the present study was to evaluate the anti-tremor effects of quercetin in 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. In rats, quercetin had no effect on apomorphine-induced rotations, but it could significantly attenuate muscle tremor of 6-OHDA lesioned rats. Interestingly, quercetin could decrease the burst frequency in a dose- and time-dependent manner. These results suggest that quercetin may have a protective effect on models to mimic muscle tremors of Parkinson's disease. This effect of quercetin may be associated with serotonergic system, but further study is needed.

  12. Normobaric hyperoxia retards the evolution of ischemic brain tissue toward infarction in a rat model of transient focal cerebral ischemia.

    PubMed

    Xu, Ji; Zhang, Yuan; Liang, Zhouyuan; Wang, Ting; Li, Weiping; Ren, Lijie; Huang, Shaonong; Liu, Wenlan

    2016-01-01

    Oxygen therapy has been long considered a logical therapy for ischemic stroke. Our previous studies showed that normobaric hyperoxia (normobaric hyperoxia (NBO), 95% O2 with 5% CO2) treatment during ischemia reduced ischemic neuronal death and cerebromicrovascular injury in animal stroke models. In this study, we studied the effects of NBO on the evolution of ischemic brain tissue to infarction in a rat model of transient focal cerebral ischemia. Male Sprague-Dawley rats were given NBO (95% O2) or normoxia (21% O2) during 90-min filament occlusion of the middle cerebral artery (MCAO), followed by 3 or 22.5 h of reperfusion. 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to evaluate the longitudinal evolution of tissue infarction. Results: In normoxic rats, MCA-supplied cortical and striatal tissue was infarcted after 90-min MCAO with 22.5 h of reperfusion. NBO-treated rats showed a 61.4% reduction in infarct size and tissue infarction mainly occurred in the ischemic striatum. When infarction was assessed at an earlier time point, i.e. at 3 h of reperfusion, normoxic rats showed significantly smaller but mature infarction (no TTC staining, white color), with the infarction mainly occurring in the striatum. Unexpectedly, NBO-treated rats only showed immature lesion (partially stained by TTC, light white color) in the ischemic striatum, indicating that NBO treatment also retarded the process of neuronal death in the ischemic core. Of note, NBO-preserved striatal tissue underwent infarction after prolonged reperfusion. Conclusions: Our results demonstrate that NBO treatment given during cerebral ischemia retards the evolution of ischemic brain tissue toward infarction and NBO-preserved cortical tissue survives better than NBO-preserved striatal tissue during the phase of reperfusion.

  13. Differential organization of cortical inputs to striatal projection neurons of the matrix compartment in rats

    PubMed Central

    Deng, Yunping; Lanciego, Jose; Goff, Lydia Kerkerian-Le; Coulon, Patrice; Salin, Pascal; Kachidian, Philippe; Lei, Wanlong; Del Mar, Nobel; Reiner, Anton

    2015-01-01

    In prior studies, we described the differential organization of corticostriatal and thalamostriatal inputs to the spines of direct pathway (dSPNs) and indirect pathway striatal projection neurons (iSPNs) of the matrix compartment. In the present electron microscopic (EM) analysis, we have refined understanding of the relative amounts of cortical axospinous vs. axodendritic input to the two types of SPNs. Of note, we found that individual dSPNs receive about twice as many axospinous synaptic terminals from IT-type (intratelencephalically projecting) cortical neurons as they do from PT-type (pyramidal tract projecting) cortical neurons. We also found that PT-type axospinous synaptic terminals were about 1.5 times as common on individual iSPNs as IT-type axospinous synaptic terminals. Overall, a higher percentage of IT-type terminals contacted dSPN than iSPN spines, while a higher percentage of PT-type terminals contacted iSPN than dSPN spines. Notably, IT-type axospinous synaptic terminals were significantly larger on iSPN spines than on dSPN spines. By contrast to axospinous input, the axodendritic PT-type input to dSPNs was more substantial than that to iSPNs, and the axodendritic IT-type input appeared to be meager and comparable for both SPN types. The prominent axodendritic PT-type input to dSPNs may accentuate their PT-type responsiveness, and the large size of axospinous IT-type terminals on iSPNs may accentuate their IT-type responsiveness. Using transneuronal labeling with rabies virus to selectively label the cortical neurons with direct input to the dSPNs projecting to the substantia nigra pars reticulata, we found that the input predominantly arose from neurons in the upper layers of motor cortices, in which IT-type perikarya predominate. The differential cortical input to SPNs is likely to play key roles in motor control and motor learning. PMID:25926776

  14. Enhancing effect of taurine in the rat caudate spindle. II. Effect of bilateral 6-hydroxydopamine lesions of the nigro-striatal dopamine system.

    PubMed

    Hashimoto-Kitsukawa, S; Okuyama, S; Aihara, H

    1988-10-01

    Bilateral injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rats resulted in destruction of dopamine (DA) nerve terminals in the striatum. DA contents decreased to 16.8, 15.0 and 13.7% of control values on 3, 5 and 7 days after the lesions, respectively. The time course of the effect of 6-OHDA lesions on apomorphine (0.5 mg/kg, IV)-induced stereotypy was investigated as the index of the development of supersensitivity. Stereotypy was unchanged on 3 days, but was enhanced 5 and 7 days after 6-OHDA lesions. Therefore, the sensitivity of postsynaptic DA receptors for apomorphine did not change 3 days after 6-OHDA lesions, although the striatal DA was depleted. The effects of bilateral injections of taurine into the striatum on the rat caudate spindle were determined 3 days after 6-OHDA lesions. Taurine, at a dose of 30 micrograms, enhanced the spindle in sham-operated rats, but this enhancement was not seen after 6-OHDA lesions. Intravenous administration of apomorphine (0.5 mg/kg) to lesioned rats suppressed the spindle, and this effect was prevented by a lower dose (3 micrograms) of taurine. These results provide further evidence that taurine enhances the spindle, possibly by decreasing the activity of the nigro-striatal DA system at the pre- and postsynaptic sites.

  15. [Halothane anesthesia decreases the level of interstitial striatal dopamine of awake freely moving rats in an in vivo microdialysis study].

    PubMed

    Adachi, Y; Uchihashi, Y; Watanabe, K; Satoh, T

    2000-02-01

    We investigated the effect of halothane on the level of interstitial dopamine of in vivo awake, free moving rats brain striatum using microdialysis techniques. Rats were implanted a microdialysis probe to right striatum of the brain and administered 1.5% of halothane (approximately 1.2 MAC) for 1 or 2 hours, and dialysates from the probe were determined every 20 minutes. Halothane anesthesia reduced the amount of dopamine derived from dialysate, and after discontinuation of halothane and at emergence from anesthesia, the level of dopamine was increased. The levels of metabolites of dopamine during anesthesia were increased lineally in a time dependent manner. We hypothesized that halothane might increase the rate of re-uptake of dopamine at nerve endings and decreased level of interstitial dopamine is compensated by dopamine releases during anesthesia.

  16. Feeding-associated alterations in striatal neurotransmitter release

    NASA Technical Reports Server (NTRS)

    Acworth, I. N.; Ressler, K.; Wurtman, R. J.

    1989-01-01

    Published evidence suggests a role for dopaminergic (DA) brain pathways in feeding-associated behaviors. Using the novel technique of brain microdialysis of striatal extracellular fluid (ECF) as an index of DA release, Church et al. described increases in levels of DA when animals had limited access to pellets, but not with free access. Dopamine release from the nucleus accumbens did increase with free access to pellets post starvation or after food reward. We used permanently implanted microdialysis probes to measure ECF levels of DA, DOPAC, HVA, and large neutral amino acids (LNAA) for up to 72 hours after implantation among rats experiencing different dietary regimens.

  17. Failure of MK-801 to suppress D1 receptor-mediated induction of locomotor activity and striatal preprotachykinin mRNA expression in the dopamine-depleted rat.

    PubMed

    Campbell, B M; Kreipke, C W; Walker, P D

    2006-01-01

    N-methyl-D-aspartate receptor antagonism exerts suppressive influences over dopamine D1 receptor-mediated striatal gene expression and locomotor behavior in the intact rat. The present study examined the effects of the N-methyl-D-aspartate receptor antagonist MK-801 on locomotor activity and striatal preprotachykinin mRNA expression stimulated by the D1 agonist (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide in rats with bilateral dopamine lesions. Two months after neonatal dopamine lesions with 6-hydroxydopamine, rats were challenged with (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1.0 mg/kg) 15 min after administration of the N-methyl-D-aspartate receptor antagonist MK-801 (0.1 mg/kg). In the intact rat, MK-801 prevented the induction of striatal preprotachykinin mRNA by D1 agonism. Similarly, direct infusion of (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3.0 microg) into the intact striatum produced an increase in locomotor activity that was suppressed by MK-801 (1.0 microg) co-infusion. In the dopamine-depleted rat, MK-801 (0.1 mg/kg) administered prior to (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1.0 mg/kg) increased, rather than suppressed, striatal preprotachykinin mRNA levels. Intrastriatal infusion of MK-801 (1.0 microg) failed to inhibit D1-mediated induction of motor activity in dopamine-depleted animals. Together, these data provide further support that N-methyl-D-aspartate receptor antagonists lose their ability to block D1-mediated behavioral activation following dopamine depletion. The activation, rather than suppression, of tachykinin neurons of the direct striatonigral pathway may play a facilitatory role in this mechanism.

  18. Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to co-ordination defects in mice.

    PubMed

    Seeher, Sandra; Carlson, Bradley A; Miniard, Angela C; Wirth, Eva K; Mahdi, Yassin; Hatfield, Dolph L; Driscoll, Donna M; Schweizer, Ulrich

    2014-08-15

    Secisbp2 [SECIS (selenocysteine insertion sequence)-binding protein 2] binds to SECIS elements located in the 3'-UTR region of eukaryotic selenoprotein mRNAs. It facilitates the incorporation of the rare amino acid selenocysteine in response to UGA codons. Inactivation of Secisbp2 in hepatocytes greatly reduced selenoprotein levels. Neuron-specific inactivation of Secisbp2 (CamK-Cre; Secisbp2fl/fl) reduced cerebral expression of selenoproteins to a lesser extent than inactivation of tRNA[Ser]Sec. This allowed us to study the development of cortical PV (parvalbumin)+ interneurons, which are completely lost in tRNA[Ser]Sec mutants. PV+ interneuron density was reduced in the somatosensory cortex, hippocampus and striatum. In situ hybridization for Gad67 (glutamic acid decarboxylase 67) confirmed the reduction of GABAergic (where GABA is γ-aminobutyric acid) interneurons. Because of the obvious movement phenotype involving a broad dystonic gait, we suspected basal ganglia dysfunction. Tyrosine hydroxylase expression was normal in substantia nigra neurons and their striatal terminals. However the densities of striatal PV+ and Gad67+ neurons were decreased by 65% and 49% respectively. Likewise, the density of striatal cholinergic neurons was reduced by 68%. Our observations demonstrate that several classes of striatal interneurons depend on selenoprotein expression. These findings may offer an explanation for the movement phenotype of selenoprotein P-deficient mice and the movement disorder and mental retardation described in a patient carrying SECISBP2 mutations.

  19. The characterization of neuroenergetic effects of chronic L-tyrosine administration in young rats: evidence for striatal susceptibility.

    PubMed

    Ferreira, Gabriela K; Carvalho-Silva, Milena; Gomes, Lara M; Scaini, Giselli; Teixeira, Leticia J; Mota, Isabella T; Schuck, Patrícia F; Ferreira, Gustavo C; Streck, Emilio L

    2015-02-01

    Tyrosinemia type II is an inborn error of metabolism caused by a deficiency in hepatic cytosolic aminotransferase. Affected patients usually present a variable degree of mental retardation, which may be related to the level of plasma tyrosine. In the present study we evaluated effect of chronic administration of L-tyrosine on the activities of citrate synthase, malate dehydrogenase, succinate dehydrogenase and complexes I, II, II-III and IV in cerebral cortex, hippocampus and striatum of rats in development. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old); rats were killed 12 h after last injection. Our results demonstrated that L-tyrosine inhibited the activity of citrate synthase in the hippocampus and striatum, malate dehydrogenase activity was increased in striatum and succinate dehydrogenase, complexes I and II-III activities were inhibited in striatum. However, complex IV activity was increased in hippocampus and inhibited in striatum. By these findings, we suggest that repeated administrations of L-tyrosine cause alterations in energy metabolism, which may be similar to the acute administration in brain of infant rats. Taking together the present findings and evidence from the literature, we hypothesize that energy metabolism impairment could be considered an important pathophysiological mechanism underlying the brain damage observed in patients with tyrosinemia type II.

  20. Kinetic characterization of l-[(3)H]glutamate uptake inhibition and increase oxidative damage induced by glutaric acid in striatal synaptosomes of rats.

    PubMed

    Magni, Danieli Valnes; Furian, Ana Flávia; Oliveira, Mauro Schneider; Souza, Mauren Assis; Lunardi, Fabiane; Ferreira, Juliano; Mello, Carlos Fernando; Royes, Luiz Fernando Freire; Fighera, Michele Rechia

    2009-02-01

    Glutaric acidemia type I (GA-I) is an inherited metabolic disease characterized by accumulation of glutaric acid (GA) and striatal degeneration. Although growing evidence suggests that excitotoxicity and oxidative stress play central role in the neuropathogenesis of this disease, mechanism underlying striatal damage in this disorder is not well established. Thus, we decided to investigate the in vitro effects of GA 10nM (a low concentration that can be present initial development this disorder) on l-[(3)H]glutamate uptake and reactive oxygen species (ROS) generation in synaptosomes from striatum of rats. GA reduced l-[(3)H]glutamate uptake in synaptosomes from 1 up to 30min after its addition. Furthermore, we also provided some evidence that GA competes with the glutamate transporter inhibitor l-trans-pyrrolidine-2,4-dicarboxylate (PDC), suggesting a possible interaction of GA with glutamate transporters on synaptosomes. Moreover, GA produced a significant decrease in the V(MAX) of l-[(3)H]glutamate uptake, but did not affect the K(D) value. Although the GA did not show oxidant activity per se, it increased the ROS generation in striatal synaptosomes. To evaluate the involvement of reactive species generation in the GA-induced l-[(3)H]glutamate uptake inhibition, trolox (0.3, 0.6 and 6muM) was added on the incubation medium. Statistical analysis showed that trolox did not decrease inhibition of GA-induced l-[(3)H]glutamate uptake, but decreased GA-induced reactive species formation in striatal synaptosomes (1, 3, 5, 10, 15 and 30min), suggesting that ROS generation appears to occur secondarily to glutamatergic overstimulation in this model of organic acidemia. Since GA induced DCFH oxidation increase, we evaluate the involvement of glutamate receptor antagonists in oxidative stress, showing that CNQX, but not MK-801, decreased the DCFH oxidation increase in striatal synaptosomes. Furthermore, the results presented in this report suggest that excitotoxicity elicited

  1. Persistent impairments in hippocampal, dorsal striatal, and prefrontal cortical function following repeated photoperiod shifts in rats.

    PubMed

    Zelinski, Erin L; Tyndall, Amanda V; Hong, Nancy S; McDonald, Robert J

    2013-01-01

    Cognitive impairments are observed when learned associations are being acquired or retrieved during a period of circadian disruption. However, the extent of the functional impacts on previously acquired associations following circadian rhythm re-entrainment is unknown. The impacts of repeated photoperiod shifts on learning and memory in male and female rats were examined. For these experiments, rats were trained on a spatial version of the Morris water task (MWT) and a visual discrimination task designed for the 8-arm radial maze. Following asymptotic performance on these tasks, rats experienced a repeating photoperiod shift procedure and were then re-entrained. Following circadian re-entrainment, retention of pre-photoperiod-shift-acquired associations was tested. In addition, an extra-dimensional set shift was performed using the 8-arm radial maze. Impaired retention of the MWT platform location was observed in photoperiod-shifted subjects relative to subjects with stable, unmanipulated photoperiods. Repeated photoperiod shifts negatively impacted retention in males and females compared with subjects with stable photoperiods. Retention and the ability to detect extra-dimensional shifts on the visual discrimination task were also impaired, though not consistently by sex or photoperiod condition. Running wheel availability was also included in the analyses to determine whether exercise influenced the effects of photoperiod shifting. The absence of a running wheel produced significant declines in memory retention on both MWT and the visual discrimination task, but only for male rats. The observed impairments indicate that multiple neural systems supporting different learning and memory functions are susceptible to circadian disruption, even if the association is acquired prior to rhythm fragmentation and tested following rhythm re-entrainment.

  2. Microdialysis study of striatal dopamine in MPTP-hemilesioned rats challenged with apomorphine and amphetamine.

    PubMed

    Dombrowski, Patricia Andreia; Carvalho, Milene Cristina; Miyoshi, Edmar; Correia, Diego; Bortolanza, Mariza; Dos Santos, Lucélia Mendes; Wietzikoski, Evellyn Claudia; Eckart, Moritz Thede; Schwarting, Rainer K W; Brandão, Marcus Lira; Da Cunha, Claudio

    2010-12-20

    Motor impairments of Parkinson's disease (PD) appear only after the loss of more than 70% of the DAergic neurons of the substantia nigra pars compacta (SNc). An earlier phase of this disease can be modeled in rats that received a unilateral infusion of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) into the SNc. Though these animals do not present gross motor impairments, they rotate towards the lesioned side when challenged with DAergic drugs, like amphetamine and apomorphine. The present study aimed to test whether these effects occur because the drugs disrupt compensatory mechanisms that keep extracellular levels of dopamine in the striatum (DA(E)) unchanged. This hypothesis was tested by an in vivo microdialysis study in awake rats with two probes implanted in the right and left striatum. Undrugged rats did not present turning behaviour and their basal DA(E) did not differ between the lesioned and sham-lesioned sides. However, after apomorphine treatment, DA(E) decreased in both sides, but to a larger extent in the lesioned side at the time the animals started ipsiversive turning behaviour. After amphetamine challenge, DA(E) increased in both sides, becoming significantly higher in the non-lesioned side at the time the animals started ipsiversive turning behaviour. These results are in agreement with the hypothesis that absence of gross motor impairments in this rat model of early phase PD depends on maintenance of extracellular DA by mechanisms that may be disrupted by events demanding its alteration to higher or lower levels. Copyright 2010 Elsevier B.V. All rights reserved.

  3. An analysis of the responses of rat striatal neurones to scrotal skin temperature.

    PubMed

    Taylor, D C; Steele, J E; Gayton, R J

    1987-09-01

    The responses of neurones in the caudate-putamen complex of anaesthetised rats to different scrotal skin temperatures were examined, together with the electroencephalogram (EEG). Caudate neuronal firing patterns did not change independently of rate, unlike the thermo-responsive cells of the hypothalamus previously reported. The scrotal skin temperature threshold for the caudate neuronal response corresponds precisely with the temperature which provokes desynchronisation of the EEG.

  4. Impairment of striatal mitochondrial function by acute paraquat poisoning.

    PubMed

    Czerniczyniec, Analía; Lanza, E M; Karadayian, A G; Bustamante, J; Lores-Arnaiz, S

    2015-10-01

    Mitochondria are essential for survival. Their primary function is to support aerobic respiration and to provide energy for intracellular metabolic pathways. Paraquat is a redox cycling agent capable of generating reactive oxygen species. The aim of the present study was to evaluate changes in cortical and striatal mitochondrial function in an experimental model of acute paraquat toxicity and to compare if the brain areas and the molecular mechanisms involved were similar to those observed after chronic exposure. Sprague-Dawley rats received paraquat (25 mg/Kg i.p.) or saline and were sacrificed after 24 h. Paraquat treatment decreased complex I and IV activity by 37 and 21 % respectively in striatal mitochondria. Paraquat inhibited striatal state 4 and state 3 KCN-sensitive respiration by 80 % and 62 % respectively, indicating a direct effect on respiratory chain. An increase of 2.2 fold in state 4 and 2.3 fold in state 3 in KCN-insensitive respiration was observed in striatal mitochondria from paraquat animals, suggesting that paraquat redox cycling also consumed oxygen. Paraquat treatment increased hydrogen peroxide production (150 %), TBARS production (42 %) and cardiolipin oxidation/depletion (12 %) in striatal mitochondria. Also, changes in mitochondrial polarization was induced after paraquat treatment. However, no changes were observed in any of these parameters in cortical mitochondria from paraquat treated-animals. These results suggest that paraquat treatment induced a clear striatal mitochondrial dysfunction due to both paraquat redox cycling reactions and impairment of the mitochondrial electron transport, causing oxidative damage. As a consequence, mitochondrial dysfunction could probably lead to alterations in cellular bioenergetics.

  5. The effects of endomorphins on striatal [3H]GABA release induced by electrical stimulation: an in vitro superfusion study in rats.

    PubMed

    Bagosi, Zsolt; Jászberényi, Miklós; Telegdy, Gyula

    2009-05-01

    The endomorphins (EM1 and EM2) are selective endogenous ligands for mu-opioid receptors (MOR1 and MOR2) with neurotransmitter and neuromodulator roles in mammals. In the present study we investigated the potential actions of EMs on striatal GABA release and the implication of different MORs in these processes. Rat striatal slices were preincubated with tritium-labelled GABA ([(3)H]GABA), pretreated with selective MOR1 and MOR2 antagonist beta-funaltrexamine and selective MOR1 antagonist naloxonazine and then superfused with the selective MOR agonists, EM1 and EM2. EM1 significantly decreased the striatal [(3)H]GABA release induced by electrical stimulation. Beta-funaltrexamine antagonized the inhibitory action of EM1, but naloxonazine did not affect it considerably. EM2 was ineffective, even in case of specific enzyme inhibitor diprotin A pretreatment. The results demonstrate that EM1 decreases GABA release in the basal ganglia through MOR2, while EM2 does not influence it.

  6. The styrene metabolite, phenylglyoxylic acid, induces striatal-motor toxicity in the rat: influence of dose escalation/reduction over time.

    PubMed

    Terre'Blanche, Gisella; Heyer, Nicolette; Bergh, Jacobus J; Mienie, Lodewyk J; van der Schyf, Cornelius J; Harvey, Brian H

    2011-07-01

    Exposure to the industrial solvent, styrene, induces locomotor and cognitive dysfunction in rats, and parkinsonian-like manifestations in man. The antipsychotic, haloperidol (HP), well known to induce striatal toxicity in man and animals, and styrene share a common metabolic pathway yielding p-fluoro phenylglyoxylic acid and phenylglyoxylic acid (PGA), respectively. Using an exposure period of 30 days and the vacous chewing movement (VCM) model as an expression of striatal-motor toxicity, we found that incremental PGA dosing (220-400 mg/kg) significantly increased VCMs up to day 25, but decreased to control levels shortly after reaching maximum dose. However, a diminishing dose of PGA (400-200 mg/kg) did not evoke an immediate worsening of VCMs but precipitated a significant increase in VCMs following dosage reduction to 200 mg/kg on day 22. PGA exposure, therefore, compromises striatal-motor function that is especially sensitive to changes in exposure dose. Longer alternating dose exposure studies are needed to establish whether motor dysfunction is progressive in severity or longevity. These findings are of significance for the environmental toxicology of styrene in the chemical industry.

  7. Pharmacological activation of the neurotensin receptor 1 abrogates the methamphetamine-induced striatal apoptosis in the mouse brain.

    PubMed

    Liu, Qingkun; Hazan, Ariela; Grinman, Eddie; Angulo, Jesus A

    2017-03-15

    Methamphetamine (METH) is a widely abused psychostimulant displaying potent addictive and neurotoxic properties. METH induces neurotoxicity of dopaminergic terminals and striatal neurons in the striatum. Despite much information on neurotransmitters, the role of neuropeptides is poorly understood. In this study, we investigated the role of the neuropeptide neurotensin on the METH-induced apoptosis of some striatal neurons in mice. We observed that a single injection of METH (30mg/kg, ip) induced the loss of approximately 15% of striatal neurons. An agonist of the neurotensin receptor 1 (PD149163, ip at various doses) attenuated the METH-induced striatal neuron apoptosis. Utilizing quantitative real time PCR, we showed that METH also up-regulated neurotensin gene expression with 96% increase in preproneurotensin mRNA levels in the striatum as compared to the control. Additionally, NTR1 agonist (ip injection) attenuated hyperthermia at 2h post-METH injection; hyperthermia is a putative and significant component of METH-induced neurotoxicity. To investigate the role of neurotensin without affecting core body temperature, we performed stereotactic injection of PD149163 into the striatum and observed that this compound maintained attenuated the METH-induced apoptosis in the striatum, while leaving core body temperature unaffected. There was no effect of NTR1 agonist on METH-induced dopamine terminal degeneration, as evidenced by tyrosine hydroxylase levels determined by Western blot. These data indicate that the neuropeptide neurotensin modulates the striatal neuronal apoptosis induced by METH through diverse mechanisms that need to be investigated. Furthermore, due to its neuroprotective properties, neurotensin receptor agonists show potential as drug candidates for the treatment of METH abuse and some neurological disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Striatal lesions interfere with acquisition of a complex maze task in rats.

    PubMed

    Pistell, Paul J; Nelson, Chris M; Miller, Marshall G; Spangler, Edward L; Ingram, Donald K; Devan, Bryan D

    2009-01-30

    The 14-unit T-maze has proven to be a valuable tool for investigating age-associated memory impairment (AAMI). While another task widely used to evaluate AAMI, the water maze, is primarily used to evaluate allocentric hippocampal-dependent spatial memory, the 14-unit T-maze can assess egocentric procedural memory. Although several brain structures, e.g. hippocampus, parietal cortex, have been implicated in acquisition and retention performance in the 14-unit T-maze, there has been no evaluation of the involvement of the striatum, a brain region implicated in procedural learning and memory. The current study revealed that excitotoxic lesions of the medial or lateral striatum significantly impaired acquisition, as measured by errors and latency, on this task without disruption of motor function. These results indicate that the 14-unit T-maze most likely is requires a large egocentric procedural learning component, and previously observed AAMI may involve age-related dysfunction of the striatum.

  9. Alteration of dopamine uptake into rat striatal vesicles and synaptosomes caused by an in vitro exposure to atrazine and some of its metabolites.

    PubMed

    Hossain, Muhammad M; Filipov, Nikolay M

    2008-06-03

    Studies have shown that both in vivo and in vitro exposure to the herbicide atrazine (ATR) results in dopaminergic neurotoxicity manifested by decreased striatal dopamine (DA) levels. However, the mechanism behind this reduction is largely unknown. A decrease in striatal DA could be due to ATR exposure affecting vesicular and/or synaptosomal uptake resulting in disrupted vesicular storage and/or cellular uptake of DA. Hence, we investigated the effects of in vitro ATR exposure on DA uptake into isolated rat striatal synaptosomes and synaptic vesicles. In addition to ATR, effects of its major mammalian metabolites, didealkyl atrazine (DACT), desethyl atrazine (DE) and desiopropyl atrazine (DIP) were investigated. ATR (1-250 microM) inhibited DA uptake into synaptic vesicles in a dose-dependent manner. Of the three ATR metabolites tested, DACT did not affect vesicular DA uptake. DE and DIP, on the other hand, significantly decreased vesicular DA uptake with the effect of 100 microM DE/DIP being similar to the effect of the same concentration of ATR. Kinetic analysis of vesicular DA uptake indicated that ATR significantly decreased the V(max) while the K(m) value was not affected. Contrary to the inhibitory effects on vesicular DA uptake, synaptosomal DA uptake was marginally (6-13%) increased by ATR and DE, but not by DACT and DIP, at concentrations of striatal DA levels, at least in part, by increasing cytosolic DA, which is prone to oxidative breakdown.

  10. Alteration of dopamine uptake into rat striatal vesicles and synaptosomes caused by an in vitro exposure to atrazine and some of its metabolites

    PubMed Central

    Hossain, Muhammad M.; Filipov, Nikolay M.

    2008-01-01

    Studies have shown that both in vivo and in vitro exposure to the herbicide atrazine (ATR) results in dopaminergic neurotoxicity manifested by decreased striatal dopamine (DA) levels. However, the mechanism behind this reduction is largely unknown. A decrease in striatal DA could be due to ATR exposure affecting vesicular and/or synaptosomal uptake resulting in disrupted vesicular storage and/or cellular uptake of DA. Hence, we investigated the effects of in vitro ATR exposure on DA uptake into isolated rat striatal synaptosomes and synaptic vesicles. In addition to ATR, effects of its major mammalian metabolites, didealkyl atrazine (DACT), desethyl atrazine (DE) and desiopropyl atrazine (DIP) were investigated. ATR (1–250 μM) inhibited DA uptake into synaptic vesicles in a dose dependent manner. Of the three ATR metabolites tested, DACT did not affect vesicular DA uptake. DE and DIP, on the other hand, significantly decreased vesicular DA uptake with the effect of 100 μM DE/DIP being similar to the effect of the same concentration of ATR. Kinetic analysis of vesicular DA uptake indicated that ATR significantly decreased the Vmax while the Km value was not affected. Contrary to the inhibitory effects on vesicular DA uptake, synaptosomal DA uptake was marginally (6–13%) increased by ATR and DE, but not by DACT and DIP, at concentrations of ≤100 μM. As a result, ATR, DIP and DE increased the synaptosomal/vesicular (DAT/VMAT-2) uptake ratio. Collectively, results from this study suggest that ATR and two of its metabolites, DIP and DE, but not its major mammalian metabolite, DACT, decrease striatal DA levels, at least in part, by increasing cytosolic DA, which is prone to oxidative breakdown. PMID:18423833

  11. miR-10b-5p expression in Huntington's disease brain relates to age of onset and the extent of striatal involvement.

    PubMed

    Hoss, Andrew G; Labadorf, Adam; Latourelle, Jeanne C; Kartha, Vinay K; Hadzi, Tiffany C; Gusella, James F; MacDonald, Marcy E; Chen, Jiang-Fan; Akbarian, Schahram; Weng, Zhiping; Vonsattel, Jean Paul; Myers, Richard H

    2015-03-01

    MicroRNAs (miRNAs) are small non-coding RNAs that recognize sites of complementarity of target messenger RNAs, resulting in transcriptional regulation and translational repression of target genes. In Huntington's disease (HD), a neurodegenerative disease caused by a trinucleotide repeat expansion, miRNA dyregulation has been reported, which may impact gene expression and modify the progression and severity of HD. We performed next-generation miRNA sequence analysis in prefrontal cortex (Brodmann Area 9) from 26 HD, 2 HD gene positive, and 36 control brains. Neuropathological information was available for all HD brains, including age at disease onset, CAG-repeat size, Vonsattel grade, and Hadzi-Vonsattel striatal and cortical scores, a continuous measure of the extent of neurodegeneration. Linear models were performed to examine the relationship of miRNA expression to these clinical features, and messenger RNA targets of associated miRNAs were tested for gene ontology term enrichment. We identified 75 miRNAs differentially expressed in HD brain (FDR q-value <0.05). Among the HD brains, nine miRNAs were significantly associated with Vonsattel grade of neuropathological involvement and three of these, miR-10b-5p, miR-10b-3p, and miR-302a-3p, significantly related to the Hadzi-Vonsattel striatal score (a continuous measure of striatal involvement) after adjustment for CAG length. Five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-10b-3p, and miR-106a-5p) were identified as having a significant relationship to CAG length-adjusted age of onset including miR-10b-5p, the mostly strongly over-expressed miRNA in HD cases. Although prefrontal cortex was the source of tissue profiled in these studies, the relationship of miR-10b-5p expression to striatal involvement in the disease was independent of cortical involvement. Correlation of miRNAs to the clinical features clustered by direction of effect and the gene targets of the observed miRNAs showed association to

  12. Characterization of solubilized human and rat brain US -endorphin-receptor complex

    SciTech Connect

    Helmeste, D.M.; Li, C.H.

    1986-01-01

    Opioid receptors have been solubilized from human striatal and rat whole-brain membranes by use of 3-((3-cholamidopropyl)dimethylammonio)-1-propanesulfonate (CHAPS). Tritiated human US -endorphin (TH-US /sub h/-EP) binding revealed high-affinity competition by morphine, naloxone, and various US -EP analogues. Lack of high-affinity competition by (+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl)benzeneacetamide methanesulfonate (U50-488, Upjohn) indicated that k sites were not labeled by TH-US -/sub h/-EP under these conditions. Affinities were similar in both soluble and membrane preparations except for (Met)enkephalin, which appears to be rapidly degraded by the solubilized extract. Size differences between human and rat solubilized TH-US /sub h/-EP-receptor complexes were revealed by exclusion chromatography.

  13. The influence of tomograph sensitivity on kinetic parameter estimation in positron emission tomography imaging studies of the rat brain.

    PubMed

    Meikle, S R; Eberl, S; Fulton, R R; Kassiou, M; Fulham, M J

    2000-08-01

    We investigated the influence of tomograph sensitivity on reliability of parameter estimation in positron emission tomography studies of the rat brain. The kinetics of two tracers in rat striatum and cerebellum were simulated. A typical injected dose of 10 MBq and a reduced dose of 1 MBq were assumed. Kinetic parameters were estimated using a region of interest (ROI) analysis and two pixel-by-pixel analyses. Striatal binding potential was estimated as a function of effective tomograph sensitivity (S(eff)) using a simplified reference tissue model. A S(eff) value of > or =1% was required to ensure reliable parameter estimation for ROI analysis and a S(eff) of 3-6% was required for pixel-by-pixel analysis. We conclude that effective tomograph sensitivity of 3% may be an appropriate design goal for rat brain imaging.

  14. Zonisamide ameliorates levodopa-induced dyskinesia and reduces expression of striatal genes in Parkinson model rats.

    PubMed

    Oki, Mitsuaki; Kaneko, Satoshi; Morise, Satoshi; Takenouchi, Norihiro; Hashizume, Takanori; Tsuge, Ayako; Nakamura, Masataka; Wate, Reika; Kusaka, Hirofumi

    2017-09-01

    To investigate the difference in results according to the mode of levodopa administration and the effect of zonisamide (ZNS), we analyzed the mRNA expression of dopaminergic and non-dopaminergic receptors in the striatum of Parkinson model rats in relation to the development of levodopa-induced dyskinesia (LID). Unilateral Parkinson model rats were subdivided into 4 groups and treated as follows: no medication (group N), continuous levodopa infusion (group C), intermittent levodopa injection (group I), and intermittent levodopa and ZNS injection (group Z). Two weeks after the treatment, LID was observed in group I and Z, but less severe in group Z. The level of both D1 and D2 receptor mRNAs was elevated in groups I and Z, but only D2 receptor mRNA expression was elevated in group C. Adenosine A2A receptor mRNA showed increased expression only in group I. The level of endocannabinoid CB1 receptor mRNA was elevated in groups N, C, and I, but not in group Z. Intermittent injection of levodopa caused LID, in association with elevated expression of D1 and A2A receptors. ZNS ameliorated the development of LID and inhibited up-regulation of A2A and CB1 receptors. Modulation of these receptors may lead to therapeutic approaches for dyskinesia. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  15. [Comparative analysis of metabotropic and ionotropic glutamate striatal receptors blockade influence on rats locomotor behaviour].

    PubMed

    Iakimovskiĭ, A F; Kerko, T V

    2013-02-01

    The influence of NMDA and metabotropic neostriatal glutamate receptors blockade to avoidance conditioning (in shuttle box) and free locomotor behavior (in open field) in chronic experiments in rats were investigated. The glutamate receptor antagonists were injected bilateral into striatum separately and with the GABA-A receptor antagonist picrotoxin (2 microg), that produced in rats the impairment of avoidance conditioning and choreo-myoklonic hyperkinesis. The most effective in preventing of negative picrotoxin influence on behavior was 5-type metabotropic glutamate receptors antagonist MTEP (3 microg). Separately injected MTEP did not influence on avoidance conditioning and free locomotor behavior. Unlike that, 1-type metabotropic glutamate receptors antagonist EMQMCM (3 microg) impaired normal locomotor behavior and did not prevent the picrotoxin effects. The NMDA glutamate receptors MK 801 (disocilpin--1 and 5 microg) impaired the picrotoxin-induced hyperkinesis, but did not to prevent the negative effects on avoidance conditioning; separately injected MK 801 reduced free locomotor activity. Based on location of investigated receptor types in neostriatal neurons membranes, we proposed that the most effective influence on 5-type metabotropic glutamate receptors is associated with their involvement in "indirect" efferent pathway, suffered in hyperkinetic extrapyramidal motor dysfunction--Huntington's chorea in human.

  16. 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

  17. Deformation-based brain morphometry in rats.

    PubMed

    Gaser, Christian; Schmidt, Silvio; Metzler, Martin; Herrmann, Karl-Heinz; Krumbein, Ines; Reichenbach, Jürgen R; Witte, Otto W

    2012-10-15

    Magnetic resonance imaging (MRI)-based morphometry provides in vivo evidence for macro-structural plasticity of the brain. Experiments on small animals using automated morphometric methods usually require expensive measurements with ultra-high field dedicated animal MRI systems. Here, we developed a novel deformation-based morphometry (DBM) tool for automated analyses of rat brain images measured on a 3-Tesla clinical whole body scanner with appropriate coils. A landmark-based transformation of our customized reference brain into the coordinates of the widely used rat brain atlas from Paxinos and Watson (Paxinos Atlas) guarantees the comparability of results to other studies. For cross-sectional data, we warped images onto the reference brain using the low-dimensional nonlinear registration implemented in the MATLAB software package SPM8. For the analysis of longitudinal data sets, we chose high-dimensional registrations of all images of one data set to the first baseline image which facilitate the identification of more subtle structural changes. Because all deformations were finally used to transform the data into the space of the Paxinos Atlas, Jacobian determinants could be used to estimate absolute local volumes of predefined regions-of-interest. Pilot experiments were performed to analyze brain structural changes due to aging or photothrombotically-induced cortical stroke. The results support the utility of DBM based on commonly available clinical whole-body scanners for highly sensitive morphometric studies on rats.

  18. Striatal and extrastriatal dopamine release in the common marmoset brain measured by positron emission tomography and [(18)F]fallypride.

    PubMed

    Ota, Miho; Ogawa, Shintaro; Kato, Koichi; Masuda, Chiaki; Kunugi, Hiroshi

    2015-12-01

    Previous studies have demonstrated that patients with schizophrenia show greater sensitivity to psychostimulants than healthy subjects. Sensitization to psychostimulants and resultant alteration of dopaminergic neurotransmission in rodents has been suggested as a useful model of schizophrenia. This study sought to examine the use of methylphenidate as a psychostimulant to induce dopamine release and that of [(18)F]fallypride as a radioligand to quantify the release in a primate model of schizophrenia. Four common marmosets were scanned by positron emission tomography twice, before and after methylphenidate challenge, to evaluate dopamine release. Four other marmosets were sensitized by repeated methamphetamine (MAP) administration. Then, they were scanned twice, before and after methylphenidate challenge, to evaluate whether MAP-sensitization induced greater sensitivity to methylphenidate. We revealed a main effect of the methylphenidate challenge but not the MAP pretreatment on the striatal binding potential. These results suggest that methylphenidate-induced striatal dopamine release in the common marmoset could be evaluated by [(18)F]fallypride.

  19. Relationship Between L-DOPA-Induced Reduction in Motor and Exploratory Activity and Striatal Dopamine D2 Receptor Binding in the Rat

    PubMed Central

    Nikolaus, Susanne; Beu, Markus; de Souza Silva, Maria A.; Huston, Joseph P.; Hautzel, Hubertus; Mattern, Claudia; Antke, Christina; Müller, Hans-Wilhelm

    2016-01-01

    Purpose: The present study assessed the influence of L-DOPA administration on neostriatal dopamine (DA) D2 receptor binding in relation to motor and exploratory behaviors in the rat. Methods: D2 receptor binding was measured in baseline, after challenge with the aromatic L-amino acid decarboxylase inhibitor benserazide, and after challenge with either 5 or 10 mg/kg L-DOPA plus benserazide. Additional rats received injections of saline. For baseline and challenges, striatal equilibrium ratios (V3″) were computed as estimation of the binding potential. Motor and exploratory behaviors were assessed for 30 min in an open field prior to administration of [123I]IBZM. D2 receptor binding was measured with small animal SPECT 2 h after radioligand administration for 60 min. Results: Both L-DOPA doses significantly reduced D2 receptor binding relative to baseline and led to significantly less ambulation, less head-shoulder motility, and more sitting relative to saline. Moreover, 10 mg/kg L-DOPA induced less head-shoulder motility, more sitting, and more grooming than 5 mg/kg L-DOPA. Analysis of time-behavior curves showed that L-DOPA-treated animals relative to saline exhibited a faster rate of decrease of ambulation frequency and a slower rate of decrease of both duration and frequency of head-shoulder motility from a lower maximum level. Conclusions: The reductions of striatal D2 receptor binding after L-DOPA may be conceived to reflect elevated concentrations of synaptic DA. L-DOPA-treated animals showed less ambulation and less head-shoulder motility than saline-treated animals, indicating an association between less behavioral activity and increased availability of striatal DA. The faster rate of decrease of ambulation frequency and the lower maximum levels of both head-shoulder motility duration and frequency may be interpreted in terms of influence of increased DA availability on behavioral habituation to a novel environment. PMID:26778989

  20. Interactions of ( sup 3 H)amphetamine with rat brain synaptosomes. II. Active transport

    SciTech Connect

    Zaczek, R.; Culp, S.; De Souza, E.B. )

    1991-05-01

    The accumulation of 5 nM d-({sup 3}H)amphetamine (d-({sup 3}H)AMPH) into rat brain synaptosomes was examined using physiological buffer conditions. The accumulation of d-({sup 3}H)AMPH into striatal synaptosomes was saturable, of high affinity, ouabain-sensitive and temperature-dependent, suggesting an active transport phenomenon. Eadee-Hofstee analysis of striatal d-({sup 3}H)AMPH transport (AMT) saturation isotherms indicated an apparent Km of 97 nM and a Vmax of 3.0 fmol/mg tissue/min. Lesion of the striatal dopaminergic innervation led to equivalent decreases of ({sup 3}H) dopamine (DA) transport and AMT, indicating that AMT occurs in DA terminals. Furthermore, AMT was not evident in cerebral cortex, a brain region with a paucity of DA terminals. In competition studies, AMT was stereospecific; d-AMPH (IC50 = 60 nM) was an 8-fold more potent inhibitor of the transport than its I-isomer (IC50 = 466 nM). DA(IC50 = 257 nM), DA uptake blockers and substrates were found to be potent inhibitors of AMT: GBR12909 IC50 = 5 nM; methamphetamine IC50 = 48 nM; methylphenidate IC50 = 53 nM; and cocaine IC50 = 172 nM. In contrast, serotonin was relatively weak in inhibiting AMT (IC50 = 7.9 microM). There was a highly significant (P less than .001; slope = 1.2) linear correlation between the AMT-inhibiting potencies of AMPH analogs and their potencies in stimulating locomotor activity in rodents. AMT may be important in the low dose effects of AMPH such as increased locomotor activity in rodents and stimulant activity in man. Differences between AMT and d-({sup 3}H)AMPH sequestration described earlier, as well as their possible relevance to behavioral and neurochemical sequelae of AMPH administration are also discussed.

  1. Neuroprotective effect of WIN55,212-2 against 3-nitropropionic acid-induced toxicity in the rat brain: involvement of CB1 and NMDA receptors

    PubMed Central

    Maya-López, Marisol; Colín-González, Ana Laura; Aguilera, Gabriela; de Lima, María Eduarda; Colpo-Ceolin, Ana; Rangel-López, Edgar; Villeda-Hernández, Juana; Rembao-Bojórquez, Daniel; Túnez, Isaac; Luna-López, Armando; Lazzarini-Lechuga, Roberto; González-Puertos, Viridiana Yazmín; Posadas-Rodríguez, Pedro; Silva-Palacios, Alejandro; Königsberg, Mina; Santamaría, Abel

    2017-01-01

    The endocannabinoid system (ECS), and agonists acting on cannabinoid receptors (CBr), are known to regulate several physiological events in the brain, including modulatory actions on excitatory events probably through N-methyl-D-aspartate receptor (NMDAr) activity. Actually, CBr agonists can be neuroprotective. The synthetic CBr agonist WIN55,212-2 acts mainly on CB1 receptor. In turn, the mitochondrial toxin 3-nitropropionic acid (3-NP) produces striatal alterations in rats similar to those observed in the brain of Huntington’s disease patients. Herein, the effects of WIN55,212-2 were tested on different endpoints of the 3-NP-induced toxicity in rat brain synaptosomes and striatal tissue. Motor activity was also evaluated. The 3-NP (1 mM)-induced mitochondrial dysfunction and lipid peroxidation was attenuated by WIN55,212-2 (1 µM) in synaptosomal fractions. The intrastriatal bilateral injection of 3-NP (500 nmol/µL) to rats increased lipid peroxidation and locomotor activity, augmented the rate of cell damage, and decreased the striatal density of neuronal cells. These alterations were accompanied by transcriptional changes in the NMDA (NR1 subunit) content. The administration of WIN55212-2 (1 mg/kg, i.p.) to rats for six consecutive days, before the 3-NP injection, exerted preventive effects on all alterations elicited by the toxin. The prevention of the 3-NP-induced NR1 transcriptional alterations by the CBr agonist together with the increase of CB1 content suggest an early reduction of the excitotoxic process via CBr activation. Our results demonstrate a protective role of WIN55,212-2 on the 3-NP-induced striatal neurotoxicity that could be partially related to the ECS stimulation and induction of NMDAr hypofunction, representing an effective therapeutic strategy at the experimental level for further studies. PMID:28337258

  2. Neuroprotective effect of WIN55,212-2 against 3-nitropropionic acid-induced toxicity in the rat brain: involvement of CB1 and NMDA receptors.

    PubMed

    Maya-López, Marisol; Colín-González, Ana Laura; Aguilera, Gabriela; de Lima, María Eduarda; Colpo-Ceolin, Ana; Rangel-López, Edgar; Villeda-Hernández, Juana; Rembao-Bojórquez, Daniel; Túnez, Isaac; Luna-López, Armando; Lazzarini-Lechuga, Roberto; González-Puertos, Viridiana Yazmín; Posadas-Rodríguez, Pedro; Silva-Palacios, Alejandro; Königsberg, Mina; Santamaría, Abel

    2017-01-01

    The endocannabinoid system (ECS), and agonists acting on cannabinoid receptors (CBr), are known to regulate several physiological events in the brain, including modulatory actions on excitatory events probably through N-methyl-D-aspartate receptor (NMDAr) activity. Actually, CBr agonists can be neuroprotective. The synthetic CBr agonist WIN55,212-2 acts mainly on CB1 receptor. In turn, the mitochondrial toxin 3-nitropropionic acid (3-NP) produces striatal alterations in rats similar to those observed in the brain of Huntington's disease patients. Herein, the effects of WIN55,212-2 were tested on different endpoints of the 3-NP-induced toxicity in rat brain synaptosomes and striatal tissue. Motor activity was also evaluated. The 3-NP (1 mM)-induced mitochondrial dysfunction and lipid peroxidation was attenuated by WIN55,212-2 (1 µM) in synaptosomal fractions. The intrastriatal bilateral injection of 3-NP (500 nmol/µL) to rats increased lipid peroxidation and locomotor activity, augmented the rate of cell damage, and decreased the striatal density of neuronal cells. These alterations were accompanied by transcriptional changes in the NMDA (NR1 subunit) content. The administration of WIN55212-2 (1 mg/kg, i.p.) to rats for six consecutive days, before the 3-NP injection, exerted preventive effects on all alterations elicited by the toxin. The prevention of the 3-NP-induced NR1 transcriptional alterations by the CBr agonist together with the increase of CB1 content suggest an early reduction of the excitotoxic process via CBr activation. Our results demonstrate a protective role of WIN55,212-2 on the 3-NP-induced striatal neurotoxicity that could be partially related to the ECS stimulation and induction of NMDAr hypofunction, representing an effective therapeutic strategy at the experimental level for further studies.

  3. c-jun expression in substantia nigra neurons following striatal 6-hydroxydopamine lesions in the rat.

    PubMed

    Jenkins, R; O'Shea, R; Thomas, K L; Hunt, S P

    1993-03-01

    The proto-oncogene c-jun is thought to play a role in the control of growth and differentiation of many cell types. It has been demonstrated previously that damage to axons of peripheral motor or sensory neurons resulted within 24 h in substantially increased levels of the c-jun gene in the parent cell bodies. These increased levels of c-jun protein and messenger RNA are maintained if the damaged nerve is ligated, but return to basal levels if the peripheral nerve is allowed to regenerate. We have examined the expression of immediate early genes in central neurons of the rat and now show that a 6-hydroxydopamine-induced axotomy of the dopaminergic nigrostriatal pathway results in a substantial increase in the levels of c-jun (but not c-fos) messenger RNA and protein within neurons of the substantia nigra pars compacta. However, the central neuronal response differs from the peripheral nerve response in that it becomes maximal at four to eight days post-lesion and is transient, declining to control levels in nigral neurons by 14 days post-lesion. These expression patterns may be related to the differential capacity of central and peripheral neurons to regenerate. The precise role of c-jun in these processes, or in the regenerative response, is unclear but it remains possible that c-jun activation following axon damage leads to an increased expression of genes which are essential for the regenerative response. The nature of the mechanism by which c-jun levels are attenuated in central neurons is also unclear, but inhibitory factors, generated by the central environment, may play a role.

  4. Performance of a high-sensitivity dedicated cardiac SPECT scanner for striatal uptake quantification in the brain based on analysis of projection data

    PubMed Central

    Park, Mi-Ae; Moore, Stephen C.; Müller, Stefan P.; McQuaid, Sarah J.; Kijewski, Marie Foley

    2013-01-01

    Purpose: The authors have previously reported the advantages of high-sensitivity single-photon emission computed tomography (SPECT) systems for imaging structures located deep inside the brain. DaTscan (Isoflupane I-123) is a dopamine transporter (DaT) imaging agent that has shown potential for early detection of Parkinson disease (PD), as well as for monitoring progression of the disease. Realizing the full potential of DaTscan requires efficient estimation of striatal uptake from SPECT images. They have evaluated two SPECT systems, a conventional dual-head gamma camera with low-energy high-resolution collimators (conventional) and a dedicated high-sensitivity multidetector cardiac imaging system (dedicated) for imaging tasks related to PD. Methods: Cramer–Rao bounds (CRB) on precision of estimates of striatal and background activity concentrations were calculated from high-count, separate acquisitions of the compartments (right striata, left striata, background) of a striatal phantom. CRB on striatal and background activity concentration were calculated from essentially noise-free projection datasets, synthesized by scaling and summing the compartment projection datasets, for a range of total detected counts. They also calculated variances of estimates of specific-to-nonspecific binding ratios (BR) and asymmetry indices from these values using propagation of error analysis, as well as the precision of measuring changes in BR on the order of the average annual decline in early PD. Results: Under typical clinical conditions, the conventional camera detected 2 M counts while the dedicated camera detected 12 M counts. Assuming a normal BR of 5, the standard deviation of BR estimates was 0.042 and 0.021 for the conventional and dedicated system, respectively. For an 8% decrease to BR = 4.6, the signal-to-noise ratio were 6.8 (conventional) and 13.3 (dedicated); for a 5% decrease, they were 4.2 (conventional) and 8.3 (dedicated). Conclusions: This implies that PD can

  5. Performance of a high-sensitivity dedicated cardiac SPECT scanner for striatal uptake quantification in the brain based on analysis of projection data

    SciTech Connect

    Park, Mi-Ae; Moore, Stephen C.; McQuaid, Sarah J.; Kijewski, Marie Foley; Mueller, Stefan P.

    2013-04-15

    Purpose: The authors have previously reported the advantages of high-sensitivity single-photon emission computed tomography (SPECT) systems for imaging structures located deep inside the brain. DaTscan (Isoflupane I-123) is a dopamine transporter (DaT) imaging agent that has shown potential for early detection of Parkinson disease (PD), as well as for monitoring progression of the disease. Realizing the full potential of DaTscan requires efficient estimation of striatal uptake from SPECT images. They have evaluated two SPECT systems, a conventional dual-head gamma camera with low-energy high-resolution collimators (conventional) and a dedicated high-sensitivity multidetector cardiac imaging system (dedicated) for imaging tasks related to PD. Methods: Cramer-Rao bounds (CRB) on precision of estimates of striatal and background activity concentrations were calculated from high-count, separate acquisitions of the compartments (right striata, left striata, background) of a striatal phantom. CRB on striatal and background activity concentration were calculated from essentially noise-free projection datasets, synthesized by scaling and summing the compartment projection datasets, for a range of total detected counts. They also calculated variances of estimates of specific-to-nonspecific binding ratios (BR) and asymmetry indices from these values using propagation of error analysis, as well as the precision of measuring changes in BR on the order of the average annual decline in early PD. Results: Under typical clinical conditions, the conventional camera detected 2 M counts while the dedicated camera detected 12 M counts. Assuming a normal BR of 5, the standard deviation of BR estimates was 0.042 and 0.021 for the conventional and dedicated system, respectively. For an 8% decrease to BR = 4.6, the signal-to-noise ratio were 6.8 (conventional) and 13.3 (dedicated); for a 5% decrease, they were 4.2 (conventional) and 8.3 (dedicated). Conclusions: This implies that PD can

  6. Activating Developmental Reserve Capacity Via Cognitive Training or Non-invasive Brain Stimulation: Potentials for Promoting Fronto-Parietal and Hippocampal-Striatal Network Functions in Old Age.

    PubMed

    Passow, Susanne; Thurm, Franka; Li, Shu-Chen

    2017-01-01

    Existing neurocomputational and empirical data link deficient neuromodulation of the fronto-parietal and hippocampal-striatal circuitries with aging-related increase in processing noise and declines in various cognitive functions. Specifically, the theory of aging neuronal gain control postulates that aging-related suboptimal neuromodulation may attenuate neuronal gain control, which yields computational consequences on reducing the signal-to-noise-ratio of synaptic signal transmission and hampering information processing within and between cortical networks. Intervention methods such as cognitive training and non-invasive brain stimulation, e.g., transcranial direct current stimulation (tDCS), have been considered as means to buffer cognitive functions or delay cognitive decline in old age. However, to date the reported effect sizes of immediate training gains and maintenance effects of a variety of cognitive trainings are small to moderate at best; moreover, training-related transfer effects to non-trained but closely related (i.e., near-transfer) or other (i.e., far-transfer) cognitive functions are inconsistent or lacking. Similarly, although applying different tDCS protocols to reduce aging-related cognitive impairments by inducing temporary changes in cortical excitability seem somewhat promising, evidence of effects on short- and long-term plasticity is still equivocal. In this article, we will review and critically discuss existing findings of cognitive training- and stimulation-related behavioral and neural plasticity effects in the context of cognitive aging, focusing specifically on working memory and episodic memory functions, which are subserved by the fronto-parietal and hippocampal-striatal networks, respectively. Furthermore, in line with the theory of aging neuronal gain control we will highlight that developing age-specific brain stimulation protocols and the concurrent applications of tDCS during cognitive training may potentially facilitate

  7. The interrelationship of dopamine D2-like receptor availability in striatal and extrastriatal brain regions in healthy humans: a principal component analysis of [18F]fallypride binding.

    PubMed

    Zald, David H; Woodward, Neil D; Cowan, Ronald L; Riccardi, Patrizia; Ansari, M Sib; Baldwin, Ronald M; Cowan, Ronald L; Smith, Clarence E; Hakyemez, Helene; Li, Rui; Kessler, Robert M

    2010-05-15

    Individual differences in dopamine D2-like receptor availability arise across all brain regions expressing D2-like receptors. However, the interrelationships in receptor availability across brain regions are poorly understood. To address this issue, we examined the relationship between D2-like binding potential (BPND) across striatal and extrastriatal regions in a sample of healthy participants. PET imaging was performed with the high affinity D2/D3 ligand [18F]fallypride in 45 participants. BPND images were submitted to voxel-wise principal component analysis to determine the pattern of associations across brain regions. Individual differences in D2-like BPND were explained by three distinguishable components. A single component explained almost all of the variance within the striatum, indicating that individual differences in receptor availability vary in a homogenous manner across the caudate, putamen, and ventral striatum. Cortical BPND was only modestly related to striatal BPND and mostly loaded on a distinct component. After controlling for the general level of cortical D2-like BPND, an inverse relationship emerged between receptor availability in the striatum and the ventral temporal and ventromedial frontal cortices, suggesting possible cross-regulation of D2-like receptors in these regions. The analysis additionally revealed evidence of: (1) a distinct component involving the midbrain and limbic areas; (2) a dissociation between BPND in the medial and lateral temporal regions; and (3) a dissociation between BPND in the medial/midline and lateral thalamus. In summary, individual differences in D2-like receptor availability reflect several distinct patterns. This conclusion has significant implications for neuropsychiatric models that posit global or regionally specific relationships between dopaminergic tone and behavior. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  8. Activating Developmental Reserve Capacity Via Cognitive Training or Non-invasive Brain Stimulation: Potentials for Promoting Fronto-Parietal and Hippocampal-Striatal Network Functions in Old Age

    PubMed Central

    Passow, Susanne; Thurm, Franka; Li, Shu-Chen

    2017-01-01

    Existing neurocomputational and empirical data link deficient neuromodulation of the fronto-parietal and hippocampal-striatal circuitries with aging-related increase in processing noise and declines in various cognitive functions. Specifically, the theory of aging neuronal gain control postulates that aging-related suboptimal neuromodulation may attenuate neuronal gain control, which yields computational consequences on reducing the signal-to-noise-ratio of synaptic signal transmission and hampering information processing within and between cortical networks. Intervention methods such as cognitive training and non-invasive brain stimulation, e.g., transcranial direct current stimulation (tDCS), have been considered as means to buffer cognitive functions or delay cognitive decline in old age. However, to date the reported effect sizes of immediate training gains and maintenance effects of a variety of cognitive trainings are small to moderate at best; moreover, training-related transfer effects to non-trained but closely related (i.e., near-transfer) or other (i.e., far-transfer) cognitive functions are inconsistent or lacking. Similarly, although applying different tDCS protocols to reduce aging-related cognitive impairments by inducing temporary changes in cortical excitability seem somewhat promising, evidence of effects on short- and long-term plasticity is still equivocal. In this article, we will review and critically discuss existing findings of cognitive training- and stimulation-related behavioral and neural plasticity effects in the context of cognitive aging, focusing specifically on working memory and episodic memory functions, which are subserved by the fronto-parietal and hippocampal-striatal networks, respectively. Furthermore, in line with the theory of aging neuronal gain control we will highlight that developing age-specific brain stimulation protocols and the concurrent applications of tDCS during cognitive training may potentially facilitate

  9. Laser scattering by transcranial rat brain illumination

    NASA Astrophysics Data System (ADS)

    Sousa, Marcelo V. P.; Prates, Renato; Kato, Ilka T.; Sabino, Caetano P.; Suzuki, Luis C.; Ribeiro, Martha S.; Yoshimura, Elisabeth M.

    2012-06-01

    Due to the great number of applications of Low-Level-Laser-Therapy (LLLT) in Central Nervous System (CNS), the study of light penetration through skull and distribution in the brain becomes extremely important. The aim is to analyze the possibility of precise illumination of deep regions of the rat brain, measure the penetration and distribution of red (λ = 660 nm) and Near Infra-Red (NIR) (λ = 808 nm) diode laser light and compare optical properties of brain structures. The head of the animal (Rattus Novergicus) was epilated and divided by a sagittal cut, 2.3 mm away from mid plane. This section of rat's head was illuminated with red and NIR lasers in points above three anatomical structures: hippocampus, cerebellum and frontal cortex. A high resolution camera, perpendicularly positioned, was used to obtain images of the brain structures. Profiles of scattered intensities in the laser direction were obtained from the images. There is a peak in the scattered light profile corresponding to the skin layer. The bone layer gives rise to a valley in the profile indicating low scattering coefficient, or frontal scattering. Another peak in the region related to the brain is an indication of high scattering coefficient (μs) for this tissue. This work corroborates the use of transcranial LLLT in studies with rats which are subjected to models of CNS diseases. The outcomes of this study point to the possibility of transcranial LLLT in humans for a large number of diseases.

  10. Genetic influence on brain catecholamines: high brain norepinephrine in salt-sensitive rats

    SciTech Connect

    Iwai, J; Friedman, R; Tassinari, L

    1980-01-01

    Rats genetically sensitive to salt-induced hypertension evinced higher levels of plasma norepinephrine and epinephrine than rats genetically resistant to hypertension. The hypertension-sensitive rats showed higher hypothalamic norepinephrine and lower epinephrine than resistant rats. In response to a high salt diet, brain stem norepinephrine increased in sensitive rats while resistant rats exhibited a decrease on the same diet.

  11. Serotonin 5-HT2A but not 5-HT2C receptor antagonism reduces hyperlocomotor activity induced in dopamine-depleted rats by striatal administration of the D1 agonist SKF 82958.

    PubMed

    Bishop, Christopher; Daut, Gregory S; Walker, Paul D

    2005-09-01

    While recent work has indicated that D1 receptor agonist-induced hyperlocomotion in DA-depleted rats is reduced by striatal 5-HT2 receptor antagonism, the 5-HT receptor(s) subtypes mediating these effects are not yet known. In the present study, we examined the influence(s) of striatal 5-HT2A and 5-HT2C receptors on locomotor behavior induced by D1 agonism in neonatal DA-depleted rats. On postnatal day 3, male Sprague-Dawley rats (n=68) were treated with either vehicle or 6-hydroxydopamine (6-OHDA; 60 microg) which produced >98% DA depletion. Sixty days later, all rats were fitted with bilateral striatal cannulae. A subset of control and 6-OHDA-lesioned rats (n=20) was tested for locomotor responses to striatal infusion of the D1 agonist SKF 82958 (0, 0.1, 1.0, 10 microg/side). The remaining rats (n=48) were tested for locomotor responses to intrastriatal SKF 82958 (2.0 microg/side) alone or in combination with the 5-HT2A- or 5-HT2C-preferring antagonists M100907 or RS102221 (0.1 or 1.0 microg/side), respectively. Intrastriatal SKF 82958 dose-dependently increased measures of motor activity within DA-depleted rats. This hyperlocomotor activity was suppressed by co-infusion of M100907, but not RS102221. These results indicate that DA depletion strengthens striatal 5-HT2A/D1 receptor interactions and suggest that 5-HT2A receptor antagonists may prove useful in reducing D1-related movements.

  12. Inhibition by apomorphine of the metoclopramide-induced catalepsy and increase in striatal homovanillic acid content.

    PubMed Central

    Ahtee, L

    1975-01-01

    1 The mechanism of the cataleptic effect of metoclopramide was analyzed by using drugs which alter the activity of dopaminergic or cholinergic neurones or the content of psi-aminobutyric acid in the central nervous system of rats. 2 The cataleptic effect of metoclopramide (20 mg/kg) was antagonized by apomorphine (10 mg/kg) and by atropine (50 mg/kg). Aminoxyacete acid (AOAA, 25-50 mg/kg) potentiated the catalepsy induced by metoclopramide (5 mg/kg). 3 Metoclopramide alone did not alter the rectal temperature of rats. It did not alter the AOAA-induced hypothermia, but it partially antagonized apomorphine-induced hypothermia. 4 Metoclopramide induced a six-fold increase in striatal homovanillic acid (HVA) concentration, but it did not change the dopamine or noradrenaline content in the brain of rats. Apomorphine decreased the striatal HVA concentration in control and in metoclopramide-treated rats. Atropine and AOAA did not alter the metoclopramide-induced increase in striatal HVA concentration. 5 The results suggest that metoclopramide produces catalepsy by blocking striatal dopamine receptors. PMID:1239323

  13. Multicistronic lentiviral vector-mediated striatal gene transfer of aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase I induces sustained transgene expression, dopamine production, and functional improvement in a rat model of Parkinson's disease.

    PubMed

    Azzouz, Mimoun; Martin-Rendon, Enca; Barber, Robert D; Mitrophanous, Kyriacos A; Carter, Emma E; Rohll, Jonathan B; Kingsman, Susan M; Kingsman, Alan J; Mazarakis, Nicholas D

    2002-12-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. This loss leads to complete dopamine depletion in the striatum and severe motor impairment. It has been demonstrated previously that a lentiviral vector system based on equine infectious anemia virus (EIAV) gives rise to highly efficient and sustained transduction of neurons in the rat brain. Therefore, a dopamine replacement strategy using EIAV has been investigated as a treatment in the 6-hydroxydopamine (6-OHDA) animal model of PD. A self-inactivating EIAV minimal lentiviral vector that expresses tyrosine hydroxylase (TH), aromatic amino acid dopa decarboxylase (AADC), and GTP cyclohydrolase 1 (CH1) in a single transcription unit has been generated. In cultured striatal neurons transduced with this vector, TH, AADC, and CH1 proteins can all be detected. After stereotactic delivery into the dopamine-denervated striatum of the 6-OHDA-lesioned rat, sustained expression of each enzyme and effective production of catecholamines were detected, resulting in significant reduction of apomorphine-induced motor asymmetry compared with control animals (p < 0.003). Expression of each enzyme in the striatum was observed for up to 5 months after injection. These data indicate that the delivery of three catecholaminergic synthetic enzymes by a single lentiviral vector can achieve functional improvement and thus open the potential for the use of this vector for gene therapy of late-stage PD patients.

  14. Effects of amphetamine on striatal dopamine release, open-field activity, and play in Fischer 344 and Sprague-Dawley rats.

    PubMed

    Siviy, Stephen M; McDowell, Lana S; Eck, Samantha R; Turano, Alexandra; Akopian, Garnik; Walsh, John P

    2015-12-01

    Previous work from our laboratories has shown that juvenile Fischer 344 (F344) rats are less playful than other strains and also appear to be compromised in dopamine (DA) functioning. To determine whether the dysfunctional play in this strain is associated with deficits in the handling and delivery of vesicular DA, the following experiments assessed the extent to which F344 rats are differentially sensitive to the effects of amphetamine. When exposed to amphetamine, striatal slices obtained from F344 rats showed a small increase in unstimulated DA release when compared with slices from Sprague-Dawley rats; they also showed a more rapid high K+-mediated release of DA. These data provide tentative support for the hypothesis that F344 rats have a higher concentration of cytoplasmic DA than Sprague-Dawley rats. When rats were tested for activity in an open field, F344 rats presented a pattern of results that was consistent with either an enhanced response to amphetamine (3 mg/kg) or a more rapid release of DA (10 mg/kg). Although there was some indication that amphetamine had a dose-dependent differential effect on play in the two strains, play in F344 rats was not enhanced to any degree by amphetamine. Although these results are not consistent with our working hypothesis that F344 rats are less playful because of a deficit in vesicular release of DA, they still suggest that this strain may be a useful model for better understanding the role of DA in social behavior during the juvenile period.

  15. Malfunctioning DNA damage response (DDR) leads to the degeneration of nigro-striatal pathway in mouse brain.

    PubMed

    Kirshner, Michal; Galron, Ronit; Frenkel, Dan; Mandelbaum, Gil; Shiloh, Yosef; Wang, Zhao-Qi; Barzilai, Ari

    2012-03-01

    Pronounced neuropathology is a feature of ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS), which are both genomic instability syndromes. The Nbs1 protein, which is defective in NBS, is a component of the Mre11/RAD50/NBS1 (MRN) complex. This complex plays a major role in the early phase of the cellular response to double strand breaks (DSBs) in the DNA. Among others, MRN is required for timely activation of the protein kinase ATM (A-T mutated), which is disrupted in patients with A-T. Earlier reports show that Atm-deficient mice exhibit severe degeneration of tyrosine hydroxylase (TH)-positive dopaminergic nigro-striatal neurons and their terminals in the striatum. This cell loss is accompanied by a large reduction in immunoreactivity for the dopamine transporter protein (DAT) in the striatum. To test whether Nbs1 inactivation also affects the integrity of the nigro-striatal pathway, we examined this pathway in a murine model with conditional inactivation of the Nbs1 gene in central nervous system (Nbs1-CNS-Δ). We report that this model has a reduction in TH-positive cells in the substantia nigra. This phenomenon was seen at very early age, while Atm-/- mice showed a progressive age-dependent reduction. Furthermore, we observed an age-dependent increase in the level of TH in the striatum of Atm-/- and Nbs1-CNS-Δ mice. In addition to the altered expression of TH, we also found a reduction of DAT in the striatum of both Atm-/- and Nbs1-CNS-Δ mice at 60 days of age. Finally, microglial recruitment and alterations in the levels of various neurotrophic factors were also observed. These results indicate that malfunctioning DNA damage response severely affects the integrity of the nigro-striatal pathway and suggest a new neurodegenerative pathway in Parkinsonian syndromes.

  16. Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward

    PubMed Central

    Stouffer, Melissa A.; Woods, Catherine A.; Patel, Jyoti C.; Lee, Christian R.; Witkovsky, Paul; Bao, Li; Machold, Robert P.; Jones, Kymry T.; de Vaca, Soledad Cabeza; Reith, Maarten E. A.; Carr, Kenneth D.; Rice, Margaret E.

    2015-01-01

    Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate–putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices. PMID:26503322

  17. Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward.

    PubMed

    Stouffer, Melissa A; Woods, Catherine A; Patel, Jyoti C; Lee, Christian R; Witkovsky, Paul; Bao, Li; Machold, Robert P; Jones, Kymry T; de Vaca, Soledad Cabeza; Reith, Maarten E A; Carr, Kenneth D; Rice, Margaret E

    2015-10-27

    Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate-putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices.

  18. Huntington's Disease and Striatal Signaling.

    PubMed

    Roze, Emmanuel; Cahill, Emma; Martin, Elodie; Bonnet, Cecilia; Vanhoutte, Peter; Betuing, Sandrine; Caboche, Jocelyne

    2011-01-01

    Huntington's Disease (HD) is the most frequent neurodegenerative disease caused by an expansion of polyglutamines (CAG). The main clinical manifestations of HD are chorea, cognitive impairment, and psychiatric disorders. The transmission of HD is autosomal dominant with a complete penetrance. HD has a single genetic cause, a well-defined neuropathology, and informative pre-manifest genetic testing of the disease is available. Striatal atrophy begins as early as 15 years before disease onset and continues throughout the period of manifest illness. Therefore, patients could theoretically benefit from therapy at early stages of the disease. One important characteristic of HD is the striatal vulnerability to neurodegeneration, despite similar expression of the protein in other brain areas. Aggregation of the mutated Huntingtin (HTT), impaired axonal transport, excitotoxicity, transcriptional dysregulation as well as mitochondrial dysfunction, and energy deficits, are all part of the cellular events that underlie neuronal dysfunction and striatal death. Among these non-exclusive mechanisms, an alteration of striatal signaling is thought to orchestrate the downstream events involved in the cascade of striatal dysfunction.

  19. Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: Association to striatal D2/D3 receptors

    SciTech Connect

    Tomasi, Dardo; Wang, Gene -Jack; Wang, Ruiliang; Caparelli, Elisabeth C.; Logan, Jean; Volkow, Nora D.

    2014-08-20

    Cocaine, through its activation of dopamine (DA) signaling, usurps pathways that process natural rewards. However, the extent to which there is overlap between the networks that process natural and drug rewards and whether DA signaling associated with cocaine abuse influences these networks have not been investigated in humans. We measured brain activation responses to food and cocaine cues with fMRI, and D2/D3 receptors in the striatum with [11C]raclopride and PET in 20 active cocaine abusers. Compared to neutral cues, food and cocaine cues increasingly engaged cerebellum, orbitofrontal, inferior frontal and premotor cortices and insula and disengaged cuneus and default mode network (DMN). These fMRI signals were proportional to striatal D2/D3 receptors. Surprisingly cocaine and food cues also deactivated ventral striatum and hypothalamus. Compared to food cues, cocaine cues produced lower activation in insula and postcentral gyrus, and less deactivation in hypothalamus and DMN regions. Activation in cortical regions and cerebellum increased in proportion to the valence of the cues, and activation to food cues in somatosensory and orbitofrontal cortices also increased in proportion to body mass. Longer exposure to cocaine was associated with lower activation to both cues in occipital cortex and cerebellum, which could reflect the decreases in D2/D3 receptors associated with chronicity. In conclusion, these findings show that cocaine cues activate similar, though not identical, pathways to those activated by food cues and that striatal D2/D3 receptors modulate these responses, suggesting that chronic cocaine exposure might influence brain sensitivity not just to drugs but also to food cues.

  20. Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: Association to striatal D2/D3 receptors

    DOE PAGES

    Tomasi, Dardo; Wang, Gene -Jack; Wang, Ruiliang; ...

    2014-08-20

    Cocaine, through its activation of dopamine (DA) signaling, usurps pathways that process natural rewards. However, the extent to which there is overlap between the networks that process natural and drug rewards and whether DA signaling associated with cocaine abuse influences these networks have not been investigated in humans. We measured brain activation responses to food and cocaine cues with fMRI, and D2/D3 receptors in the striatum with [11C]raclopride and PET in 20 active cocaine abusers. Compared to neutral cues, food and cocaine cues increasingly engaged cerebellum, orbitofrontal, inferior frontal and premotor cortices and insula and disengaged cuneus and default modemore » network (DMN). These fMRI signals were proportional to striatal D2/D3 receptors. Surprisingly cocaine and food cues also deactivated ventral striatum and hypothalamus. Compared to food cues, cocaine cues produced lower activation in insula and postcentral gyrus, and less deactivation in hypothalamus and DMN regions. Activation in cortical regions and cerebellum increased in proportion to the valence of the cues, and activation to food cues in somatosensory and orbitofrontal cortices also increased in proportion to body mass. Longer exposure to cocaine was associated with lower activation to both cues in occipital cortex and cerebellum, which could reflect the decreases in D2/D3 receptors associated with chronicity. In conclusion, these findings show that cocaine cues activate similar, though not identical, pathways to those activated by food cues and that striatal D2/D3 receptors modulate these responses, suggesting that chronic cocaine exposure might influence brain sensitivity not just to drugs but also to food cues.« less

  1. Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: association to striatal D2/D3 receptors

    PubMed Central

    Tomasi, Dardo; Wang, Gene-Jack; Wang, Ruiliang; Caparelli, Elisabeth C.; Logan, Jean; Volkow, Nora D.

    2014-01-01

    Cocaine, through its activation of dopamine (DA) signaling, usurps pathways that process natural rewards. However, the extent to which there is overlap between the networks that process natural and drug rewards and whether DA signaling associated with cocaine abuse influences these networks have not been investigated in humans. We measured brain activation responses to food and cocaine cues with fMRI, and D2/D3 receptors in the striatum with [11C]raclopride and PET in 20 active cocaine abusers. Compared to neutral cues, food and cocaine cues increasingly engaged cerebellum, orbitofrontal, inferior frontal and premotor cortices and insula and disengaged cuneus and default mode network (DMN). These fMRI signals were proportional to striatal D2/D3 receptors. Surprisingly cocaine and food cues also deactivated ventral striatum and hypothalamus. Compared to food cues, cocaine cues produced lower activation in insula and postcentral gyrus, and less deactivation in hypothalamus and DMN regions. Activation in cortical regions and cerebellum increased in proportion to the valence of the cues, and activation to food cues in somatosensory and orbitofrontal cortices also increased in proportion to body mass. Longer exposure to cocaine was associated with lower activation to both cues in occipital cortex and cerebellum, which could reflect the decreases in D2/D3 receptors associated with chronicity. These findings show that cocaine cues activate similar, though not identical, pathways to those activated by food cues and that striatal D2/D3 receptors modulate these responses, suggesting that chronic cocaine exposure might influence brain sensitivity not just to drugs but also to food cues. PMID:25142207

  2. Histamine H3 receptor activation stimulates calcium mobilization in a subpopulation of rat striatal neurons in primary culture, but not in synaptosomes.

    PubMed

    Rivera-Ramírez, Nayeli; Montejo-López, Wilber; López-Méndez, María-Cristina; Guerrero-Hernández, Agustín; Molina-Hernández, Anayansi; García-Hernández, Ubaldo; Arias-Montaño, José-Antonio

    2016-12-01

    The histamine H3 receptor (H3R) is abundantly expressed in the Central Nervous System where it regulates several functions pre and postsynaptically. H3Rs couple to Gαi/o proteins and trigger or modulate several intracellular signaling pathways, including the cAMP/PKA pathway and the opening of N- and P/Q-type voltage-gated Ca(2+) channels. In transfected cells, activation of the human H3R of 445 amino acids (hH3R445) results in phospholipase C (PLC) stimulation and release of Ca(2+) from intracellular stores. In this work we have studied whether H3R activation induces Ca(2+) mobilization from intracellular stores in native systems, either isolated nerve terminals (synaptosomes) or neurons in primary culture. In rat striatal synaptosomes H3R activation induced inositol 1,4,5-trisphosphate (IP3) formation but failed to increase the intracellular calcium concentration ([Ca(2+)]i). In striatal primary cultures H3R activation resulted in IP3 formation and increased the [Ca(2+)]i in 18 out of 70 cells that responded with an elevation in the [Ca(2+)]i to membrane depolarization with KCl (100 mM) as evaluated by microfluorometry. Confocal microscopy studies corroborated the increase in [Ca(2+)]i induced by H3R activation in a fraction of those cells that were responsive to membrane depolarization. These results indicate that H3R activation stimulates the PLC/IP3/Ca(2+) pathway but only in a subpopulation of striatal neurons.

  3. The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease.

    PubMed

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

    2015-01-01

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

  4. EVALUATION OF PERFLUOROOCTANE SULFONATE (PFOS) IN THE RAT BRAIN

    EPA Science Inventory

    This study examined whether there is a differential distribution of PFOS within the brain, and compares adult rats with neonatal rats at an age when formation of the blood-brain barrier is not yet complete (postnatal day 7). Male and female Sprague-Dawley rats (60-70 day old, 4/...

  5. EVALUATION OF PERFLUOROOCTANE SULFONATE (PFOS) IN THE RAT BRAIN

    EPA Science Inventory

    This study examined whether there is a differential distribution of PFOS within the brain, and compares adult rats with neonatal rats at an age when formation of the blood-brain barrier is not yet complete (postnatal day 7). Male and female Sprague-Dawley rats (60-70 day old, 4/...

  6. Age-dependent changes in cocaine sensitivity across early ontogeny in male and female rats: Possible role of dorsal striatal D2High receptors

    PubMed Central

    McDougall, Sanders A.; Eaton, Shannon E.; Mohd-Yusof, Alena; Crawford, Cynthia A.

    2015-01-01

    Rationale Responsiveness to acute psychostimulant administration varies across ontogeny. Objective The purpose of the present study was to determine if age-dependent changes in D2High receptors may be responsible for the ontogeny of cocaine sensitivity in preweanling, adolescent, and adult rats. Methods [3H]-Domperidone/dopamine competition assays were used to determine ontogenetic changes in the proportion of D2High receptors in male and female preweanling [postnatal day (PD) 5, 10, 15, and 20], adolescent (PD 40), and adult rats (PD 80). In the behavioral experiment, responsiveness to cocaine (2.5, 5, 10, or 20 mg/kg) was assessed on PD 20, PD 40, and PD 80 for 60 min. Male and female rats were habituated to the apparatus on the two days prior to testing. Distance traveled data were presented both untransformed and as percent of saline controls. Results Male and female preweanling rats (PD 5–PD 20) had a significantly greater percentage of dorsal striatal D2High receptors than adolescent or adult rats. Likewise, preweanling rats (PD 20) were more sensitive to the behavioral effects of cocaine than the two older age groups. Adolescent and adult rats responded in a generally similar manner, however analysis of the untransformed locomotor activity data suggested that adolescent rats were hyporesponsive to 2.5 and 20 mg/kg cocaine when compared to adults. Conclusions Data from the present study are consistent with the hypothesis that ontogenetic changes in D2High receptors are responsible for age-dependent differences in psychostimulant sensitivity. PMID:25589144

  7. Secretin: specific binding to rat brain membranes

    SciTech Connect

    Fremeau, R.T. Jr.; Jensen, R.T.; Charlton, C.G.; Miller, R.L.; O'Donohue, T.L.; Moody, T.W.

    1983-08-01

    The binding of (/sup 125/I)secretin to rat brain membranes was investigated. Radiolabeled secretin bound with high affinity (KD . 0.2 nM) to a single class of noninteracting sites. Binding was specific, saturable, and reversible. Regional distribution studies indicated that the specific binding was greatest in the cerebellum, intermediate in the cortex, thalamus, striatum, hippocampus, and hypothalamus, and lowest in the midbrain and medulla/pons. Pharmacological studies indicated that only secretin, but not other peptides, inhibits binding of (/sup 125/I)secretin with high affinity. Also, certain guanine nucleotides inhibited high affinity binding. These data indicate that rat brain membranes possess high affinity binding sites specific for secretin and that with the use of (/sup 125/I) secretin the kinetics, stoichiometry, specificity, and distribution of secretin receptors can be directly investigated.

  8. Subchronic administration of short-acting naltrexone has no effect on striatal dopamine transporter availability, food intake or body weight gain in rats.

    PubMed

    Zaaijer, Eline R; de Bruin, Kora; la Fleur, Susanne E; Goudriaan, Anna E; van den Brink, Wim; Booij, Jan

    2015-03-01

    The opioid receptor antagonist naltrexone is successfully used in the treatment of opioid and alcohol dependence. However, questions have been raised about possible anhedonic side effects, because the opioid system is directly involved in hedonic responses to natural rewarding activities, possibly due to its indirect effects on the striatal dopamine transporter (DAT). In order to test this hypothesis, 30 rats were randomized to either a 10-day treatment with 3 mg/kg short-acting naltrexone or vehicle. No significant differences between the groups were found in striatal DAT availability, cumulative food intake (for 48 or 72 h), body weight gain and abdominal fatpad weight. Thus, the results of this study suggest that (sub)chronic treatment with short-acting naltrexone does not induce possible anhedonic effects. However, it cannot be ruled out the anhedonic effect of naltrexone is only short-lived and thus not detected in the current study. Therefore, future studies are needed to study possible acute anhedonic effects at several time points shortly after short-acting naltrexone administration and to directly compare the possible anhedonic effects of long-acting with those of short-acting opioid antagonists.

  9. Effect of structural analogs of butaclamol (a new antipsychotic drug) on striatal homovanillic acid and adenyl cyclase of olfactory tubercle in rats.

    PubMed

    Pugsley, T A; Merker, J; Lippman, W

    1976-08-01

    The 3-isopropyl (I), 3-cyclohexyl (II) and 3-phenyl (III) analogs of the new antipsychotic drug butaclamol, which contains a 3-tertiary butyl group, and their respective (+)-enantiomers, but not (-)-enantiomers, caused a dose related elevation of rat striatal homovanillic acid concentration, indicative of an increased dopamine (DA) turnover; droperidol also exhibited this activity. The order of activity of the (+)-enantiomers was (butaclamol) approximately II greater than I greater than III. A decrease in striatal DA was observed with (+)-I and (+)-III at the highest dose used, but not at one-half the dose. Each analog antagonized the DA-induced increase in adenyl cyclase (EC 4.6.1.1) activity of olfactory tubercle homogenates, the order of activity of the racemates (except for II) AND (+)-ENANTIOMERS BEING (BUTACLAMOL) APPROXIMATELY I greater than III greater than II. The (+)-enantiomers of butaclamol and analogs were two to four times more potent than their respective racemates, with (+)-butaclamol and (+)-I displaying activity generally equivalent to fluphenazine. The respective (-)-enantiomers were ineffective indicating a stereochemical specificity for DA-receptor blockade. Such analogs presented should be of value in elucidating dopaminergic mechansims.

  10. Regulation of brain aromatase activity in rats

    SciTech Connect

    Roselli, C.E.; Ellinwood, W.E.; Resko, J.A.

    1984-01-01

    The distribution and regulation of aromatase activity in the adult rat brain with a sensitive in vitro assay that measures the amount of /sup 3/H/sub 2/O formed during the conversion of (1 beta-/sup 3/H)androstenedione to estrone. The rate of aromatase activity in the hypothalamus-preoptic area (HPOA) was linear with time up to 1 h, and with tissue concentrations up to 5 mgeq/200 microliters incubation mixture. The enzyme demonstrated a pH optimum of 7.4 and an apparent Michaelis-Menten constant (Km) of 0.04 microns. The greatest amount of aromatase activity was found in amygdala and HPOA from intact male rats. The hippocampus, midbrain tegmentum, cerebral cortex, cerebellum, and anterior pituitary all contained negligible enzymatic activity. Castration produced a significant decrease in aromatase activity in the HPOA, but not in the amygdala or cerebral cortex. The HPOAs of male rats contained significantly greater aromatase activity than the HPOAs of female rats. In females, this enzyme activity did not change during the estrous cycle or after ovariectomy. Administration of testosterone to gonadectomized male and female rats significantly enhanced HPOA aromatase activities to levels approximating those found in HPOA from intact males. Therefore, the results suggest that testosterone, or one of its metabolites, is a major steroidal regulator of HPOA aromatase activity in rats.

  11. Circadian influences on dopamine circuits of the brain: regulation of striatal rhythms of clock gene expression and implications for psychopathology and disease.

    PubMed

    Verwey, Michael; Dhir, Sabine; Amir, Shimon

    2016-01-01

    Circadian clock proteins form an autoregulatory feedback loop that is central to the endogenous generation and transmission of daily rhythms in behavior and physiology. Increasingly, circadian rhythms in clock gene expression are being reported in diverse tissues and brain regions that lie outside of the suprachiasmatic nucleus (SCN), the master circadian clock in mammals. For many of these extra-SCN rhythms, however, the region-specific implications are still emerging. In order to gain important insights into the potential behavioral, physiological, and psychological relevance of these daily oscillations, researchers have begun to focus on describing the neurochemical, hormonal, metabolic, and epigenetic contributions to the regulation of these rhythms. This review will highlight important sites and sources of circadian control within dopaminergic and striatal circuitries of the brain and will discuss potential implications for psychopathology and disease . For example, rhythms in clock gene expression in the dorsal striatum are sensitive to changes in dopamine release, which has potential implications for Parkinson's disease and drug addiction. Rhythms in the ventral striatum and limbic forebrain are sensitive to psychological and physical stressors, which may have implications for major depressive disorder. Collectively, a rich circadian tapestry has emerged that forces us to expand traditional views and to reconsider the psychopathological, behavioral, and physiological importance of these region-specific rhythms in brain areas that are not immediately linked with the regulation of circadian rhythms.

  12. Circadian influences on dopamine circuits of the brain: regulation of striatal rhythms of clock gene expression and implications for psychopathology and disease

    PubMed Central

    Verwey, Michael; Dhir, Sabine; Amir, Shimon

    2016-01-01

    Circadian clock proteins form an autoregulatory feedback loop that is central to the endogenous generation and transmission of daily rhythms in behavior and physiology. Increasingly, circadian rhythms in clock gene expression are being reported in diverse tissues and brain regions that lie outside of the suprachiasmatic nucleus (SCN), the master circadian clock in mammals. For many of these extra-SCN rhythms, however, the region-specific implications are still emerging. In order to gain important insights into the potential behavioral, physiological, and psychological relevance of these daily oscillations, researchers have begun to focus on describing the neurochemical, hormonal, metabolic, and epigenetic contributions to the regulation of these rhythms. This review will highlight important sites and sources of circadian control within dopaminergic and striatal circuitries of the brain and will discuss potential implications for psychopathology and disease . For example, rhythms in clock gene expression in the dorsal striatum are sensitive to changes in dopamine release, which has potential implications for Parkinson’s disease and drug addiction. Rhythms in the ventral striatum and limbic forebrain are sensitive to psychological and physical stressors, which may have implications for major depressive disorder. Collectively, a rich circadian tapestry has emerged that forces us to expand traditional views and to reconsider the psychopathological, behavioral, and physiological importance of these region-specific rhythms in brain areas that are not immediately linked with the regulation of circadian rhythms. PMID:27635233

  13. Characterization of phenytoin, carbamazepine, vinpocetine and clorgyline simultaneous effects on sodium channels and catecholamine metabolism in rat striatal nerve endings.

    PubMed

    Sitges, María; Aldana, Blanca I; Chiu, Luz M; Nekrassov, Vladimir

    2009-03-01

    The effects of two classic antiepileptic drugs (carbamazepine and phenytoin), a potential antiepileptic (vinpocetine) and a monoamine-oxidase inhibitor (clorgyline) on the simultaneous changes (detected by HPLC) on Glu, Asp, dopamine and DOPAC inside and outside striatal isolated nerve endings were investigated. Under resting conditions phenytoin, carbamazepine and clorgyline increased dopamine release. Phenytoin and clorgyline increased internal dopamine and decreased DOPAC formation. Carbamazepine decreased internal dopamine and practically did not change DOPAC formation. Glu and Asp release was unchanged. Neurotransmitter release induced by the Na+ channel opener veratridine was reduced by all the antiepileptic drugs tested, except phenytoin which, like clorgyline, facilitated veratridine-induced dopamine release. We conclude that besides the antagonism exerted by carbamazepine, phenytoin and vinpocetine on excitatory neurotransmitters release triggered by Na+ channel activation, that might importantly contribute to their anticonvulsant action, they exert different actions on striatal dopamine distribution, that might explain their different side effect profiles.

  14. Regional distribution and subcellular associations of Type II calcium and calmodulin-dependent protein kinase in rat brain

    SciTech Connect

    Erondu, N.E.

    1986-01-01

    Four monoclonal antibodies generated against the Type II CaM kinase have been characterized. Two of these antibodies were used to confirm that both alpha and beta subunits were part of the holoenzyme complex. I also developed liquid phase and solid phase radioimmunoassays for the kinase. With the solid phase radioimmunoassay, the distribution of the kinase in rat brain was examined. This study revealed that the concentration of the kinase varies markedly in different brain regions. It is most highly concentrated in the telencephalon where it comprises approximately 2% of total hippocampal protein, 1.3% of cortical protein and 0.7% of striatal protein. It is less concentrated in lower brain regions ranging from 0.3% of hypothalamic protein to 0.1% of protein in the pons/medulla.

  15. Effects of vitamin E supplementation on plasma membrane permeabilization and fluidization induced by chlorpromazine in the rat brain.

    PubMed

    Maruoka, Nobuyuki; Murata, Tetsuhito; Omata, Naoto; Takashima, Yasuhiro; Fujibayashi, Yasuhisa; Wada, Yuji

    2008-03-01

    Neurotransmitter receptors play a key role in most research on antipsychotic drugs, but little is known about the effects of these drugs on the plasma membrane in the central nervous system. Therefore, we investigated whether chlorpromazine (CPZ), a typical phenothiazine antipsychotic drug, affects the plasma membrane integrity in the rat brain, and if so, whether these membrane alterations can be prevented by dietary supplementation with vitamin E, which has been shown to be an antioxidant and also a membrane-stabilizer. Leakage of [(18)F]2-fluoro-2-deoxy-D-glucose ([(18)F]FDG)-6-phosphate from rat striatal slices and decrease in 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy were used as indexes for plasma membrane permeabilization and fluidization, respectively. CPZ induced leakage of [(18)F]FDG-6-phosphate from striatal slices, and the leakage was delayed in the vitamin E-supplemented group compared to that in the normal diet group. The decrease in plasma membrane anisotropy induced by CPZ was significantly attenuated by vitamin E supplementation. Chronic treatment with alpha-phenyl-N-tert-butyl nitrone, a free radical scavenger, had no effect on CPZ-induced plasma membrane permeabilization, and the treatment with CPZ did not induce lipid peroxidation. CPZ can reduce plasma membrane integrity in the brain, and this reduction can be prevented by vitamin E via its membrane-stabilizing properties, not via its antioxidant activity.

  16. Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats.

    PubMed

    Larsson, E; Nanobashvili, A; Kokaia, Z; Lindvall, O

    1999-11-01

    The levels of brain-derived neurotrophic factor (BDNF) vary between different forebrain areas and show region-specific changes after cerebral ischemia. The present study explores the possibility that the levels of endogenous BDNF determine the susceptibility to ischemic neuronal death. To block BDNF activity the authors used the TrkB-Fc fusion protein, which was infused intraventricularly in rats during 1 week before and 1 week after 5 or 30 minutes of global forebrain ischemia. Ischemic damage was quantified in the striatum and hippocampal formation after 1 week of reperfusion using immunocytochemistry and stereological procedures. After the 30-minute insult, there was a significantly lower number of surviving CA4 pyramidal neurons, neuropeptide Y-immunoreactive dentate hilar neurons, and choline acetyltransferase- and TrkA-positive, cholinergic striatal interneurons in the TrkB-Fc-infused rats as compared to controls. In contrast, the TrkB-Fc treatment did not influence survival of CA1 or CA3 pyramidal neurons or striatal projection neurons. Also, after the mild ischemic insult (5 minutes), neuronal death in the CA1 region was similar in the TrkB-Fc-treated and control groups. These results indicate that endogenous BDNF can protect certain neuronal populations against ischemic damage. It is conceivable, though, that efficient neuroprotection after brain insults is dependent not only on this factor but on the concerted action of a large number of neurotrophic molecules.

  17. Immunochemical characterization of rat brain protein kinase

    SciTech Connect

    Huang, K.P.; Huang, F.L.

    1986-11-05

    Polyclonal antibodies against rat brain protein kinase C (the Ca/sup 2 +//phospholipid-dependent enzyme) were raised in goat. These antibodies can neutralize completely the kinase activity in purified enzyme preparation as well as that in the crude homogenate. Immunoblot analysis of the purified and the crude protein kinase C preparations revealed a major immunoreactive band of 80 kDa. The antibodies also recognize the same enzyme from other rat tissues. Neuronal tissues (cerebral cortex, cerebellum, hypothalamus, and retina) and lymphoid organs (thymus and spleen) were found to be enriched in protein kinase C, whereas lung, kidney, liver, heart, and skeletal muscle contained relatively low amounts of this kinase. Limited proteolysis of the purified rat brain protein kinase C with trypsin results in an initial degradation of the kinase into two major fragments of 48 and 38 kDa. Both fragments are recognized by the antibodies. However, further digestion of the 48-kDa fragment to 45 kDa and the 38-kDa fragment to 33 kDa causes a loss of the immunoreactivity. Upon incubation of the cerebellar extract with Ca/sup 2 +/, the 48-kDa fragment was also identified as a major proteolytic product of protein kinase C. Proteolytic degradation of protein kinase C converts the Ca/sup 2 +//phospholipid-dependent kinase to an independent form without causing a large impairment of the binding of (/sup 3/H)phorbol 12,13-dibutyrate. The two major proteolytic fragments were separated by ion exchange chromatography and one of them (45-48 kDa) was identified as a protein kinase and the other (33-38 kDa) as a phorbol ester-binding protein. These results demonstrate that rat brain protein kinase C is composed of two functionally distinct units, namely, a protein kinase and a Ca/sup 2 +/-independent/phospholipid-dependent phorbol ester-binding protein.

  18. Striatal direct and indirect pathways control decision-making behavior.

    PubMed

    Macpherson, Tom; Morita, Makiko; Hikida, Takatoshi

    2014-01-01

    Despite our ever-changing environment, animals are remarkably adept at selecting courses of action that are predictive of optimal outcomes. While requiring the contribution of a number of brain regions, a vast body of evidence implicates striatal mechanisms of associative learning and action selection to be critical to this ability. While numerous models of striatal-based decision-making have been developed, it is only recently that we have begun to understand the precise contributions of specific subpopulations of striatal neurons. Studies utilizing contemporary cell-type-specific technologies indicate that striatal output pathways play distinct roles in controlling goal-directed and social behaviors. Here we review current models of striatal-based decision-making, discuss recent developments in defining the functional roles of striatal output pathways, and assess how striatal dysfunction may contribute to the etiology of various neuropathologies.

  19. Caffeine has greater potency and efficacy than theophylline to reverse the motor impairment caused by chronic but not acute interruption of striatal dopaminergic transmission in rats.

    PubMed

    Acuña-Lizama, Miguel M; Bata-García, José L; Alvarez-Cervera, Fernando J; Góngora-Alfaro, José L

    2013-07-01

    In order to assess whether caffeine and theophylline have the same potency and efficacy to reverse the impairment of motor function caused by acute or chronic interruption of striatal dopamine transmission, a comparison of their dose-response relationship was made in the acute model of haloperidol-induced catalepsy, and the chronic model of unilateral lesion of the dopamine nigrostriatal pathway with 6-hydroxydopamine. At equimolar doses, both drugs reduced catalepsy intensity and increased its onset latency in a dose-dependent fashion, showing comparable potencies and attaining the maximal effect at similar doses. Catalepsy intensity: caffeine ED₅₀ = 24.1 μmol/kg [95% CI, 18.4-31.5]; theophylline ED₅₀ = 22.0 μmol/kg [95% CI, 17.0-28.4]. Catalepsy latency: caffeine ED₅₀ = 27.0 μmol/kg [95% CI, 21.1-34.6]; theophylline ED₅₀ = 28.8 μmol/kg [95% CI, 22.5-36.7]. In one group of hemiparkinsonian rats (n = 5), caffeine caused a dose-dependent recovery of the contralateral forepaw stepping: ED₅₀ = 2.4 μmol/kg/day [95% CI, 1.9-3.1]), reaching its maximum at the dose of 5.15 μmol/kg/day. When the treatment of these same rats was switched to 5.15 μmol/kg/day of theophylline, the stepping recovery was only 51 ± 12% of that induced by caffeine. Assessing the dose-response relationship of theophylline in another group of hemiparkinsonian rats (n = 7) revealed that it caused stepping recovery in an all-or-none fashion. Thus, the three lower doses had no effect, but at the dose of 5.15 μmol/kg/day theophylline suddenly increased the stepping to 56 ± 5% of the maximal effect observed when the treatment of these same rats was switched to an equimolar dose of caffeine. Increasing the dose of theophylline up to 15.45 μmol/kg/day caused no further stepping improvement since it was only 41 ± 6% of the maximal effect produced by caffeine at the dose of 5.15 μmol/kg/day. Given that theophylline showed less potency and efficacy than caffeine to reverse the

  20. Chronic Stress Causes Sex-Specific and Structure-Specific Alterations in Mitochondrial Respiratory Chain Activity in Rat Brain.

    PubMed

    de Souza Mota, Carina; Weis, Simone Nardin; Almeida, Roberto Farina; Dalmaz, Carla; Guma, Fátima Therezinha Costa; Pettenuzzo, Letícia Ferreira

    2017-09-14

    Chronic restraint stress (CRS) induces a variety of changes in brain function, some of which are mediated by glucocorticoids. The response to stress occurs in a sex-specific way, and may include mitochondrial and synaptic alterations. The synapse is highly dependent on mitochondrial energy supply, and when mitochondria become dysfunctional, they orchestrate cell death. This study aimed to investigate the CRS effects on mitochondrial respiratory chain activity, as well as mitochondrial potential and mass in cell body and synapses using hippocampus, cortex and striatum of male and female rats. Rats were divided into non-stressed (control) and stressed group (CRS during 40 days). Results showed that CRS increased complex I-III activity in hippocampus. We also observed an interaction between CRS and sex in the striatal complex II activity, since CRS induced a reduction in complex II activity in males, while in females this activity was increased. Also an interaction was observed between stress and sex in cortical complex IV activity, since CRS induced increased activity in females, while it was reduced in males. Glucocorticoid receptor (GR) content in cortex and hippocampus was sexually dimorphic, with female rats presenting higher levels compared to males. No changes were observed in GR content, mitochondrial potential or mass of animals submitted to CRS. It was concluded that CRS induced changes in respiratory chain complex activities, and some of these changes are sex-dependent: these activities are increased in the striatal mitochondria by CRS protocol mainly in females, while in males it is decreased.

  1. Ethanol effects on rat brain phosphoinositide metabolism

    SciTech Connect

    Huang, H.M.

    1987-01-01

    An increase in acidic phospholipids in brain plasma and synaptic plasma membranes upon chronic ethanol administration was observed. Chronic ethanol administration resulted in an increase in {sup 32}P{sub i} incorporation into the acidic phospholipids in synaptosomes. Postdecapitative ischemic treatment resulted rapid degradation of poly-PI in rat brain. However, there was a rapid appearance of IP{sub 2} in ethanol group which indicated a more rapid turnover of IP{sub 3} in the ethanol-treated rats. Carbachol stimulated accumulation of labeled inositol phosphates in brain slices and synaptosomes. Carbachol-stimulated release of IP and IP{sub 2} was calcium dependent and was inhibited by EGTA and atropine. Adenosine triphosphates and 1 mM further enhanced carbachol-induced formation of IP and IP{sub 2}, but showed an increase and a decrease in IP{sub 3} at 1 mM and 0.01 mM, respectively. Guanosine triphosphate at 0.1 mM did not change in labeled IP, but there was a significant increase in labeled IP{sub 2} and decrease in IP{sub 3}. Mn and CMP greatly enhanced incorporation of ({sup 3}H)-inositol into PI, but not into poly-PI labeling in brain synaptosomes. Incubation of brain synaptosomes resulted in a Ca{sup 2+}, time-dependent release of labeled IP. However, the pool of PI labeled through this pathway is not susceptible to carbachol stimulation. When saponin permeabilized synaptosomal preparations were incubated with ({sup 3}H)-inositol-PI or ({sup 14}C)-arachidonoyl-PI, ATP enhanced the formation of labeled IP and DG.

  2. Iron porphyrinate Fe(TPPS) reduces brain cell damage in rats intrastriatally lesioned by quinolinate.

    PubMed

    González-Cortés, Carolina; Salinas-Lara, Citlaltepetl; Gómez-López, Marcos Artemio; Tena-Suck, Martha Lilia; Pérez-De La Cruz, Verónica; Rembao-Bojórquez, Daniel; Pedraza-Chaverrí, José; Gómez-Ruiz, Celedonio; Galván-Arzate, Sonia; Ali, Syed F; Santamaría, Abel

    2008-01-01

    It has been recently demonstrated that the reactive nitrogen species (RNS) peroxynitrite (ONOO(-)) is involved in the neurotoxic pattern produced by quinolinic acid in the rat brain [V. Pérez-De La Cruz, C. González-Cortés, S. Galván-Arzate, O.N. Medina-Campos, F. Pérez-Severiano, S.F. Ali, J. Pedraza-Chaverrí, A. Santamaría, Excitotoxic brain damage involves early peroxynitrite formation in a model of Huntington's disease in rats: protective role of iron porphyrinate 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III), Neuroscience 135 (2005) 463-474.]. The aim of this work was to investigate whether ONOO(-) can also be responsible for morphological alterations and inflammatory events in the same paradigm. For this purpose, we evaluated the effect of a pre-treatment with the iron porphyrinate Fe(TPPS), a well-known ONOO(-) decomposition catalyst (10 mg/kg, i.p., 120 min before lesion), on the quinolinate-induced striatal cell damage and immunoreactivities to glial-fibrilar acidic protein (GFAP), interleukin 6 (IL-6) and inducible nitric oxide synthase (iNOS), one and seven days after the intrastriatal infusion of quinolinate (240 nmol/microl) to rats. The striatal tissue from animals lesioned by quinolinate showed a significant degree of damage and enhanced immunoreactivities to GFAP, IL-6 and iNOS, both at 1 and 7 days post-lesion. Pre-treatment of rats with Fe(TPPS) significantly attenuated or prevented all these markers at both post-lesion times tested, except for GFAP immunoreactivity at 7 days post-lesion and iNOS immunoreactivity at 1 day post-lesion. Altogether, our results suggest that ONOO(-) is actively participating in triggering inflammatory events and morphological alterations in the toxic model produced by quinolinate, since the use of agents affecting its formation, such as Fe(TPPS), are effective experimental tools to reduce the brain lesions associated to excitotoxic and oxidative damage.

  3. Studies of aluminum in rat brain

    SciTech Connect

    Lipman, J.J.; Brill, A.B.; Som, P.; Jones, K.W.; Colowick, S.; Cholewa, M.

    1985-01-01

    The effects of high aluminum concentrations in rat brains were studied using /sup 14/C autoradiography to measure the uptake of /sup 14/C 2-deoxy-D-glucose (/sup 14/C-2DG) and microbeam proton-induced x-ray emission (microPIXE) with a 20-..mu..m resolution to measure concentrations of magnesium, aluminum, potassium, and calcium. The aluminum was introduced intracisternally in the form of aluminum tartrate (Al-T) while control animals were given sodium tartrate (Na-T). The /sup 14/C was administered intravenously. The animals receiving Al-T developed seizure disorders and had pathological changes that included cerebral cortical atrophy. The results showed that there was a decreased uptake of /sup 14/C-2DG in cortical regions in which increased aluminum levels were measured, i.e., there is a correlation between the aluminum in the rat brain and decreased brain glucose metabolism. A minimum detection limit of about 16 ppM (mass fraction) or 3 x 10/sup 9/ Al atoms was obtained for Al under the conditions employed. 14 refs., 4 figs., 1 tab.

  4. Co-localization of brain-derived neurotrophic factor (BDNF) and wild-type huntingtin in normal and quinolinic acid-lesioned rat brain.

    PubMed

    Fusco, Francesca R; Zuccato, Chiara; Tartari, Marzia; Martorana, Alessandro; De March, Zena; Giampà, Carmela; Cattaneo, Elena; Bernardi, Giorgio

    2003-09-01

    Loss of huntingtin-mediated brain-derived neurotrophic factor (BDNF) gene transcription has been described in Huntington's disease (HD) [Zuccato et al. (2001) Science, 293, 493-498]. It has been shown that BDNF is synthesized in the pyramidal layer of cerebral cortex and released in the striatum [Altar et al. (1997) Nature, 389, 856-860; Conner et al. (1997) J. Neurosci., 17, 2295-2313]. Here we show the cellular localization of BDNF in huntingtin-containing neurons in normal rat brain; our double-label immunofluorescence study shows that huntingtin and BDNF are co-contained in approximately 99% of pyramidal neurons of motor cortex. In the striatum, huntingtin is expressed in 75% of neurons containing BDNF. In normal striatum we also show that BDNF is contained in cholinergic and in NOS-containing interneurons, which are relatively resistant to HD degeneration. Furthermore, we show a reduction in huntingtin and in BDNF immunoreactivity in cortical neurons after striatal excitotoxic lesion. Our data are confirmed by an ELISA study of BDNF and by a Western blot analysis of huntingtin in cortex of quinolic acid (QUIN)-lesioned hemispheres. In the lesioned striatum we describe that the striatal subpopulation of cholinergic neurons, surviving degeneration, contain BDNF. The finding that BDNF is contained in nearly all neurons that contain huntingtin in the normal cortex, along with the reduced expression of BDNF after QUIN injection of the striatum, shows that huntingtin may be required for BDNF production in cortex.

  5. [The expression of GFAP after brain concussion in rats].

    PubMed

    Zhang, Chun-Bing; Li, Yong-Hong

    2006-04-01

    To study the expression of GFAP and pathologic changes after rats brain concussion, so that to provide evidence on brain concussion for forensic identification. Forty-five SD rats were divided into 3, 6, 12, 24 h and 2, 4, 7, 10 d and normal control groups in terms of different wounding time after brain concussion model established, and the expression of GFAP after rats brain concussion were then observed by using SP immunohistochemical method. In normal control brain, low-level GFAP expressions could be observed. After six hours' brain concussion, GFAP positive cells increased obviously. The trend reached to the peak at 7d, partly declined at 10d, then decreased gradually. Brain concussion induced the expression of GFAP. The detection of GFAP could be useful for diagnosis of brain concussion on forensic pathology, and could be a reference index for timing of injury after brain concussion.

  6. Temporal Rewiring of Striatal Circuits Initiated by Nicotine

    PubMed Central

    Adermark, Louise; Morud, Julia; Lotfi, Amir; Danielsson, Klara; Ulenius, Lisa; Söderpalm, Bo; Ericson, Mia

    2016-01-01

    Drug addiction has been conceptualized as maladaptive recruitment of integrative circuits coursing through the striatum, facilitating drug-seeking and drug-taking behavior. The aim of this study was to define temporal neuroadaptations in striatal subregions initiated by 3 weeks of intermittent nicotine exposure followed by protracted abstinence. Enhanced rearing activity was assessed in motor activity boxes as a measurement of behavioral change induced by nicotine (0.36 mg/kg), whereas electrophysiological field potential recordings were performed to evaluate treatment effects on neuronal activity. Dopamine receptor mRNA expression was quantified by qPCR, and nicotine-induced dopamine release was measured in striatal subregions using in vivo microdialysis. Golgi staining was performed to assess nicotine-induced changes in spine density of medium spiny neurons. The data presented here show that a brief period of nicotine exposure followed by abstinence leads to temporal changes in synaptic efficacy, dopamine receptor expression, and spine density in a subregion-specific manner. Nicotine may thus initiate a reorganization of striatal circuits that continues to develop despite protracted abstinence. We also show that the response to nicotine is modulated in previously exposed rats even after 6 months of abstinence. The data presented here suggests that, even though not self-administered, nicotine may produce progressive neuronal alterations in brain regions associated with goal-directed and habitual performance, which might contribute to the development of compulsive drug seeking and the increased vulnerability to relapse, which are hallmarks of drug addiction. PMID:27388328

  7. Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats.

    PubMed

    Shachar, Dorit Ben; Kahana, Nava; Kampel, Vladimir; Warshawsky, Abraham; Youdim, Moussa B H

    2004-02-01

    Significant increase in iron occurs in the substantia nigra pars compacta of Parkinsonian subjects, and in 6-hydroxydopamine (6-OHDA) treated rats and monkeys. This increase in iron has been attributed to its release from ferritin and is associated with the generation of reactive oxygen species and the onset of oxidative stress-induced neurodegeneration. Several iron chelators with hydroxyquinoline backbone were synthesized and their ability to inhibit basal as well as iron-induced mitochondrial lipid peroxidation was examined. The neuroprotective potential of the brain permeable iron chelator, VK-28 (5-[4-(2-hydroxyethyl) piperazine-1-ylmethyl]-quinoline-8-ol), injected either intraventricularly (ICV) or intraperitoneally (IP), to 6-OHDA lesioned rats was investigated. VK-28 inhibited both basal and Fe/ascorbate induced mitochondrial membrane lipid peroxidation, with an IC(50) (12.7 microM) value comparable to that of the prototype iron chelator, desferal, which does not cross the blood brain barrier. At an ICV pretreatment dose as low as 1 microg, VK-28 was able to completely protect against ICV 6-OHDA (250 microg) induced striatal dopaminergic lesion, as measured by dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) levels. IP injection of rats with VK-28 (1 and 5 mg/kg) daily for 10 and 7 days, respectively, demonstrated significant neuroprotection against ICV 6-OHDA at the higher dose, with 68% protection against loss of dopamine at 5mg/kg dosage of VK-28. The present study is the first to show neuroprotection with a brain permeable iron chelator. The latter can have implications for the treatment of Parkinson's disease and other neurodegenerative diseases (Alzheimer's disease, Friedreich ataxia, aceruloplasminemia, Hallervorden Spatz syndrome) where abnormal iron accumulation in the brain is thought to be associated with the degenerative processes.

  8. Causal discovery in an adult ADHD data set suggests indirect link between DAT1 genetic variants and striatal brain activation during reward processing.

    PubMed

    Sokolova, Elena; Hoogman, Martine; Groot, Perry; Claassen, Tom; Vasquez, Alejandro Arias; Buitelaar, Jan K; Franke, Barbara; Heskes, Tom

    2015-09-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder affecting both children and adults. One of the candidate genes for ADHD is DAT1, encoding the dopamine transporter. In an attempt to clarify its mode of action, we assessed brain activity during the reward anticipation phase of the Monetary Incentive Delay (MID) task in a functional MRI paradigm in 87 adult participants with ADHD and 77 controls (average age 36.5 years). The MID task activates the ventral striatum, where DAT1 is most highly expressed. A previous analysis based on standard statistical techniques did not show any significant dependencies between a variant in the DAT1 gene and brain activation [Hoogman et al. (2013); Neuropsychopharm 23:469-478]. Here, we used an alternative method for analyzing the data, that is, causal modeling. The Bayesian Constraint-based Causal Discovery (BCCD) algorithm [Claassen and Heskes (2012); Proceedings of the 28th Conference on Uncertainty in Artificial Intelligence] is able to find direct and indirect dependencies between variables, determines the strength of the dependencies, and provides a graphical visualization to interpret the results. Through BCCD one gets an opportunity to consider several variables together and to infer causal relations between them. Application of the BCCD algorithm confirmed that there is no evidence of a direct link between DAT1 genetic variability and brain activation, but suggested an indirect link mediated through inattention symptoms and diagnostic status of ADHD. Our finding of an indirect link of DAT1 with striatal activity during reward anticipation might explain existing discrepancies in the current literature. Further experiments should confirm this hypothesis. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  9. Cloning and expression of an A1 adenosine receptor from rat brain

    SciTech Connect

    Mahan, L.C.; McVittie, L.D.; Smyk-Randall, E.M.; Nakata, H.; Monsma, F.J. Jr.; Gerfen, C.R.; Sibley, D.R. )

    1991-07-01

    The authors have used the polymerase chain reaction technique to selectively amplify guanine nucleotide-binding regulatory protein (G protein)-coupled receptor cDNA sequences from rat striatal mRNA, using sets of highly degenerate primers derived from transmembrane sequences of previously cloned G protein-coupled receptors. A novel cDNA fragment was identified, which exhibits considerable homology to various members of the G protein-coupled receptor family. This fragment was used to isolate a full-length cDNA from a rat striatal library. A 2.2-kilobase clone was obtained that encodes a protein of 326 amino acids with seven transmembrane domains, as predicted by hydropathy analysis. Stably transfected mouse A9-L cells and Chinese hamster ovary cells that expressed mRNA for this clone were screened with putative receptor ligands. Saturable and specific binding sites for the A1 adenosine antagonist (3H)-1,3-dipropyl-8-cyclopentylxanthine were identified on membranes from transfected cells. The rank order of potency and affinities of various adenosine agonist and antagonist ligands confirmed the identity of this cDNA clone as an A1 adenosine receptor. The high affinity binding of A1 adenosine agonists was shown to be sensitive to the nonhydrolyzable GTP analog guanylyl-5{prime}-imidodiphosphate. In adenylyl cyclase assays, adenosine agonists inhibited forskolin-stimulated cAMP production by greater than 50%, in a pharmacologically specific fashion. Northern blot and in situ hybridization analyses of receptor mRNA in brain tissues revealed two transcripts of 5.6 and 3.1 kilobases, both of which were abundant in cortex, cerebellum, hippocampus, and thalamus, with lower levels in olfactory bulb, striatum, mesencephalon, and retina. These regional distribution data are in good agreement with previous receptor autoradiographic studies involving the A1 adenosine receptor.

  10. Cytokine mRNA levels in brain and peripheral tissues of the rat: relationships with plus-maze behavior.

    PubMed

    Pawlak, Cornelius R; Schwarting, Rainer K W; Bauhofer, Artur

    2005-06-13

    There is evidence that interleukin (IL)-2 may be related to anxiety as measured in the elevated plus-maze. Recently, we showed that normal adult male Wistar rats can differ systematically in this test of avoidance behavior, that is, time spent on the open arms of the elevated plus-maze. Rats with low open arm time had higher striatal levels of IL-2 mRNA than those with high open arm time, but did not differ significantly in expression of other striatal cytokine mRNA. Here, we investigated whether these expression effects are anatomically specific to the striatum. Therefore, we asked in this double-blind study whether elevated plus-maze behavior may also be related to endogenous levels of cytokine mRNA in other brain regions, which play a role for anxiety, namely the amygdala, hippocampus, and the prefrontal cortex. Additionally, and as peripheral controls, immuno-neuro-endocrine relevant tissues (adrenal glands, spleen) were analyzed. Based on open arm time in the elevated plus-maze, male Wistar rats were divided into sub-groups with either low or high open arm time behavior. Then, IL-1beta, IL-2, IL-6, and tumor necrosis factor (TNF)-alpha cDNA levels were measured post-mortem using semi-quantitative, competitive, reverse transcription polymerase chain reaction. First, we found that cytokine expressions differed considerably between and within these central and peripheral tissues. Secondly, rats with high compared to low open arm time behavior showed higher IL-2 mRNA levels in the prefrontal cortex, which is an inverse pattern to what we recently found in the striatum. These results provide new evidence indicating that cytokine mRNA in the brain can be related to elevated plus-maze behavior and that this relationship is site (prefrontal cortex, striatum)- and cytokine mRNA-specific (IL-2).

  11. Spatiotemporal characterization of brain infarction by sequential multimodal MR imaging following transient focal ischemia in a Rat model of intra-arterial middle cerebral artery occlusion.

    PubMed

    Gory, Benjamin; Chauveau, Fabien; Bolbos, Radu; Langlois, Jean-Baptiste; Labeyrie, Paul-Emile; Signorelli, Francesco; Turjman, Alexis; Turjman, Francis

    2016-12-01

    To assess spatiotemporal brain infarction evolution by sequential multimodal magnetic resonance (MR) imaging in an endovascular model of acute stroke in rats. A microwire was selectively placed in the middle cerebral artery (MCA) in 16 consecutives rats during 90 minutes occlusion. Longitudinal 7-T MR imaging, including angiography, diffusion, and perfusion was performed during ischemia, immediately after reperfusion, 3 h and 24 h after subsequent reperfusion. MCA occlusion was complete in 75 % and partial in 18.7 %. Hypoperfusion (mean ± SD) was observed in all animals during ischemia (-59 ± 18 % of contralateral hemisphere, area 31 ± 5 mm(2)). Infarction volume (mean ± SD) was 90 ± 64 mm(3) during ischemia and 57 ± 67 mm(3) at 24 h. Brain infarction was fronto-parietal cortical in five animals (31 %), striatal in four animals (25 %), and cortico-striatal in seven animals (44 %) at 24 h. All rats survived at 24 h. This model is suitable to neuroprotection studies because of possible acute and close characterization of spatiotemporal evolution of brain infarction by MR imaging techniques, and evidence of ischemic penumbra, the target of neuroprotection agents. However, optimization of the brain infarct reproducibility needs further technical and neurointerventional tools improvements. • Nitinol microwire is MRI compatible allowing spatiotemporal characterization of brain infarction in rats. • Microwire selective placement in middle cerebral artery allows complete artery occlusion in 75 %. • A diffusion/perfusion mismatch during arterial occlusion is observed in 77 % of rats.

  12. Delta FosB and AP-1-mediated transcription modulate cannabinoid CB₁ receptor signaling and desensitization in striatal and limbic brain regions.

    PubMed

    Lazenka, Matthew F; David, Bethany G; Lichtman, Aron H; Nestler, Eric J; Selley, Dana E; Sim-Selley, Laura J

    2014-10-01

    Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces cannabinoid type 1 receptor (CB₁R) desensitization and downregulation, as well as tolerance to its in vivo pharmacological effects. However, the magnitude of CB₁R desensitization varies by brain region, with CB₁Rs in the striatum and its output nuclei undergoing less desensitization than other regions. A growing body of data indicates that regional differences in CB₁R desensitization are produced, in part, by THC-mediated induction of the stable transcription factor, ΔFosB, and subsequent regulation of CB₁Rs. The purpose of the present study was to determine whether THC-mediated induction of ΔFosB in the striatum inhibits CB₁R desensitization in the striatum and output nuclei. This hypothesis was tested using bitransgenic mice with inducible expression of ΔFosB or ΔcJun, a dominant negative inhibitor of AP-1-mediated transcription, in specific forebrain regions. Mice were treated repeatedly with escalating doses of THC or vehicle for 6.5 days, and CB₁R-mediated G-protein activation was assessed using CP55,940-stimulated [(35)S]GTPγS autoradiography. Overexpression of ΔFosB in striatal dopamine type 1 receptor-containing (D1R) medium spiny neurons (MSNs) attenuated CB₁R desensitization in the substantia nigra, ventral tegmental area (VTA) and amygdala. Expression of ΔcJun in striatal D1R- and dopamine type 2 receptor (D2R)-containing MSNs enhanced CB₁R desensitization in the caudate-putamen and attenuated desensitization in the hippocampus and VTA. THC-mediated in vivo pharmacological effects were then assessed in ΔcJun-expressing mice. Tolerance to THC-mediated hypomotility was enhanced in ΔcJun-expressing mice. These data reveal that ΔFosB and possibly other AP-1 binding proteins regulate CB₁R signaling and adaptation in the striatum and limbic system. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Manganese alters rat brain amino acids levels

    PubMed Central

    Santos, Dinamene; Batoreu, M. Camila; Almeida, Isabel; Ramos, Ruben; Sidoryk-Wegrzynowicz, M.; Aschner, Michael; Marreilha dos Santos, A.P.

    2012-01-01

    Manganese (Mn) is an essential element and it acts as a cofactor for a number of enzymatic reactions, including those involved in amino acid, lipid, protein and carbohydrate metabolism. Excessive exposure to Mn can lead to poisoning, characterized by psychiatric disturbances and an extrapyramidal disorder. Mn-induced neuronal degeneration is associated with alterations in amino acids metabolism. In the present study, we analyzed whole rat brain amino acid content subsequent to 4 or 8 intraperitoneal (ip) injections, with 25 mg MnCl2/kg/day, at 48-hour (h) intervals. We noted a significant increase in glycine brain levels after 4 or 8 Mn injections (p<0.05 and p<0.01, respectively) and arginine also after 4 or 8 injections (p<0.001). Significant increases were also noted in brain proline (p<0.01), cysteine (p<0.05), phenylalanine (p<0.01) and tyrosine (p<0.01) levels after 8 Mn injections vs. the control group. These findings suggest that Mn-induced alterations in amino acid levels secondary to Mn affect the neurochemical milieu. PMID:22971893

  14. Radioiodinated tracers for the evaluation of dopamine receptors in the neonatal rat brain after hypoxic-ischemic injury.

    PubMed

    Zouakia, A; Chalon, S; Kung, H F; Dognon, A M; Saliba, E; Besnard, J C; Guilloteau, D

    1994-06-01

    In order to evaluate in vivo single-photon emission tomography (SPET) method of assessing cerebral function after hypoxic-ischemic injury in human neonates, we studied D1 and D2 dopamine receptors in a rat model. Seven-day-old rats underwent permanent unilateral common carotid ligation followed by exposure to 8% O2. Two weeks later, in brains with no visible loss of hemispheric volume, striatal dopaminergic receptors were studied, with [125I]TISCH and [125I]IBZM for the D1 and D2 dopamine receptors, respectively. Using [125I]TISCH, we observed no modifications of D1 receptors, but in contrast, ex vivo and in vitro autoradiographic experiments showed a 40% decrease in the striatal binding of [125I]IBZM on both the ipsilateral and the contralateral side to the carotid ligation. These alterations were detected with IBZM, a D2 dopamine receptor ligand usable for SPET imaging. Therefore, exploration of D2 receptors by SPET in human neonates suffering from perinatal hypoxia-ischemia may be valuable for the diagnosis and follow-up of cerebral function damages.

  15. Toxicity of the Flame-Retardant BDE-49 on Brain Mitochondria and Neuronal Progenitor Striatal Cells Enhanced by a PTEN-Deficient Background

    PubMed Central

    Giulivi, Cecilia

    2013-01-01

    Polybrominated diphenyl ethers (PBDEs) represent an important group of flame retardants extensively used, tonnage of which in the environment has been steadily increasing over the past 25 years. PBDEs or metabolites can induce neurotoxicity and mitochondrial dysfunction (MD) through a variety of mechanisms. Recently, PBDEs with < 5 Br substitutions (i.e., 2,2′,4,4′-tetrabromodiphenyl ether [BDE-47] and 2,2′,4,5′-tetrabromodiphenyl ether [BDE-49]) have gained interest because of their high bioaccumulation. In particular, congeners such as BDE-49 arise as one of the most biologically active, with concentrations typically lower than those observed for BDE-47 in biological tissues; however, its potential to cause MD at biologically relevant concentrations is unknown. To this end, the effect of BDE-49 was studied in brain mitochondria and neuronal progenitor striatal cells (NPC). BDE-49 uncoupled mitochondria at concentrations < 0.1 nM, whereas at > 1 nM, it inhibited the electron transport at Complex V (mixed type inhibition; IC50 = 6 nM) and Complex IV (noncompetitive inhibition; IC50 = 40 nM). These concentrations are easily achieved in plasma concentrations considering that BDE-49 (this study, 400-fold) and other PBDEs accumulate 1–3 orders of magnitude in the cells, particularly in mitochondria and microsomes. Similar effects were observed in NPC and exacerbated with PTEN (negative modulator of the PI3K/Akt pathway) deficiency, background associated with autism-like behavior, schizophrenia, and epilepsy. PBDE-mediated MD per se or enhanced by a background that confers susceptibility to this exposure may have profound implications in the energy balance of brain. PMID:23288049

  16. [Expression of c-myc protein on rats' brains after brain concussion].

    PubMed

    Fang, Wei-Hua; Wang, Dong-Liang; Wang, Feng

    2006-10-15

    To study the changes of expression of c-myc protein on rats' brains after brain concussion. sixty rats were randomly divided into brain concussion groups and control group. The expression of c-myc protein was microscopically observed by immunohistochemical method. No expression of c-myc protein in control group were observed. However, positive expression of c-myc protein in some neurons was seen at 20 min after brain concussion, and reach to the peak at 8h after brain concussion and then decreased gradually. These findings suggest that the detection of c-myc protein could be an index of diagnosis of brain concussion.

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

    PubMed Central

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

    2015-01-01

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

  18. Striatal cholinergic interneurons Drive GABA release from dopamine terminals.

    PubMed

    Nelson, Alexandra B; Hammack, Nora; Yang, Cindy F; Shah, Nirao M; Seal, Rebecca P; Kreitzer, Anatol C

    2014-04-02

    Striatal cholinergic interneurons are implicated in motor control, associative plasticity, and reward-dependent learning. Synchronous activation of cholinergic interneurons triggers large inhibitory synaptic currents in dorsal striatal projection neurons, providing one potential substrate for control of striatal output, but the mechanism for these GABAergic currents is not fully understood. Using optogenetics and whole-cell recordings in brain slices, we find that a large component of these inhibitory responses derive from action-potential-independent disynaptic neurotransmission mediated by nicotinic receptors. Cholinergically driven IPSCs were not affected by ablation of striatal fast-spiking interneurons but were greatly reduced after acute treatment with vesicular monoamine transport inhibitors or selective destruction of dopamine terminals with 6-hydroxydopamine, indicating that GABA release originated from dopamine terminals. These results delineate a mechanism in which striatal cholinergic interneurons can co-opt dopamine terminals to drive GABA release and rapidly inhibit striatal output neurons. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Striatal cholinergic interneurons drive GABA release from dopamine terminals

    PubMed Central

    Nelson, Alexandra B.; Hammack, Nora; Yang, Cindy F.; Shah, Nirao M.; Seal, Rebecca P.; Kreitzer, Anatol C.

    2014-01-01

    Summary Striatal cholinergic interneurons are implicated in motor control, associative plasticity, and reward-dependent learning. Synchronous activation of cholinergic interneurons triggers large inhibitory synaptic currents in dorsal striatal projection neurons, providing one potential substrate for control of striatal output, but the mechanism for these GABAergic currents is not fully understood. Using optogenetics and whole-cell recordings in brain slices, we find that a large component of these inhibitory responses derive from action-potential-independent disynaptic neurotransmission mediated by nicotinic receptors. Cholinergically-driven IPSCs were not affected by ablation of striatal fast-spiking interneurons, but were greatly reduced after acute treatment with vesicular monoamine transport inhibitors or selective destruction of dopamine terminals with 6-hydroxydopamine, indicating that GABA release originated from dopamine terminals. These results delineate a mechanism in which striatal cholinergic interneurons can co-opt dopamine terminals to drive GABA release and rapidly inhibit striatal output neurons. PMID:24613418

  20. Cortical ionotropic glutamate receptor antagonism protects against methamphetamine-induced striatal neurotoxicity

    PubMed Central

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

    2011-01-01

    Binge administration of the psychostimulant drug, methamphetamine (mAMPH), produces long-lasting structural and functional abnormalities in the striatum. mAMPH binges produce non-exocytotic release of dopamine (DA), and mAMPH-induced activation of excitatory afferent inputs to cortex and striatum is evidenced by elevated extracellular glutamate (GLU) in both regions. The mAMPH-induced increases in DA and GLU neurotransmission are thought to combine to injure striatal DA nerve terminals of mAMPH-exposed brains. Systemic pretreatment with either competitive or noncompetitive N-methyl-D-aspartic acid (NMDA) antagonists protects against mAMPH-induced striatal DA terminal damage, but the locus of these antagonists’ effects has not been determined. Here, we applied either the NMDA receptor antagonist, (DL)-amino-5-phosphonovaleric acid (AP5), or the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, dinitroquinoxaline-2,3-dione (DNQX), directly to the dura mater over frontoparietal cortex to assess their effects on mAMPH-induced cortical and striatal immediate-early gene (c-fos) expression. In a separate experiment we applied AP5 or DNQX epidurally in the same cortical location of rats during a binge regimen of mAMPH, and assessed mAMPH-induced striatal dopamine transporter (DAT) depletions one week later. Our results indicate that both ionotropic glutamate receptor antagonists reduced the mAMPH-induced Fos expression in cerebral cortex regions near the site of epidural application and reduced Fos immunoreactivity in striatal regions innervated by the affected cortical regions. Also, epidural application of the same concentration of either antagonist during a binge mAMPH regimen blunted the mAMPH-induced striatal DAT depletions with a topography similar to its effects on Fos expression. These findings demonstrate that mAMPH-induced dopaminergic injury depends upon cortical NMDA and AMPA receptor activation and suggest the involvement

  1. Changes in brain lipid composition in thiamine deficient rats.

    PubMed

    Okazaki, M; Sakamoto, H; Ohtsuki, A; Oguchi, K

    1990-10-01

    Brain lipid composition was studied in thiamine deficient rats treated with thiamine antimetabolites (oxythiamine: OT, and pyrithiamine: PT) and thiamine deficient diet (TDD). After intraperitoneal injection of OT (40 mg/kg/day) or TDD feeding for 6 days, body weight gain decreased. However, the PT (500 micrograms/kg/day) treated rats or the pair fed control (PFC: TDD + thiamine of 5 mg/kg, i.p.) showed no decrease in body weight gain compared with the regular diet control (C). Brain lipid levels (total lipid, total cholesterol, triglyceride, phospholipid, sphingomyelin and cerebroside) were examined in four brain regions (cerebral cortex, subcortical structure, brain stem and cerebellum). Total lipid level increased in four regions in OT or TDD treated rats, but total lipid level in the cerebellum in PT treated rats decreased. Total cholesterol level increased in all treated rats, while the triglyceride level in the brain stem decreased dramatically in OT or TDD treated rats. Cerebroside levels of four regions in the PT, OT or TDD group remarkably decreased, and PFC rats showed a significant improvement of the decrease in cerebroside level. It is conceivable that these changes in brain lipid composition provided some clues for the histological and morphological changes of the brain as manifested by the myelin degradation in acute thiamine deficiency.

  2. Hybridizable ribonucleic acid of rat brain

    PubMed Central

    Bondy, S. C.; Roberts, Sidney

    1968-01-01

    1. Cerebral RNA of adult and newborn rats was labelled in vivo by intracervical injection of [5-3H]uridine or [32P]phosphate. Hepatic RNA of similar animals was labelled by intraperitoneal administration of [6-14C]orotic acid. Nuclear and cytoplasmic fractions were isolated and purified by procedures involving extraction with phenol and repeated precipitation with ethanol. 2. The fraction of pulse-labelled RNA from cerebral nuclei that hybridized to homologous DNA exhibited a wide range of turnover values and was heterogeneous in sucrose density gradients. 3. Base composition of the hybridizable RNA was similar to that of the total pulse-labelled material; both were DNA-like. 4. Pulse-labelled cerebral nuclear RNA hybridized to a greater extent than cytoplasmic RNA for at least a week after administration of labelled precursor. This finding suggested that cerebral nuclei contained a hybridizable component that was not transferred to cytoplasm. 5. The rates of decay of the hybridizable fractions of cerebral nuclei and cytoplasm were faster in the newborn animal than in the adult. Presumably a larger proportion of labile messenger RNA molecules was present in the immature brain. 6. Cerebral nuclear and cytoplasmic RNA fractions from newborn or adult rats, labelled either in vivo for periods varying from 4min. to 7 days or in vitro by exposure to [3H]-dimethyl sulphate, uniformly hybridized more effectively than the corresponding hepatic preparation. These data suggested that a larger proportion of RNA synthesis was oriented towards messenger RNA formation in brain than in liver. PMID:5683505

  3. [The effect of sevoflurane and isoflurane on striatal dopamine of awake freely moving rats observed in an in vivo microdialysis study].

    PubMed

    Adachi, Y; Taoda, M; Uchihashi, Y; Watanabe, K; Satoh, T

    1999-09-01

    We investigated the effect of sevoflurane and isoflurane on the level of interstitial dopamine of in vivo awake, free moving rats brain striatum using microdialysis techniques. Rats were implanted with a microdialysis probe to the right striatum of the brain and administered with 1.2 MAC of each volatile anesthetics for 1 hour, and dialysates from the probe were determined every 20 minutes. Both anesthetics reduced the amount of dopamine derived from dialysate, and increased the efflux of dopamine with pretreatment of nomifensine 10mg. kg-1 i.p. The change of metabolites of dopamine during anesthesia was increased. No significant difference was found between sevoflurane and isoflurane. We hypothesized that these anesthetics might have special actions on interactions between metabolism and re-uptake of dopamine in rats striatum during anesthesia.

  4. Platelet-activating factor: diminished acetylcholine release from rat brain slices is mediated by a Gi protein.

    PubMed

    Wang, H Y; Yue, T L; Feuerstein, G; Friedman, E

    1994-11-01

    The effect of platelet-activating factor (PAF) on neurotransmitter release from rat brain slices prelabeled with [3H]acetylcholine ([3H]ACh), [3H]norepinephrine ([3H]NE), or [3H]serotonin ([3H]5-HT) was studied. PAF inhibited K+ depolarization-induced [3H]ACh release in slices of brain cortex and hippocampus by up to 59% at 10 nM but did not inhibit [3H]ACh release in striatal slices. PAF did not affect 5-HT or NE release from cortical brain slices. The inhibition of K(+)-evoked [3H]ACh release induced by PAF was prevented by pretreating tissues with several structurally different PAF receptor antagonists. The effect of PAF was reversible and was not affected by pretreating brain slices with tetrodotoxin. PAF-induced inhibition of [3H]ACh release was blocked 90 +/- 3 and 86 +/- 2% by pertussis toxin and by anti-G alpha i1/2 antiserum incorporated into cortical synaptosomes, respectively. The results suggest that PAF inhibits depolarization-induced ACh release in brain slices via a G alpha i1/2 protein-mediated action and that PAF may serve as a neuromodulator of brain cholinergic system.

  5. A review of fronto-striatal and fronto-cortical brain abnormalities in children and adults with Attention Deficit Hyperactivity Disorder (ADHD) and new evidence for dysfunction in adults with ADHD during motivation and attention.

    PubMed

    Cubillo, Ana; Halari, Rozmin; Smith, Anna; Taylor, Eric; Rubia, Katya

    2012-02-01

    Attention Deficit Hyperactivity Disorder (ADHD) has long been associated with abnormalities in frontal brain regions. In this paper we review the current structural and functional imaging evidence for abnormalities in children and adults with ADHD in fronto-striatal, fronto-parieto-temporal, fronto-cerebellar and fronto-limbic regions and networks. While the imaging studies in children with ADHD are more numerous and consistent, an increasing number of studies suggests that these structural and functional abnormalities in fronto-cortical and fronto-subcortical networks persist into adulthood, despite a relative symptomatic improvement in the adult form of the disorder. We furthermore present new data that support the notion of a persistence of neurofunctional deficits in adults with ADHD during attention and motivation functions. We show that a group of medication-naïve young adults with ADHD behaviours who were followed up 20 years from a childhood ADHD diagnosis show dysfunctions in lateral fronto-striato-parietal regions relative to controls during sustained attention, as well as in ventromedial orbitofrontal regions during reward, suggesting dysfunctions in cognitive-attentional as well as motivational neural networks. The lateral fronto-striatal deficit findings, furthermore, were strikingly similar to those we have previously observed in children with ADHD during the same task, reinforcing the notion of persistence of fronto-striatal dysfunctions in adult ADHD. The ventromedial orbitofrontal deficits, however, were associated with comorbid conduct disorder (CD), highlighting the potential confound of comorbid antisocial conditions on paralimbic brain deficits in ADHD. Our review supported by the new data therefore suggest that both adult and childhood ADHD are associated with brain abnormalities in fronto-cortical and fronto-subcortical systems that mediate the control of cognition and motivation. The brain deficits in ADHD therefore appear to be multi

  6. Cholinotoxic effects of aluminum in rat brain.

    PubMed

    Gulya, K; Rakonczay, Z; Kása, P

    1990-03-01

    The in vivo and in vitro effects of Al on the cholinergic system of rat brain were studied. The amount of Al accumulated after the chronic, intraperitoneal administration of aluminium gluconate (Al-G) or AlCl3, both at a dose of 1 mg/ml/100 g of body weight, increased in the frontal and parietal cortices, the hippocampus, and the striatum. Significantly decreased choline acetyltransferase activities after chronic Al treatment were measured in the parietal cortex, the hippocampus, and the striatum, but not in the frontal cortex. The acetylcholinesterase activity was not changed significantly in any brain area investigated. Both Al-G and AlCl3 administrations resulted in a general decrease (to 40-70% of the control values) in the specific l-[3H]nicotine binding, involving all brain areas studied. The specific (-)-[3H]quinuclidinyl benzilate binding was reduced (to 40-60% of the control values) only after 25 days of Al treatment. Al-G and AlCl3 were equivalent in eliciting these reductions in vitro studies revealed different alterations of the cholinergic system in response to Al treatment. No changes were observed either in choline acetyltransferase activity or in cholinergic receptor bindings. Both Al-G and Al2(SO4)3 treatments, however, exhibited a biphasic effect on the acetylcholinesterase activity. At low Al concentrations (10(-8)-10(-6) M), the activity was slightly increased, whereas at higher concentrations (10(-6)-10(-4) M), it was inhibited by a maximum of 25% as compared to the controls. Thus, these cholinotoxic effects are probably due not to a direct interaction between the metal and the cholinergic marker proteins, but rather to a manifestation and consequence of its neurodegenerative effects.

  7. Chronic atrazine exposure causes disruption of the spontaneous locomotor activity and alters the striatal dopaminergic system of the male Sprague-Dawley rat.

    PubMed

    Bardullas, Ulises; Giordano, Magda; Rodríguez, Verónica M

    2011-01-01

    The herbicide atrazine (ATR) is widely used around the world, and is a potential toxicant of the dopaminergic systems. Nigrostriatal and mesolimbic systems are the two major dopaminergic pathways of the central nervous system; they play key roles mediating a wide array of critical motor and cognitive functions. We evaluated the effects of exposing male rats for one year to 10 mg ATR/kg B.W. on these systems using motor and cognitive tasks and measuring monoamine content in the striatum, nucleus accumbens, prefrontal cortex, and hypothalamus. ATR administration resulted in impaired motor coordination and greater spontaneous locomotor activity only after 10 to 12 months of exposure. Chronic exposure to 10 mg ATR decreased striatal dopamine, but had no effect on accumbal, hypothalamic or cortical monoamine content. Chronic ATR exposure caused discrete changes in learning tasks that involve either the striatum or the nucleus accumbens. These results indicate that chronic exposure to ATR preferentially targets the nigrostriatal dopaminergic pathway, in comparison to the other dopaminergic pathways evaluated in this study, inducing behavioral and neurochemical alterations. In order to unveil the full extent of atrazine's effects on the nervous system, other neurochemical systems should be considered in future studies. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. Protective effect of tert-butylhydroquinone on the quinolinic-acid-induced toxicity in rat striatal slices: role of the Nrf2-antioxidant response element pathway.

    PubMed

    Tasset, Inmaculada; Pérez-De La Cruz, Verónica; Elinos-Calderón, Diana; Carrillo-Mora, Paul; González-Herrera, Irma Gabriela; Luna-López, Armando; Konigsberg, Mina; Pedraza-Chaverrí, José; Maldonado, Perla D; Ali, Syed F; Túnez, Isaac; Santamaría, Abel

    2010-01-01

    Tert-butylhydroquinone (tBHQ) is a xenobiotic with reported antioxidant properties. tBHQ has been shown to induce nuclear translocation of the transcription factor NF-E2-related factor 2 (Nrf2) to further activate the antioxidant response element (ARE). In turn, the Nrf2/ARE pathway is responsible for the induction of phase 2 antioxidant enzymes that detoxify oxidant promoters from different toxic insults. In this work, the antioxidant and protective actions of tBHQ were explored for the first time on different biomarkers of the neurotoxic model produced by the excitotoxic and pro-oxidant molecule quinolinic acid (QUIN) in rat striatal slices. For comparison purposes, 3-nitropropionic acid was used as reference model. Our results show that tBHQ (25 μM) prevented the QUIN-induced lipid peroxidation and mitochondrial dysfunction. In addition, tBHQ enhanced glutathione-S-transferase activity, partially recovering its depletion induced by QUIN treatment. Our results also demonstrated that tBHQ was able to induce nuclear accumulation of Nrf2 and further antioxidant protection: while QUIN alone decreased the nuclear Nrf2, a treatment with tBHQ preserved the nuclear levels Nrf2 in the presence of QUIN. Therefore, the tBHQ-mediated Nrf2/ARE induction constitutes a signaling-mediated antioxidant strategy and therapeutic tool to be tested in different neurotoxic models. Copyright © 2009 S. Karger AG, Basel.

  9. Purification and characterization of rat striatal tyrosine hydroxylase. Comparison of the activation by cyclic AMP-dependent phosphorylation and by other effectors.

    PubMed

    Richtand, N M; Inagami, T; Misono, K; Kuczenski, R

    1985-07-15

    Purification of rat striatal tyrosine hydroxylase in the presence of protease inhibitors effected a high yield of apparently homogeneous enzyme which is stable to prolonged storage. The purified enzyme migrates as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a molecular weight of 61,300. Removal of protease inhibitors results in the appearance of additional bands with molecular weights of 59,800 and 57,000. Cyclic AMP-dependent protein kinase incorporates 1 mol of phosphate/61,000-Da subunit of tyrosine hydroxylase, and concomitantly decreases the apparent Km of the enzyme for cofactor. Phosphorylated tyrosine hydroxylase is unstable at 37 degrees C, exhibiting a 50% decrease in apparent Vmax in 40 min with no change in Km for cofactor. Levels of incorporated phosphate remain constant over this time period. Tyrosine hydroxylase activated by and in the presence of phosphatidylinositol or high concentrations of NaCl exhibited a similar loss of activity at 37 degrees C, whereas enzyme activated by heparin was relatively stable. The rate of phosphorylation of tyrosine hydroxylase is markedly increased in the presence of any of these effectors, suggesting that they promote a common conformation. Further, heparin appears to bind to tyrosine hydroxylase at a site distant from the phosphorylation site. Physiological effectors of tyrosine hydroxylase may act in concert with cyclic AMP-dependent phosphorylation, perhaps by binding to an allosteric site, to regulate enzyme activity in vivo.

  10. Effects of semiconductor substrate and glia-free culture on the development of voltage-dependent currents in rat striatal neurones.

    PubMed

    Parak, W J; George, M; Kudera, M; Gaub, H E; Behrends, J C

    2001-01-01

    An essential requirement for successful long-term coupling between neuronal assemblies and semiconductor devices is that the neurones must be able to fully develop their electrogenic repertoire when growing on semiconductor (silicon) substrates. While it has for some time been known that neurones may be cultured on silicon wafers insulated with SiO2 and Si3N4, an electrophysiological characterisation of their development under such conditions is lacking. The development of voltage-dependent membrane currents, especially of the rapid sodium inward current underlying the action potential, is of particular importance because the conductance change during the action potential determines the quality of cell-semiconductor coupling. We have cultured rat striatal neurones on either glass coverslips or silicon wafers insulated with SiO2 and Si3N4 using both serum-containing and serum-free media. We here report evidence that not only serum-free culture media but also growth on semiconductor surfaces may negatively affect the development of voltage-dependent currents in neurones. Furthermore, using surface-charge measurements with the atomic force microscope, we demonstrate a reduced negativity of the semiconductor surface compared to glass. The reduced surface charge may affect cellular development through an effect on the binding and/or orientation of extracellular matrix proteins, such as laminin. Our findings therefore suggest that semiconductor substrates are not entirely equivalent to glass in terms of their effects on neuronal cell growth and differentiation.

  11. Brain adaptation to acute hyponatremia in young rats.

    PubMed

    Silver, S M; Schroeder, B M; Bernstein, P; Sterns, R H

    1999-06-01

    Brain swelling after acute hyponatremia in prepubescent rats, in contrast to adults, has recently been associated with an increase in brain sodium and a high mortality that could be prevented by preadministration of testosterone. To reexamine the effect of acute hyponatremia in young brain, we measured brain water and solute content in prepubescent rats after induction of hyponatremia over 4 h with water and arginine vasopressin. An 18% decrease in plasma sodium was associated with a 13% increase in brain water and a decrease in brain sodium and glutamate contents. No animals died. To assess the effect of sex hormones on brain adaptation, prepubescent rats were pretreated with estrogen or testosterone before acute hyponatremia. Brain sodium and potassium contents were significantly reduced in comparison to normonatremia in testosterone-pretreated but not estrogen-pretreated animals. However, there was no difference between estrogen-pretreated and testosterone-pretreated groups in mortality or in brain contents of water, electrolytes, or major organic osmolytes. In conclusion, we found that brain adaptation to acute hyponatremia in prepubescent rats is similar to that observed in adults.

  12. Brain Injury After Intracerebral Hemorrhage in Spontaneously Hypertensive Rats

    PubMed Central

    Wu, Gang; Bao, Xuhui; Xi, Guohua; Keep, Richard; Thompson, B. Gregory; Hua, Ya

    2011-01-01

    Object Hypertension is the main cause of spontaneous intracerebral hemorrhages (ICH), but the effects of hypertension on ICH-induced brain injury have not been well studied. In this study, we examined ICH-induced brain injury in spontaneously hypertensive rats (SHR). Methods This two-part study was performed on 12 weeks old male SHR and Wistar Kyoto (WKY) rats. First, rats received an intracaudate injection of 0.3 units collagenase and hematoma sizes were determined at 24 hours. Second, rats were injected with 100-μL autologous whole blood into the right basal ganglia. Brain edema, neuronal death, ferritin expression, microglia activation, and neurological deficits were examined. Results Hematoma sizes were the same in SHR and WKY rats 24 hours after collagenase injection. SHR had greater neuronal death and neurological deficits after blood injection. ICH also resulted in higher brain ferritin levels and stronger activation of microglia in SHR. However, perihematomal brain edema was same in the SHR and WKY rats. Conclusion Moderate chronic hypertension resulted in more severe ICH-induced neuronal death and neurological deficits, but did not exaggerate hematoma enlargement and perihematomal brain edema in the rat ICH models. PMID:21294617

  13. Transcription Mapping of Embryonic Rat Brain Reveals EGR-1 Induction in SOX2 Neural Progenitor Cells.

    PubMed

    Wells, Timothy; Rough, Kirsty; Carter, David A

    2011-01-01

    Neuronal expression of the early growth response-1 (EGR-1; NGFI-A/Zif268) transcription factor has been extensively studied in the adult mammalian brain and linked to aspects of mature physiological/behavioral function. In contrast, this factor has not been studied in detail in the embryonic brain. Here, we used a fluorescent protein-encoding Egr-1 transgene to map the cellular distribution of Egr-1 transcription in embryonic rat brain. We identified a novel, widely distributed population of GFP(+) cells, characterized as a precursor/stem cell phenotype by co-localization with SOX2/nestin/vimentin/S-100β and exclusion from other known cellular markers including DCX/BLBP/TBR2/NURR1. At both E18 and E20, these cells were located across the developing brain but concentrated in the subplate and intermediate zones. The transgene was also highly expressed in developing (NeuN(+)) striatal neurons. The authentic expression pattern that we observed for the rEgr-1 transgene sequence indicates that restriction to neuronal/precursor cells is largely driven by proximal 5(') sequence. Deletion of conserved Egr-1 silencer (neuron restrictive silencer factor) elements did not markedly alter transcriptional activity in transfected cells; this is consistent with a dominant role for positive factors in the control of cell-specific Egr-1 expression. Induction of Egr-1 in a population of SOX2(+) cells indicates a co-incidence of extrinsic (EGR-1) and cell-intrinsic (SOX2) cellular signals that may form a novel level of progenitor cell regulation. The wide distribution of EGR-1 signaling in SOX2(+) cells suggests an organizational role during late embryonic brain development.

  14. Transcription Mapping of Embryonic Rat Brain Reveals EGR-1 Induction in SOX2+ Neural Progenitor Cells

    PubMed Central

    Wells, Timothy; Rough, Kirsty; Carter, David A.

    2011-01-01

    Neuronal expression of the early growth response-1 (EGR-1; NGFI-A/Zif268) transcription factor has been extensively studied in the adult mammalian brain and linked to aspects of mature physiological/behavioral function. In contrast, this factor has not been studied in detail in the embryonic brain. Here, we used a fluorescent protein-encoding Egr-1 transgene to map the cellular distribution of Egr-1 transcription in embryonic rat brain. We identified a novel, widely distributed population of GFP+ cells, characterized as a precursor/stem cell phenotype by co-localization with SOX2/nestin/vimentin/S-100β and exclusion from other known cellular markers including DCX/BLBP/TBR2/NURR1. At both E18 and E20, these cells were located across the developing brain but concentrated in the subplate and intermediate zones. The transgene was also highly expressed in developing (NeuN+) striatal neurons. The authentic expression pattern that we observed for the rEgr-1 transgene sequence indicates that restriction to neuronal/precursor cells is largely driven by proximal 5′ sequence. Deletion of conserved Egr-1 silencer (neuron restrictive silencer factor) elements did not markedly alter transcriptional activity in transfected cells; this is consistent with a dominant role for positive factors in the control of cell-specific Egr-1 expression. Induction of Egr-1 in a population of SOX2+ cells indicates a co-incidence of extrinsic (EGR-1) and cell-intrinsic (SOX2) cellular signals that may form a novel level of progenitor cell regulation. The wide distribution of EGR-1 signaling in SOX2+ cells suggests an organizational role during late embryonic brain development. PMID:21629823

  15. Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment.

    PubMed

    Robertson, Chelsea L; Ishibashi, Kenji; Chudzynski, Joy; Mooney, Larissa J; Rawson, Richard A; Dolezal, Brett A; Cooper, Christopher B; Brown, Amira K; Mandelkern, Mark A; London, Edythe D

    2016-05-01

    Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [(18)F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence.

  16. Ceftriaxone attenuates hypoxic-ischemic brain injury in neonatal rats

    PubMed Central

    2011-01-01

    Background Perinatal brain injury is the leading cause of subsequent neurological disability in both term and preterm baby. Glutamate excitotoxicity is one of the major factors involved in perinatal hypoxic-ischemic encephalopathy (HIE). Glutamate transporter GLT1, expressed mainly in mature astrocytes, is the major glutamate transporter in the brain. HIE induced excessive glutamate release which is not reuptaked by immature astrocytes may induce neuronal damage. Compounds, such as ceftriaxone, that enhance the expression of GLT1 may exert neuroprotective effect in HIE. Methods We used a neonatal rat model of HIE by unilateral ligation of carotid artery and subsequent exposure to 8% oxygen for 2 hrs on postnatal day 7 (P7) rats. Neonatal rats were administered three dosages of an antibiotic, ceftriaxone, 48 hrs prior to experimental HIE. Neurobehavioral tests of treated rats were assessed. Brain sections from P14 rats were examined with Nissl and immunohistochemical stain, and TUNEL assay. GLT1 protein expression was evaluated by Western blot and immunohistochemistry. Results Pre-treatment with 200 mg/kg ceftriaxone significantly reduced the brain injury scores and apoptotic cells in the hippocampus, restored myelination in the external capsule of P14 rats, and improved the hypoxia-ischemia induced learning and memory deficit of P23-24 rats. GLT1 expression was observed in the cortical neurons of ceftriaxone treated rats. Conclusion These results suggest that pre-treatment of infants at risk for HIE with ceftriaxone may reduce subsequent brain injury. PMID:21933448

  17. Neurotoxic methamphetamine regimens produce long-lasting changes in striatal G-proteins.

    PubMed

    Boikess, Steven R; O'Dell, Steven J; Marshall, John F

    2010-11-01

    Animals repeatedly dosed with methamphetamine during a single day suffer damage to brain dopamine and serotonin terminals and show behavioral deficits. These methamphetamine regimens also produce long-term reductions in dopamine agonist-stimulated immediate-early gene responses both in striatum and several cortical areas, but the mechanism(s) underlying these long-lasting effects of methamphetamine remain uncertain. Six weeks after a neurotoxic regimen of methamphetamine (4 × 4 mg/kg) or saline, α subunit levels of striatal G-proteins that couple dopamine receptors to second messenger systems were measured. Because the damage to striatal monoamine terminals produced by methamphetamine is regionally heterogeneous, we used radioimmunocytochemistry, which combines quantification with regional resolution. We found significant increases in G(iα) and G(olfα) expression in the ventral striatum (but not in the dorsolateral striatum or nucleus accumbens) of methamphetamine-pretreated rats, a regional pattern similar to that reported for methamphetamine effects on dopamine terminal markers. By contrast, G(qα) expression was unaffected in all striatal subregions. The central roles of G(i) and G(olf) in modulating the activity of a series of interlinked intracellular signaling pathways suggest that methamphetamine-induced changes in G(i) and G(olf) can have lasting effects on striatal neuronal function.

  18. Glutamine triggers long-lasting increase in striatal network activity in vitro.

    PubMed

    Fleischer, Wiebke; Theiss, Stephan; Schnitzler, Alfons; Sergeeva, Olga

    2017-04-01

    Accumulation of ammonium and glutamine in blood and brain is a key factor in hepatic encephalopathy (HE) - a neuropsychiatric syndrome characterized by various cognitive and motor deficits. MRI imaging identified abnormalities notably in the basal ganglia of HE patients, including its major input station, the striatum. While neurotoxic effects of ammonia have been extensively studied, glutamine is primarily perceived as "detoxified" form of ammonia. We applied ammonium and glutamine to striatal and cortical cells from newborn rats cultured on microelectrode arrays. Glutamine, but not ammonium significantly increased spontaneous spike rate with a long-lasting excitation outlasting washout. This effect was more prominent in striatal than in cortical cultures. Calcium imaging revealed that glutamine application caused a rise in intracellular calcium that depended both on system A amino acid transport and activation of ionotropic glutamate receptors. This pointed to downstream glutamate release that was triggered by intracellular glutamine. Using an enzymatic assay kit we confirmed glutamine-provoked glutamate release from striatal cells. Real-time PCR and immunocytochemistry demonstrated the presence of vesicular glutamate transporters (VGLUT1 and VGLUT2) necessary for synaptic glutamate release in striatal neurons. We conclude that extracellular glutamine is taken up by neurons, triggers synaptic release of glutamate which is then taken up by astrocytes and again converted to glutamine. This feedback-loop causes a sustained long-lasting excitation of network activity. Thus, apart from ammonia also its "detoxified" form glutamine might be responsible for the neuropsychiatric symptoms in HE. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Polychlorinated biphenyls and methylmercury act synergistically to reduce rat brain dopamine content in vitro.

    PubMed Central

    Bemis, J C; Seegal, R F

    1999-01-01

    Consumption of contaminated Great Lakes fish by pregnant women is associated with decreased birth weight and deficits in cognitive function in their infants and children. These fish contain many known and suspected anthropogenic neurotoxicants, making it difficult to determine which contaminant(s) are responsible for the observed deficits. We have undertaken a series of experiments to determine the relevant toxicants by comparing the neurotoxic effects of two of these contaminants--polychlorinated biphenyls (PCBs) and methylmercury (MeHg)--both of which are recognized neurotoxicants. Striatal punches obtained from adult rat brain were exposed to PCBs only, MeHg only, or the two in combination, and tissue and media concentrations of dopamine (DA) and its metabolites were determined by high performance liquid chromatography. Exposure to PCBs only reduced tissue DA and elevated media DA in a dose-dependent fashion. Exposure to MeHg only did not significantly affect either measure. However, when striatal punches were simultaneously exposed to PCBs and MeHg, there were significantly greater decreases in tissue DA concentrations and elevations in media DA than those caused by PCBs only, in the absence of changes in media lactate dehydrogenase concentrations. Elevations in both tissue and media 3, 4-dihydroxyphenylacetic acid concentrations were also observed. We suggest that the significant interactions between these two toxicants may be due to a common site of action (i.e., toxicant-induced increases in intracellular calcium and changes in second messenger systems) that influences DA function. The synergism between these contaminants suggests that future revisions of fish-consumption guidelines should consider contaminant interactions. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:10544155

  20. Effects of 5-HT1A receptor stimulation on striatal and cortical M1 pERK induction by L-DOPA and a D1 receptor agonist in a rat model of Parkinson's disease.

    PubMed

    Lindenbach, David; Dupre, Kristin B; Eskow Jaunarajs, Karen L; Ostock, Corinne Y; Goldenberg, Adam A; Bishop, Christopher

    2013-11-06

    Motor symptoms of Parkinson's disease are commonly treated using l-DOPA although long-term treatment usually causes debilitating motor side effects including dyskinesias. A putative source of dyskinesia is abnormally high levels of phosphorylated extracellular-regulated kinase (pERK) within the striatum. In animal models, the serotonin 1A receptor agonist ±8-OH-DPAT reduces dyskinesia, suggesting it may exhibit efficacy through the pERK pathway. The present study investigated the effects of ±8-OH-DPAT on pERK density in rats treated with l-DOPA or the D1 receptor agonist SKF81297. Rats were given a unilateral dopamine lesion with 6-hydroxydopamine and primed with a chronic regimen of l-DOPA, SKF81297 or their vehicles. On the final test day, rats were given two injections: first with ±8-OH-DPAT, the D1 receptor antagonist SCH23390 or their vehicles, and second with l-DOPA, SKF81297 or their vehicles. Rats were then transcardially perfused for immunohistological analysis of pERK expression in the striatum and primary motor cortex. Rats showed greater dyskinesia in response to l-DOPA and SKF81297 after repeated injections. Although striatal pERK induction was similar between acute and chronic l-DOPA, SKF81297 caused the largest increase in striatal pERK after the first exposure. Neither compound alone affected motor cortex pERK. Surprisingly, in the ventromedial striatum, ±8-OH-DPAT potentiated l-DOPA-induced pERK; in the motor cortex, ±8-OH-DPAT potentiated pERK with l-DOPA or SKF81297. Our results support previous work that the striatal pERK pathway is dysregulated after dopamine depletion, but call into question the utility of pERK as a biomarker of dyskinesia expression.

  1. The connection between the hippocampal and the striatal memory systems of the brain: a review of recent findings.

    PubMed

    Izquierdo, I; Bevilaqua, L R M; Rossato, J I; Bonini, J S; Da Silva, W C; Medina, J H; Cammarota, M

    2006-10-01

    Two major memory systems have been recognized over the years (Squire, in Memory and Brain, 1987): the declarative memory system, which is under the control of the hippocampus and related temporal lobe structures, and the procedural or habit memory system, which is under the control of the striatum and its connections (Mishkin et al., in Neurobiology of Learning by G Lynch et al., 1984; Knowlton et al., Science 273:1399, 1996). Most if not all learning tasks studied in animals, however, involve either the performance or the suppression of movement. Animals acquire connections between environmental or discrete sensory cues (conditioned stimuli, CSs) and emotionally or otherwise significant stimuli (unconditioned stimuli, USs). As a result, they learn to perform or to inhibit the performance of certain motor responses to the CS which, when learned well, become what can only be called habits (Mishkin et al., 1984): to regularly walk or swim to a place or away from a place, or to inhibit one or several forms of movement. These responses can be viewed as conditioned responses (CRs) and may sometimes be very complex. This is of course also seen in humans: people learn how to play on a keyboard in response to a mental or written script and perform the piano or write a text; with practice, the performance improves and eventually reaches a high criterion and becomes a habit, performed almost if not completely without awareness. Commuting to school in a big city in the shortest possible time and eschewing the dangers is a complex learning that children acquire to the point of near-perfection. It is agreed that the rules that connect the perception of the CS and the expression of the CR change from their first association to those that take place when the task is mastered. Does this change of rules involve a switch from one memory system to another? Are different brain systems used the first time one plays a sonata or goes to school as compared with the 100th time? Here we

  2. Striatal changes underlie MPEP-mediated suppression of the acquisition and expression of pramipexole-induced place preference in an alpha-synuclein rat model of Parkinson's disease.

    PubMed

    Loiodice, Simon; McGhan, Portia; Gryshkova, Vitalina; Fleurance, Renaud; Dardou, David; Hafidi, Aziz; Nogueira da Costa, Andre; Durif, Franck

    2017-10-01

    Impulsive-compulsive disorders in Parkinson's disease patients have been described as behavioural or substance addictions including pathological gambling or compulsive medication use of dopamine replacement therapy. A substantial gap remains in the understanding of these disorders. We previously demonstrated that the rewarding effect of the D2/D3 agonist pramipexole was enhanced after repeated exposure to L-dopa and alpha-synuclein mediated dopaminergic nigral loss with specific transcriptional signatures suggesting a key involvement of the glutamatergic pathway. Here, we further investigate the therapeutic potential of metabotropic glutamate receptor 5 antagonism in Parkinson's disease/dopamine replacement therapy related bias of reward-mediated associative learning. We identified protein changes underlying the striatal remodelling associated with the pramipexole-induced conditioned place preference. Acquisition and expression of the pramipexole-induced conditioned place preference were abolished by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-phenylethynyl (pyridine) (conditioned place preference scores obtained with pramipexole conditioning were reduced by 12.5% and 125.8% when 2-methyl-6-phenylethynyl (pyridine) was co-administrated with pramipexole or after the pramipexole conditioning, respectively). Up-regulation of the metabotropic glutamate receptor 5 was found in the dorsomedial-striatum and nucleus accumbens core. Activation of these two brain sub-regions was also highlighted through FosB immunohistochemistry. Convergent molecular and pharmacological data further suggests metabotropic glutamate receptor 5 as a promising therapeutic target for the management of Parkinson's disease/dopamine replacement therapy related reward bias.

  3. Electrically-evoked dopamine and acetylcholine release from rat striatal slices perfused without magnesium: regulation by glutamate acting on NMDA receptors

    PubMed Central

    Jin, Shaoyu; Fredholm, Bertil B

    1997-01-01

    Rat striatal slices, preincubated with [3H]-dopamine and [14C]-choline, were continuously superfused and electrically stimulated. Electrically evoked release of [3H]-dopamine and [14C]-acetylcholine (ACh) was not significantly changed by elimination of Mg2+ from superfusion buffer, but the basal release of [3H]-dopamine was doubled. Kynurenic acid (100–800  μM) caused, in the absence but not presence of Mg2+, a concentration-dependent decrease in the evoked release of these two transmitters. The addition of glycine reversed the inhibition of the evoked release of both transmitters caused by kynurenic acid (400  μM) in a concentration-dependent manner. In addition, glycine increased the evoked release of [3H]-dopamine via a site inhibitable by strychnine (1  μM). Another two antagonists at N-methyl-D-aspartate (NMDA) receptors, 2-amino-5-phosphonovaleric acid and dizocilpine, also decreased significantly the evoked release of the two transmitters in a concentration-dependent manner in the absence, but not presence of Mg2+. By contrast, an antagonist of non-NMDA receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (10  μM) significantly decreased the evoked release of the two transmitters in the presence, but not in the absence of Mg2+. Electrical field stimulation evoked release of endogenous adenosine, and this release tended to be higher in the absence of Mg2+. However, the addition of a selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (200 nM) did not influence the evoked release of the two transmitters, showing that the released adenosine is of little importance in controlling ACh and dopamine release from striatal slices. Non-NMDA receptors may play a similar role when Mg2+ ions are present. The results indicate that NMDA receptors activated in the absence of Mg2+ participate in the electrically-evoked release of [3H]-dopamine and [14C]-ACh from the striatum. PMID:9257903

  4. Aluminium toxicity in the rat liver and brain

    NASA Astrophysics Data System (ADS)

    Yumoto, S.; Ohashi, H.; Nagai, H.; Kakimi, S.; Ishikawa, A.; Kobayashi, K.; Ogawa, Y.; Ishii, K.

    1993-04-01

    To investigate the etiology of Alzheimer's disease, we examined the brain and liver tissue uptake of aluminium 5-75 days after aluminium injection into healthy rats. Ten days after the last injection, Al was detected in the brain and the brain cell nuclei by particle-induced X-ray emission (PIXE) analysis. Al was also demonstrated in the liver and the liver cell nuclei by PIXE analysis and electron energy loss spectrometry (EELS). The morphological changes of the rat brain examined 75 days after the injection were similar to those which have been reportedly observed in the brain of patients with Alzheimer's disease. These results support the theory that Alzheimer's disease is caused by irreversible accumulation of aluminium in the brain, as well as in the nuclei of brain cells.

  5. 26Al uptake and accumulation in the rat brain

    NASA Astrophysics Data System (ADS)

    Yumoto, S.; Nagai, H.; Imamura, M.; Matsuzaki, H.; Hayashi, K.; Masuda, A.; Kumazawa, H.; Ohashi, H.; Kobayashi, K.

    1997-03-01

    To investigate the cause of Alzheimer's disease (senile dementia), 26Al incorporation in the rat brain was studied by accelerator mass spectrometry (AMS). When 26Al was injected into healthy rats, a considerable amount of 26Al entered the brain (cerebrum) through the blood-brain barrier 5 days after a single injection, and the brain 26Al level remained almost constant from 5 to 270 days. On the other hand, the level of 26Al in the blood decreased remarkably 75 days after injection. Approximately 89% of the 26Al taken in by the brain cell nuclei bound to chromatin. This study supports the theory that Alzheimer's disease is caused by irreversible accumulation of aluminium (Al) in the brain, and brain cell nuclei.

  6. Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain

    SciTech Connect

    Volkow, N. D.; Wang, G. -J.; Logan, J.; Alexoff, D.; Fowler, J. S.; Thanos, P. K.; Wong, C.; Casado, V.; Ferre, S.; Tomasi, D.

    2015-04-14

    Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [11C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). Furthermore, the association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors.

  7. Effect of Buspirone, Fluoxetine and 8-OH-DPAT on Striatal Expression of Bax, Caspase-3 and Bcl-2 Proteins in 6-Hydroxydopamine-Induced Hemi-Parkinsonian Rats.

    PubMed

    Sharifi, Hamdollah; Mohajjel Nayebi, Alireza; Farajnia, Safar; Haddadi, Rasool

    2015-11-01

    The exact pathogenesis of sporadic parkinson's disease (PD) is still unclear. Numerous evidences suggest involvement of apoptosis in the death of dopaminergic neurons. In this study we investigated the effect of sub-chronic administration of buspirone, fluoxetine and 8-hydroxy-2-[di-n-propylamino]tetralin (8-OH-DPAT) in 6-hydroxydopamine (6-OHDA)-lesioned rats and assayed striatal concentrations of apoptotic (Bax, Caspase3) and anti-apoptotic (Bcl-2) proteins. 6-OHDA (8μg/2μl/rat) was injected unilaterally into the central region of the substantia nigra pars copmacta (SNc) of male Wistar rats and then, after 21 days lesioned rats were treated with intraperitonel (i.p) 1 mg/kg injections of buspirone, fluoxetine and 8-OH-DPAT for 10 consecutive days. Striatum of rats was removed at tenth day of drugs administration and were analyzed by western blotting method to measure Bax, caspase3 and Bcl-2 expression. The results showed that the expression of Bax and caspase3 proteins was increased three weeks after 6-OHDA injection while they were decreased significantly in parkinsonian rats which were treated by buspirone, fluoxetine and 8-OH-DPAT. Bcl-2 was decreased and increased in parkinsonian rats and parkinsonian rats treated with buspirone, fluoxetine and 8-OH-DPAT, respectively. Our study indicates that sub-chronic administration of serotonergic drugs such as buspirone, fluoxetine and 8-OH-DPAT restores striatal concentration of apoptotic and anti-apoptotic factors to the basal levels of normal non-lesioned rats. We suggest that these drugs can be used as a potential adjunctive therapy in PD through attenuating neuronal apoptotic process.

  8. Transcranial Optical Imaging of Cold-Injured Brain in Rat

    NASA Astrophysics Data System (ADS)

    Ueda, Yoshinori; Sato, Shunichi; Ooigawa, Hidetoshi; Nawashiro, Hiroshi; Saitoh, Daizoh; Shima, Katsuji; Ashida, Hiroshi; Obara, Minoru

    2005-06-01

    We performed a transcranial optical imaging of a cold-injured brain in a rat. The rat skull was illuminated with a 633 nm HeNe laser, and the distribution of reflected light intensity was imaged with a cooled charge-coupled device (CCD) camera. An increase in reflected light intensity was observed in the injured area. The analysis of brain tissues perfused with India ink suggested that a reduced blood flow rate in the area of injury enhances reflection.

  9. Striatal but not frontal cortical up-regulation of the epidermal growth factor receptor in rats exposed to immune activation in utero and cannabinoid treatment in adolescence.

    PubMed

    Idrizi, Rejhan; Malcolm, Peter; Weickert, Cynthia Shannon; Zavitsanou, Katerina; Suresh Sundram

    2016-06-30

    In utero maternal immune activation (MIA) and cannabinoid exposure during adolescence constitute environmental risk factors for schizophrenia. We investigated these risk factors alone and in combination ("two-hit") on epidermal growth factor receptor (EGFR) and neuregulin-1 receptor (ErbB4) levels in the rat brain. EGFR but not ErbB4 receptor protein levels were significantly increased in the nucleus accumbens and striatum of "two-hit" rats only, with no changes seen at the mRNA level. These findings support region specific EGF-system dysregulation as a plausible mechanism in this animal model of schizophrenia pathogenesis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. The effect of phencyclidine on [3H]GABA and [3H]flunitrazepam binding in the brain of naive and handling-habituated rats.

    PubMed

    Lillrank, S M; Oja, S S; Saransaari, P

    1995-01-01

    The effects of handling and handling combined with phencyclidine (PCP) treatment on GABAergic neurotransmission were studied in Sprague-Dawley rats. The animal material consisted of handling-habituated (HH, for 11 d), acutely handled (naive, N), handling-habituated and PCP-treated (10 mg kg-1 i.p., HH + PCP) and acutely handled (naive) PCP-treated (N + PCP) and unhandled 'control' rats. The binding of [3H]GABA and [3H]flunitrazepam (FLU) was studied with membranes and the release of [3H]GABA with slices prepared from the striatum and frontal cortex. In the striatum the maximal binding capacity (Bmax) and the binding constant (KD) of [3H]GABA were the same in N and HH rats, but in the frontal cortex KD was lower in N rats. KD constants of [3H]FLU were significantly lower in both brain areas in N rats than in HH rats. After PCP treatment both Bmax and KD for [3H]FLU increased in these two brain areas in handling-habituated rats, whereas Bmax of [3H]GABA diminished. Neither handling nor PCP had any effect on [3H]GABA release from striatal and frontal cortical slices. Handling prior to killing thus affects differently the GABAergic parameters studied and modulates the PCP-induced effects.

  11. Spatial Discrimination Reversal Learning in Weanling Rats Is Impaired by Striatal Administration of an NMDA-Receptor Antagonist

    ERIC Educational Resources Information Center

    Watson, Deborah J.; Stanton, Mark E.

    2009-01-01

    The striatum plays a major role in both motor control and learning and memory, including executive function and "behavioral flexibility." Lesion, temporary inactivation, and infusion of an N-methyl-d-aspartate (NMDA)-receptor antagonist into the dorsomedial striatum (dmSTR) impair reversal learning in adult rats. Systemic administration of MK-801…

  12. Spatial Discrimination Reversal Learning in Weanling Rats Is Impaired by Striatal Administration of an NMDA-Receptor Antagonist

    ERIC Educational Resources Information Center

    Watson, Deborah J.; Stanton, Mark E.

    2009-01-01

    The striatum plays a major role in both motor control and learning and memory, including executive function and "behavioral flexibility." Lesion, temporary inactivation, and infusion of an N-methyl-d-aspartate (NMDA)-receptor antagonist into the dorsomedial striatum (dmSTR) impair reversal learning in adult rats. Systemic administration of MK-801…

  13. Persistent behavioral impairments and alterations of brain dopamine system after early postnatal administration of thimerosal in rats.

    PubMed

    Olczak, Mieszko; Duszczyk, Michalina; Mierzejewski, Pawel; Meyza, Ksenia; Majewska, Maria Dorota

    2011-09-30

    The neurotoxic organomercurial thimerosal (THIM), used for decades as vaccine preservative, is a suspected factor in the pathogenesis of some neurodevelopmental disorders. Previously we showed that neonatal administration of THIM at doses equivalent to those used in infant vaccines or higher, causes lasting alterations in the brain opioid system in rats. Here we investigated neonatal treatment with THIM (at doses 12, 240, 1440 and 3000 μg Hg/kg) on behaviors, which are characteristically altered in autism, such as locomotor activity, anxiety, social interactions, spatial learning, and on the brain dopaminergic system in Wistar rats of both sexes. Adult male and female rats, which were exposed to the entire range of THIM doses during the early postnatal life, manifested impairments of locomotor activity and increased anxiety/neophobia in the open field test. In animals of both sexes treated with the highest THIM dose, the frequency of prosocial interactions was reduced, while the frequency of asocial/antisocial interactions was increased in males, but decreased in females. Neonatal THIM treatment did not significantly affect spatial learning and memory. THIM-exposed rats also manifested reduced haloperidol-induced catalepsy, accompanied by a marked decline in the density of striatal D₂ receptors, measured by immunohistochemical staining, suggesting alterations to the brain dopaminergic system. Males were more sensitive than females to some neurodisruptive/neurotoxic actions of THIM. These data document that early postnatal THIM administration causes lasting neurobehavioral impairments and neurochemical alterations in the brain, dependent on dose and sex. If similar changes occur in THIM/mercurial-exposed children, they could contribute do neurodevelopmental disorders.

  14. Blood-brain transfer and metabolism of 6-( sup 18 F)fluoro-L-dopa in rat

    SciTech Connect

    Reith, J.; Dyve, S.; Kuwabara, H.; Guttman, M.; Diksic, M.; Gjedde, A. )

    1990-09-01

    In a study designed to reveal the rates of blood-brain transfer and decarboxylation of fluoro-L-3,4-dihydroxyphenylalanine (FDOPA), we discovered a major discrepancy between the DOPA decarboxylase activity reported in the literature and the rate of FDOPA decarboxylation measured in the study. Donor rats received intravenous injections of 6 mCi fluorine-18-labeled FDOPA. The donor rats synthesized methyl-FDOPA. Arterial plasma, containing both FDOPA and methyl-FDOPA, was sampled from the donor rats at different times and reinjected into recipient rats in which it circulated for 20 s. The blood-brain clearance of the mixture of labeled tracers in the plasma was determined by an integral method. The individual permeabilities were determined by linear regression analysis, according to which the average methyl-FDOPA permeability in the blood-brain barrier was twice that of FDOPA, which averaged 0.037 ml g-1 min-1. The permeability ratio was used to determine the fractional clearance from the brain of FDOPA (and hence of methyl-FDOPA), which averaged 0.081 min-1. In the striatum, the measured average FDOPA decarboxylation rate constant (kD3) was 0.010 min-1, or no more than 1% of the rate of striatal decarboxylation of DOPA measured in vitro and in vivo. We interpreted this finding as further evidence in favor of the hypothesis that striatum has two dopamine (DA) pools, of which only DA in the large pool is protected from metabolism. Hence, no more than 1% of the quantity of fluoro-DA theoretically synthesized was actually retained in striatum.

  15. Transcranial Photoacoustic Measurements of Cold-Injured Brains in Rats

    NASA Astrophysics Data System (ADS)

    Ueda, Yoshinori; Sato, Shunichi; Hasegawa, Makoto; Nawashiro, Hiroshi; Saitoh, Daizoh; Shima, Katsuji; Ashida, Hiroshi; Obara, Minoru

    2005-09-01

    We performed transcranial photoacoustic measurements of cold-injured brains in rats. Before inducing injury, a signal peak was observed at two locations corresponding to the surfaces of the skull and brain, while after injury, a third peak appeared at a location corresponding to the back surface of the skull; the third peak was found to be caused by subdural hematoma. The signal peak for the brain surface shifted to a deeper region with elapse of time after injury, indicating deformation of the brain. These findings suggest that small hemorrhage and morphological change of the brain can be transcranially detected by photoacoustic measurement.

  16. Cannabinoid receptor agonists reduce the short-term mitochondrial dysfunction and oxidative stress linked to excitotoxicity in the rat brain.

    PubMed

    Rangel-López, E; Colín-González, A L; Paz-Loyola, A L; Pinzón, E; Torres, I; Serratos, I N; Castellanos, P; Wajner, M; Souza, D O; Santamaría, A

    2015-01-29

    The endocannabinoid system (ECS) is involved in a considerable number of physiological processes in the Central Nervous System. Recently, a modulatory role of cannabinoid receptors (CBr) and CBr agonists on the reduction of the N-methyl-d-aspartate receptor (NMDAr) activation has been demonstrated. Quinolinic acid (QUIN), an endogenous analog of glutamate and excitotoxic metabolite produced in the kynurenine pathway (KP), selectively activates NMDAr and has been shown to participate in different neurodegenerative disorders. Since the early pattern of toxicity exerted by this metabolite is relevant to explain the extent of damage that it can produce in the brain, in this work we investigated the effects of the synthetic CBr agonist WIN 55,212-2 (WIN) and other agonists (anandamide or AEA, and CP 55,940 or CP) on early markers of QUIN-induced toxicity in rat striatal cultured cells and rat brain synaptosomes. WIN, AEA and CP exerted protective effects on the QUIN-induced loss of cell viability. WIN also preserved the immunofluorescent signals for neurons and CBr labeling that were decreased by QUIN. The QUIN-induced early mitochondrial dysfunction, lipid peroxidation and reactive oxygen species (ROS) formation were also partially or completely prevented by WIN pretreatment, but not when this CBr agonist was added simultaneously with QUIN to brain synaptosomes. These findings support a neuroprotective and modulatory role of cannabinoids in the early toxic events elicited by agents inducing excitotoxic processes.

  17. Effect of Jian-Pi-Zhi-Dong Decoction on striatal glutamate and γ-aminobutyric acid levels detected using microdialysis in a rat model of Tourette syndrome

    PubMed Central

    Zhang, Wen; Wei, Li; Yu, Wenjing; Cui, Xia; Liu, Xiaofang; Wang, Qian; Wang, Sumei

    2016-01-01

    Background Jian-Pi-Zhi-Dong Decoction (JPZDD) is a dedicated treatment of Tourette syndrome (TS). The balance of neurotransmitters in the cortico-striato-pallido-thalamo-cortical network is crucial to the occurrence of TS and related to its severity. This study evaluated the effect of JPZDD on glutamate (Glu) and γ-aminobutyric acid (GABA) and their receptors in a TS rat model. Materials and methods Rats were divided into four groups (n=12 each). TS was induced in three of the groups by injecting them with 3,3′-iminodipropionitrile for 7 consecutive days. Two model groups were treated with tiapride (Tia) or JPZDD, while the control and the remaining model group were gavaged with saline. Behavior was assessed by stereotypic score and autonomic activity. Striatal Glu and GABA contents were detected using microdialysis. Expressions of N-methyl-D-aspartate receptor 1 and GABAA receptor (GABAAR) were observed using Western blot and real-time polymerase chain reaction. Results Tia and JPZDD groups had decreased stereotypy compared with model rats; however, the JPZDD group showed a larger decrease in stereotypy than the Tia group at a 4-week time point. In a spontaneous activity test, the total distance of the JPZDD and Tia groups was significantly decreased compared with the model group. The Glu levels of the model group were higher than the control group and decreased with Tia or JPZDD treatment. The GABA level was higher in the model group than the control group. Expressions of GABAAR protein in the model group were higher than in the control group. Treatment with Tia or JPZDD reduced the expression of GABAAR protein. In the case of the mRNA expression, only Tia reduced the expression of N-methyl-D-aspartate receptor 1, compared with the model group. Conclusion JPZDD could alleviate impairments in behavior and dysfunctional signaling by downregulating GABAAR in the striatum. We suggest that this acts to maintain the balance of Glu and GABA. PMID:27279743

  18. 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

  19. Actin purification from a gel of rat brain extracts.

    PubMed

    Levilliers, N; Peron-Renner, M; Coffe, G; Pudles, J

    1984-01-01

    Actin, 99% pure, has been recovered from rat brain with a high yield (greater than 15 mg/100 g brain). We have shown that: 1. a low ionic strength extract from rat brain tissue is capable of giving rise to a gel; 2. actin is the main gel component and its proportion is one order of magnitude higher than in the original extract; 3. actin can be isolated from this extract by a three-step procedure involving gelation, dissociation of the gel in 0.6 M KCl, followed by one or two depolymerization-polymerization cycles.

  20. A simple method to induce focal brain hypothermia in rats.

    PubMed

    Clark, Darren L; Colbourne, Frederick

    2007-01-01

    Hypothermia reduces cell death and promotes recovery in models of cerebral ischemia, intracerebral hemorrhage and trauma. Clinical studies report significant benefit for treating cardiac arrest and studies are investigating hypothermia for stroke and related conditions. Both local (head) and generalized hypothermia have been used. However, selective brain cooling has fewer side effects than systemic cooling. In this study, we developed a method to induce local (hemispheric) brain hypothermia in rats. The method involves using a small metal coil implanted between the Temporalis muscle and adjacent skull. This coil is then cooled by flushing it with cold water. In our first experiment, we tested whether this method induces focal brain hypothermia in anesthetized rats. Brain temperature was assessed in the ipsilateral cortex and striatum, and contralateral striatum, while body temperature was kept normothermic. Focal, ipsilateral cooling was successfully produced, while the other locations remained normothermic. In the second experiment, we implanted the coil, and brain and body temperature telemetry probes. The coil was connected via overhead swivel to a cold-water source. Brain hypothermia was produced for 24 h, while body temperature remained normothermic. A third experiment measured brain and body temperature along with heart rate and blood pressure. Brain cooling was produced for 24 h without significant alterations in pressure, heart rate or body temperature. In summary, our simple method allows for focal brain hypothermia to be safely induced in anesthetized or conscious rats, and is, therefore, ideally suited to stroke and trauma studies.

  1. Diversity of endurance training effects on antioxidant defenses and oxidative damage in different brain regions of adolescent male rats.

    PubMed

    Chalimoniuk, M; Jagsz, S; Sadowska-Krepa, E; Chrapusta, S J; Klapcinska, B; Langfort, J

    2015-08-01

    Studies on the effect of physical activity on brain oxidative stress, performed mostly in adult rats, have shown that moderate aerobic activity increases resistance to oxidative stress and reduces cellular damage. These effects can greatly differ between various brain regions. The postnatal period of the highest brain sensitivity to various stimuli is adolescence. We hypothesized that endurance training will modify brain antioxidant barrier differently in various regions, depending on their role in locomotion. Therefore, we studied the effect of moderate intensity endurance training on the activities of selected antioxidant enzymes (superoxide dismutase, gluthathione peroxidase and catalase and the contents of thiobarbituric acid-reactive substances (the key index of lipid peroxidation) and glutathione in several brain regions with dissimilar relationship to locomotion, as well as in circulating blood. Additionally, we investigated the effect of the training on nitric oxide synthase activity that may be a major player in exercise-related oxidative stress in brain regions that are directly involved in the locomotion control and execution (the striatum, midbrain and cerebellum). The training significantly enhanced nitric oxide synthase activity only in the latter three regions. Surprisingly, it elevated the activities of all studied antioxidant enzymes (excepting gluthathione peroxidase) in the neocortex, while no appreciable change in these activities was found in either the cerebellum (except for elevated catalase activity), or the striatum, or the midbrain. The training also elevated total glutathione content (a key protector of brain proteins under the conditions of enhanced nitric oxide production) in the cerebellum and striatum, but not in the other regions. The observed brain changes greatly differed from those in circulating blood and did not prevent the training-related increases in oxidative damage as evidenced by elevations in cerebellar and striatal

  2. Effects of photoradiation therapy on normal rat brain

    SciTech Connect

    Cheng, M.K.; McKean, J.; Boisvert, D.; Tulip, J.; Mielke, B.W.

    1984-12-01

    Laser photoradiation of the brain via an optical fiber positioned 5 mm above a burr hole was performed after the injection of hematoporphyrin derivative (HpD) in 33 normal rats and 6 rats with an intracerebral glioma. Normal rats received HpD, 5 or 10 mg/kg of body weight, followed by laser exposure at various doses or were exposed to a fixed laser dose after the administration of HpD, 2.5 to 20 mg/kg. One control group received neither HpD nor laser energy, and another was exposed to laser energy only. The 6 rats bearing an intracranial 9L glioma were treated with HpD, 5 mg/kg, followed by laser exposure at various high doses. The temperature in the cortex or tumor was measured with a probe during laser exposure. The rats were killed 72 hours after photoradiation, and the extent of necrosis of cerebral tissue was measured microscopically. In the normal rats, the extent of brain damage correlated with increases in the dose of both the laser and the HpD. In all 6 glioma-bearing rats, the high laser doses produced some focal necrosis in the tumors but also damaged adjacent normal brain tissue. The authors conclude that damage to normal brain tissue may be a significant complication of high dose photoradiation therapy for intracranial tumors.

  3. Acute nigro-striatal blockade alters cortico-striatal encoding: an in vivo electrophysiological study.

    PubMed

    Prosperetti, Chiara; Di Giovanni, Giuseppe; Stefani, Alessandro; Möller, Jens C; Galati, Salvatore

    2013-09-01

    Spreading of slow cortical rhythms into the basal ganglia (BG) is a relatively well-demonstrated phenomenon in the Parkinsonian state, both in humans and animals. Accordingly, striatal dopamine (DA) depletion, either acute or chronic, drives cortical-globus pallidus (GP) and cortical-substantia nigra pars reticulata (SNr) slow wave coherences in urethane-anesthetized rats. This paper investigates the striatal dynamics following acute DA depletion by tetrodotoxin (TTX) injection in the medial forebrain bundle (MFB) with respect to the transmission of slow cortical rhythms throughout the BG in more detail. The acute DA depletion offers the advantage of detecting electrophysiological changes irrespectively of chronically developing compensatory mechanisms. We observed that the acute blockade of the dopaminergic nigro-striatal pathway reshapes the firing rate and pattern of the different striatal neuron subtypes according to cortical activity, possibly reflecting a remodeled intrastriatal network. The observed alterations differ amongst striatal neuronal subtypes with the striatal medium spiny neurons and fast-spiking neurons being the most affected, while the tonically active neurons seem to be less affected. These acute changes might contribute to the diffusion of cortical activity to BG and the pathophysiology of Parkinson's disease (PD). Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Arc mRNA induction in striatal efferent neurons associated with response learning.

    PubMed

    Daberkow, D P; Riedy, M D; Kesner, R P; Keefe, K A

    2007-07-01

    The dorsal striatum is involved in motor-response learning, but the extent to which distinct populations of striatal efferent neurons are differentially involved in such learning is unknown. Activity-regulated, cytoskeleton-associated (Arc) protein is an effector immediate-early gene implicated in synaptic plasticity. We examined arc mRNA expression in striatopallidal vs. striatonigral efferent neurons in dorsomedial and dorsolateral striatum of rats engaged in reversal learning on a T-maze motor-response task. Male Sprague-Dawley rats learned to turn right or left for 3 days. Half of the rats then underwent reversal training. The remaining rats were yoked to rats undergoing reversal training, such that they ran the same number of trials but ran them as continued-acquisition trials. Brains were removed and processed using double-label fluorescent in situ hybridization for arc and preproenkephalin (PPE) mRNA. In the reversal, but not the continued-acquisition, group there was a significant relation between the overall arc mRNA signal in dorsomedial striatum and the number of trials run, with rats reaching criterion in fewer trials having higher levels of arc mRNA expression. A similar relation was seen between the numbers of PPE(+) and PPE(-) neurons in dorsomedial striatum with cytoplasmic arc mRNA expression. Interestingly, in behaviourally activated animals significantly more PPE(-) neurons had cytoplasmic arc mRNA expression. These data suggest that Arc in both striatonigral and striatopallidal efferent neurons is involved in striatal synaptic plasticity mediating motor-response learning in the T-maze and that there is differential processing of arc mRNA in distinct subpopulations of striatal efferent neurons.

  5. Impaired Brain Dopamine and Serotonin Release and Uptake in Wistar Rats Following Treatment with Carboplatin

    PubMed Central

    2016-01-01

    Chemotherapy-induced cognitive impairment, known also as “chemobrain”, is a medical complication of cancer treatment that is characterized by a general decline in cognition affecting visual and verbal memory, attention, complex problem solving skills, and motor function. It is estimated that one-third of patients who undergo chemotherapy treatment will experience cognitive impairment. Alterations in the release and uptake of dopamine and serotonin, central nervous system neurotransmitters that play important roles in cognition, could potentially contribute to impaired intellectual performance in those impacted by chemobrain. To investigate how chemotherapy treatment affects these systems, fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes was used to measure dopamine and serotonin release and uptake in coronal brain slices containing the striatum and dorsal raphe nucleus, respectively. Measurements were taken from rats treated weekly with selected doses of carboplatin and from control rats treated with saline. Modeling the stimulated dopamine release plots revealed an impairment of dopamine release per stimulus pulse (80% of saline control at 5 mg/kg and 58% at 20 mg/kg) after 4 weeks of carboplatin treatment. Moreover, Vmax, the maximum uptake rate of dopamine, was also decreased (55% of saline control at 5 mg/kg and 57% at 20 mg/kg). Nevertheless, overall dopamine content, measured in striatal brain lysates by high performance liquid chromatography, and reserve pool dopamine, measured by FSCV after pharmacological manipulation, did not significantly change, suggesting that chemotherapy treatment selectively impairs the dopamine release and uptake processes. Similarly, serotonin release upon electrical stimulation was impaired (45% of saline control at 20 mg/kg). Measurements of spatial learning discrimination were taken throughout the treatment period and carboplatin was found to alter cognition. These studies support the need for additional

  6. Impaired Brain Dopamine and Serotonin Release and Uptake in Wistar Rats Following Treatment with Carboplatin.

    PubMed

    Kaplan, Sam V; Limbocker, Ryan A; Gehringer, Rachel C; Divis, Jenny L; Osterhaus, Gregory L; Newby, Maxwell D; Sofis, Michael J; Jarmolowicz, David P; Newman, Brooke D; Mathews, Tiffany A; Johnson, Michael A

    2016-06-15

    Chemotherapy-induced cognitive impairment, known also as "chemobrain", is a medical complication of cancer treatment that is characterized by a general decline in cognition affecting visual and verbal memory, attention, complex problem solving skills, and motor function. It is estimated that one-third of patients who undergo chemotherapy treatment will experience cognitive impairment. Alterations in the release and uptake of dopamine and serotonin, central nervous system neurotransmitters that play important roles in cognition, could potentially contribute to impaired intellectual performance in those impacted by chemobrain. To investigate how chemotherapy treatment affects these systems, fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes was used to measure dopamine and serotonin release and uptake in coronal brain slices containing the striatum and dorsal raphe nucleus, respectively. Measurements were taken from rats treated weekly with selected doses of carboplatin and from control rats treated with saline. Modeling the stimulated dopamine release plots revealed an impairment of dopamine release per stimulus pulse (80% of saline control at 5 mg/kg and 58% at 20 mg/kg) after 4 weeks of carboplatin treatment. Moreover, Vmax, the maximum uptake rate of dopamine, was also decreased (55% of saline control at 5 mg/kg and 57% at 20 mg/kg). Nevertheless, overall dopamine content, measured in striatal brain lysates by high performance liquid chromatography, and reserve pool dopamine, measured by FSCV after pharmacological manipulation, did not significantly change, suggesting that chemotherapy treatment selectively impairs the dopamine release and uptake processes. Similarly, serotonin release upon electrical stimulation was impaired (45% of saline control at 20 mg/kg). Measurements of spatial learning discrimination were taken throughout the treatment period and carboplatin was found to alter cognition. These studies support the need for additional

  7. 3- and 4-O-sulfoconjugated and methylated dopamine: highly reduced binding affinity to dopamine D2 receptors in rat striatal membranes.

    PubMed

    Werle, E; Lenz, T; Strobel, G; Weicker, H

    1988-07-01

    The binding properties of 3- and 4-O-sulfo-conjugated dopamine (DA-3-O-S, DA-4-O-S) as well as 3-O-methylated dopamine (MT) to rat striatal dopamine D2 receptors were investigated. 3H-spiperone was used as a radioligand in the binding studies. In saturation binding experiments (+)butaclamol, which has been reported to bind to dopaminergic D2 and serotoninergic 5HT2 receptors, was used in conjunction with ketanserin and sulpiride, which preferentially label 5HT2 and D2 receptors, respectively, in order to discriminate between 3H-spiperone binding to D2 and to 5HT2 receptors. Under our particular membrane preparation and assay conditions, 3H-spiperone binds to D2 and 5HT2 receptors with a maximal binding capacity (Bmax) of 340 fmol/mg protein in proportions of about 75%:25% with similar dissociation constants KD (35 pmol/l; 43 pmol/l). This result was verified by the biphasic competition curve of ketanserin, which revealed about 20% high (KD = 24 nmol/l) and 80% low (KD = 420 nmol/l) affinity binding sites corresponding to 5HT2 and D2 receptors, respectively. Therefore, all further competition experiments at a tracer concentration of 50 pmol/l were performed in the presence of 0.1 mumol/l ketanserin to mask the 5HT2 receptors. DA competition curves were best fitted assuming two binding sites, with high (KH = 0.12 mumol/l) and low (KL = 18 mumol/l) affinity, present in a ratio of 3:1. The high affinity binding sites were interconvertible by 100 mumol/l guanyl-5-yl imidodiphosphate [Gpp(NH)p], resulting in a homogenous affinity state of DA receptors (KD = 2.8 mumol/l).2+ off

  8. Huntington’s Disease and Striatal Signaling

    PubMed Central

    Roze, Emmanuel; Cahill, Emma; Martin, Elodie; Bonnet, Cecilia; Vanhoutte, Peter; Betuing, Sandrine; Caboche, Jocelyne

    2011-01-01

    Huntington’s Disease (HD) is the most frequent neurodegenerative disease caused by an expansion of polyglutamines (CAG). The main clinical manifestations of HD are chorea, cognitive impairment, and psychiatric disorders. The transmission of HD is autosomal dominant with a complete penetrance. HD has a single genetic cause, a well-defined neuropathology, and informative pre-manifest genetic testing of the disease is available. Striatal atrophy begins as early as 15 years before disease onset and continues throughout the period of manifest illness. Therefore, patients could theoretically benefit from therapy at early stages of the disease. One important characteristic of HD is the striatal vulnerability to neurodegeneration, despite similar expression of the protein in other brain areas. Aggregation of the mutated Huntingtin (HTT), impaired axonal transport, excitotoxicity, transcriptional dysregulation as well as mitochondrial dysfunction, and energy deficits, are all part of the cellular events that underlie neuronal dysfunction and striatal death. Among these non-exclusive mechanisms, an alteration of striatal signaling is thought to orchestrate the downstream events involved in the cascade of striatal dysfunction. PMID:22007160

  9. Striatal cholinergic interneuron regulation and circuit effects

    PubMed Central

    Lim, Sean Austin O.; Kang, Un Jung; McGehee, Daniel S.

    2014-01-01

    The striatum plays a central role in motor control and motor learning. Appropriate responses to environmental stimuli, including pursuit of reward or avoidance of aversive experience all require functional striatal circuits. These pathways integrate synaptic inputs from limbic and cortical regions including sensory, motor and motivational information to ultimately connect intention to action. Although many neurotransmitters participate in striatal circuitry, one critically important player is acetylcholine (ACh). Relative to other brain areas, the striatum contains exceptionally high levels of ACh, the enzymes that catalyze its synthesis and breakdown, as well as both nicotinic and muscarinic receptor types that mediate its postsynaptic effects. The principal source of striatal ACh is the cholinergic interneuron (ChI), which comprises only about 1–2% of all striatal cells yet sends dense arbors of projections throughout the striatum. This review summarizes recent advances in our understanding of the factors affecting the excitability of these neurons through acute effects and long term changes in their synaptic inputs. In addition, we discuss the physiological effects of ACh in the striatum, and how changes in ACh levels may contribute to disease states during striatal dysfunction. PMID:25374536

  10. Induction of oxidative stress in rat brain by acrylonitrile (ACN).

    PubMed

    Jiang, J; Xu, Y; Klaunig, J E

    1998-12-01

    Chronic treatment with acrylonitrile (ACN) has been shown to produce a dose-related increase in glial cell tumors (astrocytomas) in rats. The mechanism(s) for ACN-induced carcinogenicity remains unclear. While ACN has been reported to induce DNA damage in a number of short-term systems, evidence for a genotoxic mechanism of tumor induction is the brain is not strong. Other toxic mechanisms appear to participate in the induction of tumor or induce the astrocytomas solely. In particular, nongenotoxic mechanisms of carcinogen induction have been implicated in this ACN-induced carcinogenic effect in the rat brain. One major pathway of ACN metabolism is through glutathione (GSH) conjugation. Extensive utilization and depletion of GSH, an important intracellular antioxidant, by ACN may lead to cellular oxidative stress. The present study examined the ability of ACN to induce oxidative stress in male Sprague-Dawley rats. Rats were administered ACN at concentrations of 0, 5, 10, 100, or 200 ppm in the drinking water and sampled after 14, 28, or 90 days of continuous treatment. Oxidative DNA damage indicated by the presence of 8-hydroxy-2'-deoxyguanosine (OH8dG) and lipid peroxidation indicated by the presence of malondialdehyde (MDA), a lipid peroxidation product, in rat brains and livers were examined. The levels of reactive oxygen species (ROS) were also determined in different rat tissues. Both the levels of nonenzymatic antioxidants (GSH, vitamin E) and the activities of enzymatic antioxidants (catalase, superoxide dismutase, glutathione peroxidase) in rat brains and livers were measured. Increased levels of OH8dG, MDA, and ROS were found in the brains of ACN-treated rats. Decreased levels of GSH and activities of catalase and SOD were also observed in the brains of ACN-treated rats compared to the control group. Interestingly, there were no changes of these indicators of oxidative stress in the livers of ACN-treated rats. Rat liver is not a target for ACN

  11. Platonin preserves blood-brain barrier integrity in septic rats.

    PubMed

    Yeh, Chia-Tse; Kao, Ming-Chang; Chen, Cay-Huyen; Huang, Chun-Jen

    2015-03-01

    Platonin possesses potent anti-inflammatory and antioxidative capacities. Because systemic inflammation and oxidative stress are crucial in mediating sepsis-induced blood-brain barrier (BBB) integrity loss, this study elucidated the effects of platonin on preserving BBB integrity in septic rats. A total of 72 adult male rats (200-250 g) were randomized to receive cecal ligation and puncture (CLP), CLP plus platonin, sham operation, or sham operation plus platonin (n = 18 in each group). Systemic inflammation and oxidation levels and BBB integrity in the surviving rats were determined after 24-hour monitoring. Plasma levels of interleukin-6 (IL-6) and malondialdehyde (MDA)-markers of systemic inflammation and oxidation-and the grading of Evans blue staining of the brains, BBB permeability to Evans blue dye, and brain edema levels-markers of BBB integrity-in rats that received CLP were significantly higher than rats that received sham operation (all p < 0.001). By contrast, the plasma levels of IL-6 (p < 0.001) and MDA (p < 0.001), and the grading of Evans blue staining (p = 0.015), BBB permeability to Evans blue dye (p = 0.043), and brain edema levels (p = 0.034) in rats that received CLP plus platonin were significantly lower than rats that received CLP. Experimental data further revealed that the concentration of tight junction protein claudin-5, a major structural component of BBB, in rats that received CLP was significantly lower than rats that received CLP plus platonin (p = 0.023). Platonin could attenuate sepsis-induced BBB integrity loss in rats. Copyright © 2015. Published by Elsevier B.V.

  12. Transport of 3-hydroxybutyrate by cultured rat brain astrocytes

    SciTech Connect

    McKenna, M.C.; Tildon, J.T.; Stevenson, J.H.; Couto, R.; Caprio, F.J. )

    1990-02-26

    Studies by a number of investigators have shown that 3-hydroxybutyrate is a preferred energy substrate for brain during early development. Since recent studies by the authors group suggest that the utilization of oxidizable substrates by brain may be regulated in part by transport across the plasma membrane, the authors investigated the transport of ({sup 3}H) D- and L-3-hydroxybutyrate and 3-hydroxy-(3-{sup 14}C) butyrate by primary cultures of rat brain astrocytes. The data is consistent with the hypothesis that 3-hydroxybutyrate is taken up into cultured rat brain astrocytes by both diffusion and a carrier mediated transport system, and further support the concept that transport at the cellular level contributes to the regulation of substrate utilization by brain cells.

  13. [Evaluation of the survival of bone marrow mononucleate cells transplanted in a rat model of striatal lesion with quinolinic acid].

    PubMed

    Alberti-Amador, E; García-Miniet, R; Serrano-Sánchez, T; Blanco-Lezcano, L; Martínez-Marti, L; Mendoza-Mari, Y; Rosillo-Martí, J C; Castillo-Díaz, L; de la Cuétara-Bernal, K

    Transplant is one of the alternatives available for the treatment of neurodegenerative diseases aimed at replacing the cells lost during the course of the disease. One promising source of cells for the development of transplants could be the mononucleate cells from bone marrow. AIMS. The purpose of this study was to study the capacity of bone marrow mononucleate cells to survive the transplant process, and to search for a method that enables tracking of these cells in vivo once they have been implanted. Bone marrow mononucleate cells were extracted from the femur of rats by means of a Ficoll-Hypaque gradient. The cells under study were modified genetically with an adenovirus that expresses the PFV or which are marked with Hoechst dye. The marked cells were implanted in the striatum of rats with lesions caused by quinolinic acid. The viability of the genetically modified cells was low, whereas that of the cells marked with Hoechst dye was above 90%. The implanted cells survived the transplant at least a month and dispersed away from the site of entry towards the corpus callosum and cortex. We consider that the use of Hoechst dye offers more advantages for tracking these cells in vivo. Mononucleate cells have a number of characteristics that allow them to be included as candidate sources of cells for the treatment of neurodegenerative diseases.

  14. Effect of carnosine on rats under experimental brain ischemia.

    PubMed

    Gallant, S; Kukley, M; Stvolinsky, S; Bulygina, E; Boldyrev, A

    2000-06-01

    The effect of dietary carnosine on the behavioral and biochemical characteristics of rats under experimental ischemia was studied. Carnosine was shown to improve the animals orientation and learning in "Open Field" and "T-Maze" tests, and this effect was accompanied with an increase in glutamate binding to N-methyl-D-aspartate (NMDA) receptors in brain synaptosomes. Long-term brain ischemia induced by both sides' occlusion of common carotid arteries resulted in 55% mortality of experimental rats, and those who survived were characterized by partial suppression of orientation in T-maze. In the group of rats treated with carnosine, mortality after ischemic attack was decreased (from 55% to 17%) and most of the learning parameters were kept at the pre-ischemic level. Monoamine oxidase B (MAO B) activity in brain of the carnosine treated rats was not changed by ischemia significantly (compared to that of ischemic untreated rats) but NMDA binding to brain synaptosomal membranes being increased by ischemic attack was significantly suppressed and reached the level characteristic of normal brain. The suggestion was made that carnosine possesses a dual effect on NMDA receptors resulting in increase in their amount after long-term treatment but decrease the capacity to bind NMDA after ischemic attack.

  15. Non-signalling energy use in the developing rat brain.

    PubMed

    Engl, Elisabeth; Jolivet, Renaud; Hall, Catherine N; Attwell, David

    2017-03-01

    Energy use in the brain constrains its information processing power, but only about half the brain's energy consumption is directly related to information processing. Evidence for which non-signalling processes consume the rest of the brain's energy has been scarce. For the first time, we investigated the energy use of the brain's main non-signalling tasks with a single method. After blocking each non-signalling process, we measured oxygen level changes in juvenile rat brain slices with an oxygen-sensing microelectrode and calculated changes in oxygen consumption throughout the slice using a modified diffusion equation. We found that the turnover of the actin and microtubule cytoskeleton, followed by lipid synthesis, are significant energy drains, contributing 25%, 22% and 18%, respectively, to the rate of oxygen consumption. In contrast, protein synthesis is energetically inexpensive. We assess how these estimates of energy expenditure relate to brain energy use in vivo, and how they might differ in the mature brain.

  16. Non-signalling energy use in the developing rat brain

    PubMed Central

    Engl, Elisabeth; Jolivet, Renaud; Hall, Catherine N

    2016-01-01

    Energy use in the brain constrains its information processing power, but only about half the brain's energy consumption is directly related to information processing. Evidence for which non-signalling processes consume the rest of the brain's energy has been scarce. For the first time, we investigated the energy use of the brain's main non-signalling tasks with a single method. After blocking each non-signalling process, we measured oxygen level changes in juvenile rat brain slices with an oxygen-sensing microelectrode and calculated changes in oxygen consumption throughout the slice using a modified diffusion equation. We found that the turnover of the actin and microtubule cytoskeleton, followed by lipid synthesis, are significant energy drains, contributing 25%, 22% and 18%, respectively, to the rate of oxygen consumption. In contrast, protein synthesis is energetically inexpensive. We assess how these estimates of energy expenditure relate to brain energy use in vivo, and how they might differ in the mature brain. PMID:27170699

  17. Quantitative autoradiography of /sup 3/H-nomifensine binding sites in rat brain

    SciTech Connect

    Scatton, B.; Dubois, A.; Dubocovich, M.L.; Zahniser, N.R.; Fage, D.

    1985-03-04

    The distribution of /sup 3/H-nomifensine binding sites in the rat brain has been studied by quantitative autoradiography. The binding of /sup 3/H-nomifensine to caudate putamen sections was saturable, specific, of a highly affinity (Kd = 56 nM) and sodium-dependent. The dopamine uptake inhibitors benztropine, nomifensine, cocaine, bupropion and amfonelic acid were the most potent competitors of /sup 3/H-nomifensine binding to striatal sections. The highest levels of (benztropine-displaceable) /sup 3/H-nomifensine binding sites were found in the caudate-putamen, the olfactory tubercle and the nucleus accumbens. 6-Hydroxy-dopamine-induced lesion of the ascending dopaminergic bundle resulted in a marked decrease in the /sup 3/H-ligand binding in these areas. Moderately high concentrations of the /sup 3/H-ligand were observed in the bed nucleus of the stria terminalis, the anteroventral thalamic nucleus, the cingulate cortex, the lateral septum, the hippocampus, the amygdala, the zona incerta and some hypothalamic nuclei. There were low levels of binding sites in the habenula, the dorsolateral geniculate body, the substantia nigra, the ventral tegmental area and the periaqueductal gray matter. These autoradiographic data are consistent with the hypothesis that /sup 3/H-nomifensine binds primarily to the presynaptic uptake site for dopamine but also labels the norepinephrine uptake site. 33 references, 2 figures, 1 table.

  18. SEROTONIN BINDING TO PREPARATIONS FROM RAT BRAIN,

    DTIC Science & Technology

    BRAIN , SEROTONIN, SEROTONIN, OXIDOREDUCTASES, LYSERGIC ACIDS, RESERPINE, CHLORPROMAZINE, ACETYLCHOLINE, FATTY ACIDS, NOREPINEPHRINE, LEARNING, PERMEABILITY, MITOCHONDRIA, MORPHOLOGY(BIOLOGY), DRUGS, PHYSIOLOGY.

  19. Adenylate cyclase in striatal cholinergic interneurons regulates acetylcholine release.

    PubMed

    Login, I S; Hewlett, E L

    1996-10-07

    Fractional [3H]ACH efflux from dissociated rat striata tested whether tonic inhibition prevents stimulation of acetylcholine (ACH) release by adenylate cyclase. Forskolin stimulated release from the dissociated cells (threshold at 300 nM; EC50 > or = 1 MicroM). Release was also stimulated by 3-isobutyl-1-methylxanthine and was additive with forskolin. The 1,9-dideoxy forskolin analog that lacks cyclase-stimulating activity was ineffective. Thus, stimulation of adenylate cyclase within striatal cholinergic interneurons increases ACH secretion but is tonically inhibited by endogenous striatal transmitters. Disinhibition of the excitatory cyclase by denervation of striatal cholinergic interneurons in situ could contribute to supersensitivity without receptor upregulation.

  20. Hydrogen-rich water attenuates brain damage and inflammation after traumatic brain injury in rats.

    PubMed

    Tian, Runfa; Hou, Zonggang; Hao, Shuyu; Wu, Weichuan; Mao, Xiang; Tao, Xiaogang; Lu, Te; Liu, Baiyun

    2016-04-15

    Inflammation and oxidative stress are the two major causes of apoptosis after traumatic brain injury (TBI). Most previous studies of the neuroprotective effects of hydrogen-rich water on TBI primarily focused on antioxidant effects. The present study investigated whether hydrogen-rich water (HRW) could attenuate brain damage and inflammation after traumatic brain injury in rats. A TBI model was induced using a controlled cortical impact injury. HRW or distilled water was injected intraperitoneally daily following surgery. We measured survival rate, brain edema, blood-brain barrier (BBB) breakdown and neurological dysfunction in all animals. Changes in inflammatory cytokines, inflammatory cells and Cho/Cr metabolites in brain tissues were also detected. Our results demonstrated that TBI-challenged rats exhibited significant brain injuries that were characterized by decreased survival rate and increased BBB permeability, brain edema, and neurological dysfunction, while HRW treatment ameliorated the consequences of TBI. HRW treatment also decreased the levels of pro-inflammatory cytokines (TNF-α, IL-1β and HMGB1), inflammatory cell number (Iba1) and inflammatory metabolites (Cho) and increased the levels of an anti-inflammatory cytokine (IL-10) in the brain tissues of TBI-challenged rats. In conclusion, HRW could exert a neuroprotective effect against TBI and attenuate inflammation, which suggests HRW as an effective therapeutic strategy for TBI patients.

  1. Brain perfusion in acute and chronic hyperglycemia in rats

    SciTech Connect

    Kikano, G.E.; LaManna, J.C.; Harik, S.I. )

    1989-08-01

    Recent studies show that acute and chronic hyperglycemia cause a diffuse decrease in regional cerebral blood flow and that chronic hyperglycemia decreases the brain L-glucose space. Since these changes can be caused by a decreased density of perfused brain capillaries, we used 30 adult male Wistar rats to study the effect of acute and chronic hyperglycemia on (1) the brain intravascular space using radioiodinated albumin, (2) the anatomic density of brain capillaries using alkaline phosphatase histochemistry, and (3) the fraction of brain capillaries that are perfused using the fluorescein isothiocyanate-dextran method. Our results indicate that acute and chronic hyperglycemia do not affect the brain intravascular space nor the anatomic density of brain capillaries. Also, there were no differences in capillary recruitment among normoglycemic, acutely hyperglycemic, and chronically hyperglycemic rats. These results suggest that the shrinkage of the brain L-glucose space in chronic hyperglycemia is more likely due to changes in the blood-brain barrier permeability to L-glucose.

  2. Proinflammatory cytokines in injured rat brain following perinatal asphyxia.

    PubMed

    Maślińska, Danuta; Laure-Kamionowska, Milena; Kaliszek, Agnieszka; Makarewicz, Dorota

    2002-01-01

    In contrast to astrogliosis, which is common to injuries of the adult CNS, in the developing brain this process is minimal. Reasons postulated for this include the relative immaturity of the immune system and the consequent insufficient production of cytokines to evoke astrogliosis. To explore this hypothesis, the study was undertaken to detect the presence of some proinflammatory cytokines in the injured rat brain following perinatal asphyxia (ischaemia/hypoxia). The localisation of TNF-alpha, IL-15, IL-17 and IL-17 receptors was visualised by means of immunohistochemistry. In numerous neurones of the rat brain, the IL-17 appeared to be constitutively expressed. In the early period of inflammation the IL-15 was produced mainly by the blood cells penetrating the injured brain but later it was synthesised also by reactive astrocytes surrounding brain cysts and forming dense astrogliosis around necrotic brain regions. The direct effect on astrogliosis of other estimated cytokines seems to be negligible. All the results lead to the conclusion that from all cytokines identified in the injured immature rat brain the IL-15 plays the most important role during inflammatory response and participates in the gliosis of reactive astrocytes.

  3. Thermal imaging of brain tumors in a rat glioma model

    NASA Astrophysics Data System (ADS)

    Papaioannou, Thanassis; Thompson, Reid C.; Kateb, Babak; Sorokoumov, Oleg; Grundfest, Warren S.; Black, Keith L.

    2002-05-01

    We have explored the capability of thermal imaging for the detection of brain tumors in a rat glioma mode. Fourteen Wistar rats were injected stereotactically with 100,000 C6 glioma cells. Approximately one and two weeks post implantation, the rats underwent bilateral craniotomy and the exposed brain surface was imaged with a short wave thermal camera. Thermal images were obtained at both low (approximately 28.7 degree(s)C) and high (approximately 38 degree(s)C) core temperatures. Temperature gradients between the tumor site and the contralateral normal brain were calculated. Overall, the tumors appeared cooler than normal brain, for both high and low core temperatures. Average temperature difference between tumor and normal brain were maximal in more advanced tumors (two weeks) and at higher core temperatures. At one week (N equals 6), the average temperature gradient between tumor and normal sites was 0.1 degree(s)C and 0.2 degree(s)C at low and high core temperatures respectively (P(greater than)0.05). At two weeks (N equals 8), the average temperature gradient was 0.3 degree(s)C and 0.7 degree(s)C at low and high core temperatures respectively (P<0.05). We conclude that thermal imaging can detect temperature differences between tumor and normal brain tissue in this model, particularly in more advanced tumors. Thermal imaging may provide a novel means to identify brain tumors intraoperatively.

  4. Neuropeptide Y receptors in rat brain: autoradiographic localization

    SciTech Connect

    Martel, J.C.; St-Pierre, S.; Quirion, R.

    1986-01-01

    Neuropeptide Y (NPY) receptor binding sites have been characterized in rat brain using both membrane preparations and receptor autoradiography. Radiolabelled NPY binds with high affinity and specificity to an apparent single class of sites in rat brain membrane preparations. The ligand selectivity pattern reveals strong similarities between central and peripheral NPY receptors. NPY receptors are discretely distributed in rat brain with high densities found in the olfactory bulb, superficial layers of the cortex, ventral hippocampus, lateral septum, various thalamic nuclei and area postrema. The presence of high densities of NPY and NPY receptors in such areas suggests that NPY could serve important functions as a major neurotransmitter/neuromodulator in the central nervous system.

  5. Transcriptional activity of novel ALDH1L1 promoters in the rat brain following AAV vector-mediated gene transfer

    PubMed Central

    Mudannayake, Janitha M; Mouravlev, Alexandre; Fong, Dahna M; Young, Deborah

    2016-01-01

    Aldehyde dehydrogenase family 1, member L1 (ALDH1L1) is a recently characterized pan-astrocytic marker that is more homogenously expressed throughout the brain than the classic astrocytic marker, glial fibrillary acidic protein. We generated putative promoter sequence variants of the rat ALDH1L1 gene for use in adeno-associated viral vector-mediated gene transfer, with an aim to achieve selective regulation of transgene expression in astrocytes in the rat brain. Unexpectedly, ALDH1L1 promoter variants mediated transcriptional activity exclusively in neurons in the substantia nigra pars compacta as assessed by luciferase reporter expression at 3 weeks postvector infusion. This selectivity for neurons in the substantia nigra pars compacta also persisted in the context of adeno-associated viral serotype 5, 8 or 9 vector-mediated gene delivery. An in vivo promoter comparison showed the highest performing ALDH1L1 promoter variant mediated higher transgene expression than the neuronal-specific synapsin 1 and tyrosine hydroxylase promoters. The ALDH1L1 promoter was also transcriptionally active in dentate granule neurons following intrahippocampal adeno-associated viral vector infusion, whereas transgene expression was detected in both striatal neurons and astrocytes following vector infusion into the striatum. Our results demonstrate the potential suitability of the ALDH1L1 promoter as a new tool in the development of gene therapy and disease modelling applications. PMID:27990448

  6. Differences between high-affinity forskolin binding sites in dopamine-riche and other regions of rat brain

    SciTech Connect

    Poat, J.A.; Cripps, H.E.; Iversen, L.L.

    1988-05-01

    Forskolin labelled with (/sup 3/H) bound to high- and low-affinity sites in the rat brain. The high-affinity site was discretely located, with highest densities in the striatum, nucleus accumbens, olfactory tubercule, substantia nigra, hippocampus, and the molecular layers of the cerebellum. This site did not correlate well with the distribution of adenylate cyclase. The high-affinity striatal binding site may be associated with a stimulatory guanine nucleotide-binding protein. Thus, the number of sites was increased by the addition of Mg/sup 2 +/ and guanylyl imidodiphosphate. Cholera toxin stereotaxically injected into rat striatum increased the number of binding sites, and no further increase was noted following the subsequent addition of guanyl nucleotide. High-affinity forskolin binding sites in non-dopamine-rich brain areas (hippocampus and cerebullum) were modulated in a qualitatively different manner by guanyl nucleotides. In these areas the number of binding sites was significantly reduced by the addition of guanyl nucleotide. These results suggest that forskolin may have a potential role in identifying different functional/structural guanine nucleotide-binding proteins.

  7. Dopamine receptor alterations in female rats with diet-induced decreased brain docosahexaenoic acid (DHA): interactions with reproductive status

    PubMed Central

    Davis, Paul F.; Ozias, Marlies K.; Carlson, Susan E.; Reed, Gregory A.; Winter, Michelle K.; McCarson, Kenneth E.; Levant, Beth

    2010-01-01

    Decreased tissue levels of n-3 (omega-3) fatty acids, particularly docosahexaenoic acid (DHA), are implicated in the etiologies of non-puerperal and postpartum depression. This study examined the effects of a diet-induced loss of brain DHA content and concurrent reproductive status on dopaminergic parameters in adult female Long–Evans rats. An α-linolenic acid-deficient diet and breeding protocols were used to produce virgin and parous female rats with cortical phospholipid DHA levels 20–22% lower than those fed a control diet containing adequate α-linolenic acid. Decreased brain DHA produced a significant main effect of decreased density of ventral striatal D2-like receptors. Virgin females with decreased DHA also exhibited higher density of D1-like receptors in the caudate nucleus than virgin females with normal DHA. These receptor alterations are similar to those found in several rodent models of depression, and are consistent with the proposed hypodopaminergic basis for anhedonia and motivational deficits in depression. PMID:20670471

  8. D1 dopamine receptors of NS20Y neuroblastoma cells are functionally similar to rat striatal D1 receptors.

    PubMed

    Lovenberg, T W; Roth, R H; Nichols, D E; Mailman, R B

    1991-11-01

    Dopamine or agonists with D1 receptor potency stimulated cyclic AMP (cAMP) accumulation in whole cell preparations of NS20Y neuroblastoma cells. The accumulation of cAMP after D1 stimulation was rapid and linear for 3 min. Both dopamine and the novel D1 receptor agonist dihydrexidine stimulated cAMP accumulation two- to three-fold over baseline. The pseudo-Km for dopamine was approximately 2 microM, whereas for dihydrexidine it was approximately 30 nM. The effects of both drugs were blocked by either the D1-selective antagonist SCH23390 (Ki, 0.3 nM) or the nonselective antagonist (+)-butaclamol (Ki, 5 nM). Both (-)-butaclamol and the D2-selective antagonist (-)-sulpiride were ineffective (Ki greater than 3 microM). Forskolin (10 microM), prostaglandin E1 (1 microM), and adenosine (10 microM) also stimulated cAMP accumulation, but none were antagonized by SCH23390 (1 microM). Finally, muscarinic receptor stimulation (100 microM carbachol) inhibited both D1- and forskolin-stimulated increases in cAMP accumulation by 80%. The present results indicate that NS20Y neuroblastoma cells have D1 receptors that are coupled to adenylate cyclase, and that these receptors have a pharmacological profile similar to that of the D1 receptor(s) found in rat striatum.

  9. Influence of paraquat on dopaminergic transporter in the rat brain.

    PubMed

    Ossowska, Krystyna; Wardas, Jadwiga; Kuter, Katarzyna; Nowak, Przemysław; Dabrowska, Joanna; Bortel, Aleksandra; Labus, Łukasz; Kwieciński, Adam; Krygowska-Wajs, Anna; Wolfarth, Stainsław

    2005-01-01

    Selective toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a parkinsonism inducing compound, is well known to be related to an uptake of its active metabolite MPP+ into dopaminergic neurons by dopamine transporter (DAT). The aim of the present study was to examine whether paraquat, a commonly used herbicide, which is an 1-methyl-4-phenyl-pyridinium ion (MPP+) analogue, affects DAT in vivo in rats. Paraquat administered at a dose of 10 mg/kg ip decreased the binding of [3H]GBR 12,935 to DAT measured by quantitative autoradiography in the dorsal and ventral caudate-putamen, but not in the substantia nigra pars compacta. Moreover, this compound increased the level of 3-methoxytyramine (3-MT) and 3-MT/dopamine ratio in the anterior and posterior caudate-putamen measured by HPLC with electrochemical detection. No other alterations in the levels of dopamine and its metabolites were found in the caudate-putamen and substantia nigra. The present study seems to suggest that systemic paraquat administration affects striatal DAT and dopamine metabolism in the nigrostriatal neurons in rats which may be crucial for its neurotoxic effects on dopaminergic neurons.

  10. Dysfunction and Dysconnection in Cortical–Striatal Networks during Sustained Attention: Genetic Risk for Schizophrenia or Bipolar Disorder and its Impact on Brain Network Function

    PubMed Central

    Diwadkar, Vaibhav A.; Bakshi, Neil; Gupta, Gita; Pruitt, Patrick; White, Richard; Eickhoff, Simon B.

    2014-01-01

    Abnormalities in the brain’s attention network may represent early identifiable neurobiological impairments in individuals at increased risk for schizophrenia or bipolar disorder. Here, we provide evidence of dysfunctional regional and network function in adolescents at higher genetic risk for schizophrenia or bipolar disorder [henceforth higher risk (HGR)]. During fMRI, participants engaged in a sustained attention task with variable demands. The task alternated between attention (120 s), visual control (passive viewing; 120 s), and rest (20 s) epochs. Low and high demand attention conditions were created using the rapid presentation of two- or three-digit numbers. Subjects were required to detect repeated presentation of numbers. We demonstrate that the recruitment of cortical and striatal regions are disordered in HGR: relative to typical controls (TC), HGR showed lower recruitment of the dorsal prefrontal cortex, but higher recruitment of the superior parietal cortex. This imbalance was more dramatic in the basal ganglia. There, a group by task demand interaction was observed, such that increased attention demand led to increased engagement in TC, but disengagement in HGR. These activation studies were complemented by network analyses using dynamic causal modeling. Competing model architectures were assessed across a network of cortical–striatal regions, distinguished at a second level using random-effects Bayesian model selection. In the winning architecture, HGR were characterized by significant reductions in coupling across both frontal–striatal and frontal–parietal pathways. The effective connectivity analyses indicate emergent network dysconnection, consistent with findings in patients with schizophrenia. Emergent patterns of regional dysfunction and dysconnection in cortical–striatal pathways may provide functional biological signatures in the adolescent risk-state for psychiatric illness. PMID:24847286

  11. Hydrophilic solute transport across the rat blood-brain barrier

    SciTech Connect

    Lucchesi, K.J.

    1987-01-01

    Brain capillary permeability-surface area products (PS) of hydrophilic solutes ranging in size from 180 to 5,500 Daltons were measured in rats according to the method of Ohno, Pettigrew and Rapoport. The distribution volume of 70 KD dextran at 10 minutes after i.v. injection was also measured to determine the residual volume of blood in brain tissue at the time of sacrifice. Small test solutes were injected in pairs in order to elucidate whether their transfer into the brain proceeds by diffusion through water- or lipid-filled channels or by vesicular transport. This issue was examined in rats whose blood-brain barrier (BBB) was presumed to be intact (untreated) and in rats that received intracarotid infusions to open the BBB (isosmotic salt (ISS) and hyperosmolar arabinose). Ohno PS values of {sup 3}H-inulin and {sup 14}C-L-glucose in untreated rats were found to decrease as the labelling time was lengthened. This was evidence that a rapidly equilibrating compartment exists between blood and brain that renders the Ohno two-compartment model inadequate for computing true transfer rate constants. When the data were reanalyzed using a multi-compartment graphical analysis, solutes with different molecular radii were found to enter the brain at approximately equal rates. Furthermore, unidirectional transport is likely to be initiated by solute adsorption to a glycocalyx coat on the luminal surface of brain capillary endothelium. Apparently, more inulin than L-glucose was adsorbed, which may account for its slightly faster transfer across the BBB. After rats were treated with intracarotid infusions of ISS or hyperosmolar arabinose, solute PS values were significantly increased, but the ratio of PS for each of the solute pairs approached that of their free-diffusion coefficients.

  12. Spectral and lifetime domain measurements of rat brain tumors.

    PubMed

    Haidar, D Abi; Leh, B; Zanello, M; Siebert, R

    2015-04-01

    During glioblastoma surgery, delineation of the brain tumor margins is difficult because the infiltrated and normal tissues have the same visual appearance. We use a fiber-optical fluorescence probe for spectroscopic and time domain measurements to assist surgeon in differentiating the healthy and the infiltrated tissues. First study was performed on rats that were previously injected with tumorous cells. Measurements of endogenous tissue fluorescence were performed on fresh and fixed rat tumor brain slices. Spectral characteristics, fluorescence redox ratios and fluorescence lifetime measurements were analyzed. The study aimed at defining an optical index that can act as an indicator for discriminating healthy from tumorous tissue.

  13. Parallel decrease in ω-conotoxin-sensitive transmission and dopamine-induced inhibition at the striatal synapse of developing rats

    PubMed Central

    Momiyama, Toshihiko

    2003-01-01

    Whole-cell patch-clamp recordings of GABAergic IPSCs were made from cholinergic interneurones in slices of striatum from developing rats aged 21–60 days postnatal. In addition, the Ca2+ channel subtypes involved in synaptic transmission, as well as dopamine (DA)-induced presynaptic inhibition, were investigated pharmacologically with development by bath application of Ca2+ channel blockers and DA receptor agonists. The IPSC amplitude was reduced by ω-conotoxin GVIA (ω-CgTX) or ω-agatoxin TK (ω-Aga-TK) across the whole age range, suggesting that multiple types of Ca2+ channels mediate transmission of the synapse. The IPSC fraction reduced by ω-CgTX significantly decreased, whereas that reduced by ω-Aga-TK remained unchanged with development. DA or quinpirole, a D2-like receptor agonist, presynaptically reduced the IPSC amplitude throughout development. The DA-induced inhibition decreased with age in parallel with the decrease in N-type Ca2+ channels. DA showed no further inhibition of IPSCs after the inhibitory effect of ω-CgTX had reached steady state throughout development. These results demonstrate that there is a functional link between presynaptic N-type Ca2+ channels and D2-like DA receptors at inhibitory synapses in the striatum. They also demonstrate that the suppression of GABAergic transmission by D2-like receptors is mediated by modulation of N-type Ca2+ channels and decreases in parallel with the developmental decline in the contribution of N-type Ca2+ channels to exocytosis. PMID:12527734

  14. Striatal mRNA expression patterns underlying peak dose L-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat.

    PubMed

    Smith, L M; Parr-Brownlie, L C; Duncan, E J; Black, M A; Gemmell, N J; Dearden, P K; Reynolds, J N J

    2016-06-02

    L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson's disease (PD). With prolonged treatment (⩾5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. We used the 6-hydroxydopamine (6-OHDA) rat model of PD treated with a three-week dosing regimen of L-DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kgs.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, non-dyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 min after L-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence.

  15. CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat.

    PubMed

    Krasnova, Irina N; Chiflikyan, Margarit; Justinova, Zuzana; McCoy, Michael T; Ladenheim, Bruce; Jayanthi, Subramaniam; Quintero, Cynthia; Brannock, Christie; Barnes, Chanel; Adair, Jordan E; Lehrmann, Elin; Kobeissy, Firas H; Gold, Mark S; Becker, Kevin G; Goldberg, Steven R; Cadet, Jean Lud

    2013-10-01

    Neuroplastic changes in the dorsal striatum participate in the transition from casual to habitual drug use and might play a critical role in the development of methamphetamine (METH) addiction. We examined the influence of METH self-administration on gene and protein expression that may form substrates for METH-induced neuronal plasticity in the dorsal striatum. Male Sprague-Dawley rats self-administered METH (0.1mg/kg/injection, i.v.) or received yoked saline infusions during eight 15-h sessions and were euthanized 2h, 24h, or 1month after cessation of METH exposure. Changes in gene and protein expression were assessed using microarray analysis, RT-PCR and Western blots. Chromatin immunoprecipitation (ChIP) followed by PCR was used to examine epigenetic regulation of METH-induced transcription. METH self-administration caused increases in mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and the synaptic protein, synaptophysin (Syp) in the dorsal striatum. METH also caused changes in ΔFosB, BDNF and TrkB protein levels, with increases after 2 and 24h, but decreases after 1month of drug abstinence. Importantly, ChIP-PCR showed that METH self-administration caused enrichment of phosphorylated CREB (pCREB), but not of histone H3 trimethylated at lysine 4 (H3K4me3), on promoters of c-fos, fosb, Bdnf and Syp at 2h after cessation of drug intake. These findings show that METH-induced changes in gene expression are mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, METH self-administration might trigger epigenetic changes that mediate alterations in expression of genes and proteins serving as substrates for addiction-related synaptic plasticity.

  16. Anhydroecgonine Methyl Ester (AEME), a Product of Cocaine Pyrolysis, Impairs Spatial Working Memory and Induces Striatal Oxidative Stress in Rats.

    PubMed

    Gomes, Elisa Fraga; Lipaus, Ingryd Fortes Souza; Martins, Cleciane Waldetário; Araújo, Andrezza Menezes; Mendonça, Josidéia Barreto; Pelição, Fabrício Souza; Lebarch, Evandro Carlos; de Melo Rodrigues, Lívia Carla; Nakamura-Palacios, Ester Miyuki

    2017-09-15

    When burning crack cocaine, the pyrolysis of cocaine generates anhydroecgonine methyl ester (AEME). AEME has been shown to be highly neurotoxic but its effects on cognitive function and oxidative stress are still unknown. Thus, this study investigated the effects of AEME on spatial working memory and on parameters of oxidative stress in the prefrontal cortex, hippocampus, and striatum. First, 18 well-trained rats in 8-arm radial maze (8-RM) procedures received acute intracerebroventricular (icv) administration of AEME at doses of 10, 32, or 100 μg or saline (SAL) in a counterbalanced order and were tested 5 min later in 1-h delayed tasks in the 8-RM. Secondly, separated animals received acute icv administration of AEME at doses of 10 (n = 5), 32 (n = 5), or 100 μg (n = 5) or SAL (n = 5) for analysis of advanced oxidation protein products, thiobarbituric acid, catalase, glutathione peroxidase, and superoxide dismutase. A higher number of errors were seen in the 1-h post-delay performance after AEME 32 μg and AEME 100 μg when compared to SAL. In the striatum, animals receiving AEME 100 μg icv showed increased advanced oxidation protein products levels when compared to 10 μg, and also showed increased activity of glutathione peroxidase enzyme when compared to SAL but also comparing to AEME 32 μg and AEME 10 μg. These results showed that AEME impairs long-term spatial working memory and also induces greater protein oxidation and increased levels of antioxidant enzymes in the striatum.

  17. Where fMRI and electrophysiology agree to disagree: corticothalamic and striatal activity patterns in the WAG/Rij rat

    PubMed Central

    Mishra, Asht Mangal; Ellens, Damien J.; Schridde, Ulrich; Motelow, Joshua E.; Purcaro, Michael J.; DeSalvo, Matthew N.; Enev, Miro; Sanganahalli, Basavaraju G.; Hyder, Fahmeed; Blumenfeld, Hal

    2012-01-01

    The relationship between neuronal activity and hemodynamic changes plays a central role in functional neuroimaging. Under normal conditions and in neurological disorders such as epilepsy it is commonly assumed that increased functional magnetic resonance imaging (fMRI) signals reflect increased neuronal activity, and that fMRI decreases represent neuronal activity decreases. Recent work suggests these assumptions usually hold true in the cerebral cortex. However, less is known about the basis of fMRI signals from subcortical structures such as the thalamus and basal ganglia. We used Wistar Albino Glaxo rats of Rijswijk (WAG/Rij), an established animal model of human absence epilepsy, to perform fMRI studies with blood oxygen level dependent (BOLD) and cerebral blood volume (CBV) contrasts at 9.4 Tesla; as well as laser Doppler cerebral blood flow (CBF), local field potential (LFP), and multiunit activity (MUA) recordings. We found that during spike-wave discharges, the somatosensory cortex and thalamus showed increased fMRI, CBV, CBF, LFP and MUA signals. However, the caudate-putamen showed fMRI, CBV and CBF decreases despite increases in LFP and MUA signals. Similarly, during normal whisker stimulation the cortex and thalamus showed increases in CBF and MUA, while the caudate-putamen showed decreased CBF with increased MUA. These findings suggest that neuroimaging-related signals and electrophysiology tend to agree in the cortex and thalamus, but disagree in the caudate-putamen. These opposite changes in vascular and electrical activity indicate that caution should be applied when interpreting fMRI signals in both health and disease from the caudate-putamen, as well as possibly from other subcortical structures. PMID:22016539

  18. Ontogenetic development of the striatal [3H]spiperone binding: regulation by sodium and guanine nucleotide in rats.

    PubMed

    Nomura, Y; Oki, K; Segawa, T

    1982-04-01

    Ontogenetic development of specific [3H]spiperone binding to crude synaptic membranes and its regulation by Na+ and GTP was investigated in the rat striatum. (d)-Butaclamol more effectively inhibited [3H]spiperone binding than (l)-butaclamol. The ratio of inhibitory activity of (d)- and (l)-butaclamol for [3H]spiperone binding was not different between 1-, 7-, and 70-day-old animals but eight- to ninefold lower at 18 days of gestation than during the postnatal period. A Scatchard plot of specific binding indicated the presence of two types of binding: low-affinity (KD = 1.51 nM) and high-affinity (KD = 0.09 nM) binding on day 70. Only one component (KD = 0.075 nM) was observed on days 1 and 7 and both types of binding were found on day 15. Bmax gradually increased with age and reached a peak on day 30, followed by a decline on days 70 and 360. Na+, 100 mM, significantly increased specific binding on days 1, 7, 15, and 70. GTP, 50 microM, completely reversed the Na+-induced decrease in IC50 of apomorphine on both days 15 and 70, but not on day 7. It is suggested that receptors could recognize ligand stereospecificity on day 1. The density in dopamine receptors in the striatum reaches a peak on day 30, followed by a decrease on days 70 and 360. In addition, regulation by Na+ and GTP in agonist binding to dopamine receptors seems to become functional between 1 and 2 weeks after birth.

  19. Brain endocannabinoid system is involved in fluoxetine-induced anorexia.

    PubMed

    Zarate, Jon; Churruca, Itziar; Pascual, Jesús; Casis, Luis; Sallés, Joan; Echevarría, Enrique

    2008-06-01

    In order to describe the effects of chronic fluoxetine administration on the brain endocannabinoid system in lean and obese Zucker rats, brain immunostaining for the CB1 and CB1-phosphorylated cannabinoid receptors was carried out. Obese Zucker rats showed significantly increased the numbers of neural cells positively immunostained for the CB1-phosphorylated receptor in the striatum, compared to their lean litter-mates. Chronic fluoxetine administration decreased the number of neural cells immunostained for CB1-phosphorylated receptor in several striatal and hippocampal regions of obese Zucker rats, compared to controls treated with saline. In contrast, no change in CB1-phosphorylated receptor immunostaining was observed in fluoxetine-treated lean rats, with respect to controls. Taken together, these results suggest the involvement of the hippocampal and striatal endocannabinoid receptor system in fluoxetine-induced anorexia in lean and obese Zucker rats.

  20. 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.

  1. Accumulation of neurotoxic thioether metabolites of 3,4-(+/-)-methylenedioxymethamphetamine in rat brain.

    PubMed

    Erives, Gladys V; Lau, Serrine S; Monks, Terrence J

    2008-01-01

    The serotonergic neurotoxicity of 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism because direct injection of MDMA into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-alpha-MeDA are neurotoxic and are present in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, the present study was designed to determine the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. Administration of MDMA (20 mg/kg s.c.) at 12-h intervals for a total of four injections led to a significant accumulation of the N-Me-alpha-MeDA thioether metabolites in striatal dialysate. The area under the curve (AUC)(0-300 min) for 5-(glutathion-S-yl)-N-Me-alpha-MeDA increased 33% between the first and fourth injections and essentially doubled for 2,5-bis-(glutathion-S-yl)-N-Me-alpha-MeDA. Likewise, accumulation of the mercapturic acid metabolites was reflected by increases in the AUC(0-300 min) for both 5-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA (35%) and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA (85%), probably because processes for their elimination become saturated. Indeed, the elimination half-life of 5-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA increased by 53 and 28%, respectively, between the first and third doses. Finally, although the C(max) values for the monothioether conjugates were essentially unchanged after each injection, the values increased by 38 and approximately 50% for 2,5-bis-(glutathion-S-yl)-N-Me-alpha-MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA, respectively, between the first and fourth injections. The data indicate that neurotoxic metabolites of MDMA may accumulate in brain after

  2. Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat

    PubMed Central

    Feng, Yangzheng; Paul, Ian A.; LeBlanc, Michael H.

    2011-01-01

    Nicotinamide reduces ischemic brain injury in adult rats. Can similar brain protection be seen in newborn animals? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of 8% oxygen. Nicotinamide 250 or 500 mg/kg was administered i.p. 5 min after reoxygenation, with a second dose given at 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Nicotinamide 500 mg/kg reduced brain weight loss from 24.6 ± 3.6% in vehicle pups (n = 28) to 11.9 ± 2.6% in the treated pups (n = 29, P < 0.01), but treatment with 250 mg/kg did not affect brain weight. Nicotinamide 500 mg/kg also improved behavior in rotarod performance. Levels of 8-isoprostaglandin F2α measured in the cortex by enzyme immune assay 16 h after reoxygenation was 115 ± 7 pg/g in the shams (n = 6), 175 ± 17 pg/g in the 500 mg/kg nicotinamide treated (n = 7), and 320 ± 79 pg/g in the vehicle treated pups (n = 7, P < 0.05 versus sham, P < 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia (P < 0.01). Nicotinamide reduces brain injury in the neonatal rat, possibly by reducing oxidative stress and caspase-3 activity. PMID:16533659

  3. Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat.

    PubMed

    Feng, Yangzheng; Paul, Ian A; LeBlanc, Michael H

    2006-03-31

    Nicotinamide reduces ischemic brain injury in adult rats. Can similar brain protection be seen in newborn animals? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of 8% oxygen. Nicotinamide 250 or 500 mg/kg was administered i.p. 5 min after reoxygenation, with a second dose given at 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Nicotinamide 500 mg/kg reduced brain weight loss from 24.6 +/- 3.6% in vehicle pups (n = 28) to 11.9 +/- 2.6% in the treated pups (n = 29, P < 0.01), but treatment with 250 mg/kg did not affect brain weight. Nicotinamide 500 mg/kg also improved behavior in rotarod performance. Levels of 8-isoprostaglandin F2alpha measured in the cortex by enzyme immune assay 16 h after reoxygenation was 115 +/- 7 pg/g in the shams (n = 6), 175 +/- 17 pg/g in the 500 mg/kg nicotinamide treated (n = 7), and 320 +/- 79 pg/g in the vehicle treated pups (n = 7, P < 0.05 versus sham, P < 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia (P < 0.01). Nicotinamide reduces brain injury in the neonatal rat, possibly by reducing oxidative stress and caspase-3 activity.

  4. Isatin, regional distribution in rat brain and tissues.

    PubMed

    Watkins, P; Clow, A; Glover, V; Halket, J; Przyborowska, A; Sandler, M

    1990-01-01

    Isatin has recently been identified in rat tissues and normal human urine, where it forms the major proportion of the endogenous monoamine oxidase inhibitor, tribulin. In this paper, we show that isatin, measured by gas chromatography/mass spectrometry, has a distinct regional distribution in rat tissues, with highest concentrations in seminal vesicles (1.6 ?g/g) and vas deferens (3.4 ?g/g). There was also a discontinuous distribution within rat brain, concentrations being highest in the hippocampus (0.13 ?g/g).

  5. Antioxidant-Rich Fraction of Urtica dioica Mediated Rescue of Striatal Mito-Oxidative Damage in MPTP-Induced Behavioral, Cellular, and Neurochemical Alterations in Rats.

    PubMed

    Bisht, Rohit; Joshi, Bhuwan Chandra; Kalia, Ajudhiya Nath; Prakash, Atish

    2017-09-01

    Parkinson's disease (PD) having a complex and multi-factorial neuropathology includes mainly the degeneration of the dopaminergic nigrostriatal pathway, which is a cumulative effect of depleted endogenous antioxidant enzymes, increased oxidative DNA damage, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. The present study was designed to investigate the neuroprotective effect of a potent antioxidant from Urtica dioica in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. MPTP was administered intranigrally for the induction of PD in male Wistar rats. Behavioral alterations were assessed in between the study period. Animals were sacrificed immediately after behavioral session, and different biochemical, cellular, and neurochemical parameters were measured. Intranigrally repeated administration of MPTP showed significant impairment of motor co-ordination and marked increase of mito-oxidative damage and neuroinflammation in rats. Intranigral MPTP significantly decreases the dopamine and its metabolites with impairment of dopaminergic cell density in rat brain. However, post-treatment with the potent antioxidant fraction of Urtica dioica Linn. (UD) (20, 40, 80 mg/kg) improved the motor function, mito-oxidative defense alteration significantly and dose dependently in MPTP-treated rats. In addition, the potent antioxidant fraction of UD attenuated the pro-inflammatory cytokines (TNF-α and IL-β) and restored the level of dopamine and its metabolites in MPTP-induced PD in rats. Moreover, minocycline (30 mg/kg) with lower dose of UD (20 mg/kg) had significantly potentiated the protective effect of minocycline as compared to its effect with other individual drug-treated groups. In conclusion, Urtica dioica protected the dopaminergic neurons probably by reducing mito-oxidative damage, neuroinflammation, and cellular alteration along with enhanced neurotrophic potential. The above results revealed that the antioxidant rich

  6. GC/MS/MS DETECTION OF EXTRACELLULAR KYNURENINE AND RELATED METABOLITES IN NORMAL AND LESIONED RAT BRAIN

    PubMed Central

    Notarangelo, Francesca M.; Wu, Hui-Qiu; Macherone, Anthony; Graham, David R.; Schwarcz, Robert

    2012-01-01

    We describe here a GC/MS/MS method for the sensitive and concurrent determination of extracellular tryptophan and the kynurenine pathway metabolites kynurenine, 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) in rat brain. This metabolic cascade is increasingly linked to the pathophysiology of several neurological and psychiatric diseases. Methodological refinements, including optimization of MS conditions and addition of deuterated standards, resulted in assay linearity to the low nanomolar range. Measured in samples obtained by striatal microdialysis in vivo, basal levels of tryptophan, kynurenine and QUIN were 415, 89 and 8 nM, respectively, but 3-HK levels were below the limit of detection (<2 nM). Systemic injection of kynurenine (100 mg/kg, i.p.) did not affect extracellular tryptophan but produced detectable levels of extracellular 3-HK (peak after 2-3 h: ~50 nM) and raised extracellular QUIN levels (peak after 2 h: ~105 nM). The effect of this treatment on QUIN, but not on 3-HK, was potentiated in the NMDA-lesioned striatum. Our results indicate that the novel methodology, which allowed the measurement of extracellular kynurenine and 3-HK in the brain in vivo, will facilitate studies of brain kynurenines and of the interplay between peripheral and central kynurenine pathway function under physiological and pathological conditions. PMID:22239963

  7. Extracellular matrix molecules and synaptic plasticity: immunomapping of intracellular and secreted Reelin in the adult rat brain.

    PubMed

    Ramos-Moreno, Tania; Galazo, Maria J; Porrero, Cesar; Martínez-Cerdeño, Verónica; Clascá, Francisco

    2006-01-01

    Reelin, a large extracellular matrix glycoprotein, is secreted by several neuron populations in the developing and adult rodent brain. Secreted Reelin triggers a complex signaling pathway by binding lipoprotein and integrin membrane receptors in target cells. Reelin signaling regulates migration and dendritic growth in developing neurons, while it can modulate synaptic plasticity in adult neurons. To identify which adult neural circuits can be modulated by Reelin-mediated signaling, we systematically mapped the distribution of Reelin in adult rat brain using sensitive immunolabeling techniques. Results show that the distribution of intracellular and secreted Reelin is both very widespread and specific. Some interneuron and projection neuron populations in the cerebral cortex contain Reelin. Numerous striatal neurons are weakly immunoreactive for Reelin and these cells are preferentially located in striosomes. Some thalamic nuclei contain Reelin-immunoreactive cells. Double-immunolabeling for GABA and Reelin reveals that the Reelin-immunoreactive cells in the visual thalamus are the intrinsic thalamic interneurons. High local concentrations of extracellular Reelin selectively outline several dendrite spine-rich neuropils. Together with previous mRNA data, our observations suggest abundant axoplasmic transport and secretion in pathways such as the retino-collicular tract, the entorhino-hippocampal ('perforant') path, the lateral olfactory tract or the parallel fiber system of the cerebellum. A preferential secretion of Reelin in these neuropils is consistent with reports of rapid, activity-induced structural changes in adult brain circuits.

  8. Striatal degeneration in childhood.

    PubMed Central

    Erdohazi, M; Marshall, P

    1979-01-01

    The clinical features, and the radiological and neuropathological findings of 3 unrelated children with striatal degeneration are presented. In one case the father had recently developed choreiform movements while in the other two the family history was negative for neurological disorders. Two patients had juvenile onset of psychiatric symptoms, seizures, and rigidity. The 3rd child presented with focal seizures at 9 weeks of age. The neuropathological findings are virtually identical in all 3 cases. The classification of striatal degeneration in childhood is discussed. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:434899

  9. Oxidative damage to rat brain in iron and copper overloads.

    PubMed

    Musacco-Sebio, Rosario; Ferrarotti, Nidia; Saporito-Magriñá, Christian; Semprine, Jimena; Fuda, Julián; Torti, Horacio; Boveris, Alberto; Repetto, Marisa G

    2014-08-01

    This study reports on the acute brain toxicity of Fe and Cu in male Sprague-Dawley rats (200 g) that received 0 to 60 mg kg(-1) (ip) FeCl2 or CuSO4. Brain metal contents and time-responses were determined for rat survival, in situ brain chemiluminescence and phospholipid and protein oxidation products. Metal doses hyperbolically defined brain metal content. Rat survival was 91% and 60% after Fe and Cu overloads. Brain metal content increased from 35 to 114 μg of Fe per g and from 3.6 to 34 μg of Cu per g. Brain chemiluminescence (10 cps cm(-2)) increased 3 and 2 times after Fe and Cu overloads, with half maximal responses (C50) of 38 μg of Fe per g of brain and 15 μg of Cu per g of brain, and with half time responses (t1/2) of 12 h for Fe and 20 h for Cu. Phospholipid peroxidation increased by 56% and 31% with C50 of 40 μg of Fe per g and 20 μg of Cu per g and with t1/2 of 9 h and 14 h. Protein oxidation increased by 45% for Fe with a C50 of 40 μg of Fe per g and 18% for Cu with a C50 of 10 μg of Cu per g and a t1/2 of 12 h for both metals. Fe and Cu brain toxicities are likely mediated by Haber-Weiss type HO˙ formation with subsequent oxidative damage.

  10. Regulation of atrial natriuretic peptide receptors in the rat brain

    SciTech Connect

    Saavedra, J.M.

    1987-06-01

    We have studied the localization, kinetics, and regulation of receptors for the circulating form of the atrial natriuretic peptide (ANP; 99-126) in the rat brain. Quantitative autoradiographic techniques and a /sup 125/I-labeled ligand, /sup 125/I-ANP (99-126), were employed. After in vitro autoradiography, quantification was achieved by computerized microdensitometry followed by comparison with /sup 125/I-standards. ANP receptors were discretely localized in the rat brain, with the highest concentrations in circumventricular organs, the choroid plexus, and selected hypothalamic nuclei involved in the production of the antidiuretic hormone vasopressin and in blood-pressure control. Spontaneously (genetic) hypertensive rats showed much lower numbers of ANP receptors than normotensive controls in the subfornical organ, the area postrema, the nucleus of the solitary tract, and the choroid plexus. These changes are in contrast to those observed for receptors of angiotensin II, another circulating peptide with actions opposite to those of ANP. Under conditions of acute dehydration after water deprivation, as well as under conditions of chronic dehydration such as those present in homozygous Brattleboro rats, there was an up-regulation of ANP receptors in the subfornical organ. Our results indicate that in the brain, circumventricular organs contain ANP receptors which could respond to variations in the concentration of circulating ANP. In addition, brain areas inside the blood-brain barrier contain ANP receptors probably related to the endogenous, central ANP system. The localization of ANP receptors and the alterations in their regulation present in genetically hypertensive rats and after dehydration indicate that brain ANP receptors are probably related to fluid regulation, including the secretion of vasopressin, and to cardiovascular function.

  11. [Bcl-2 expression following the brain concussion in rats].

    PubMed

    Zhu, Xu-yang; Wang, Feng; Fang, Wei-hua; Wu, Mao-wang

    2007-02-15

    To evaluate the expression of Bcl-2 protein after brain concussion. Expression levels of Bel-2 protein in cortex, pontine and cerebellum of rats were investigated using immunohistochemistry. There was no expression of Bcl-2 protein in control group seen. The expression of Bcl-2 protein in brain concussion groups was detected at l hour, and the expression level reached its peak 4 days after the concussion and then declined gradually. Our findings suggest that the detection of Bel-2 protein could be an indicator for diagnosis of brain concussion and for estimation of the post injury time interval.

  12. Demonstration of endogenous imipramine like material in rat brain

    SciTech Connect

    Rehavi, M.; Ventura, I.; Sarne, Y.

    1985-02-18

    The extraction and partial purification of an endogenous imipramine-like material from rat brain is described. The endogenous factor obtained after gel filtration and silica chromatography inhibits (/sup 3/H) imipramine specific binding and mimics the inhibitory effect of imipramine on (/sup 3/H) serotonin uptake in both brain and platelet preparations. The effects of the endogenous material are dose-dependent and it inhibits (/sup 3/H) imipramine binding in a competitive fashion. The factor is unevenly distributed in the brain with high concentration in the hypothalamus and low concentration in the cerebellum.

  13. Intrinsic excitability varies by sex in prepubertal striatal medium spiny neurons

    PubMed Central

    Dorris, David M.; Cao, Jinyan; Willett, Jaime A.; Hauser, Caitlin A.

    2014-01-01

    Sex differences in neuron electrophysiological properties were traditionally associated with brain regions directly involved in reproduction in adult, postpubertal animals. There is growing acknowledgement that sex differences can exist in other developmental periods and brain regions as well. This includes the dorsal striatum (caudate/putamen), which shows robust sex differences in gene expression, neuromodulator action (including dopamine and 17β-estradiol), and relevant sensorimotor behaviors and pathologies such as the responsiveness to drugs of abuse. Here we examine whether these sex differences extend to striatal neuron electrophysiology. We test the hypothesis that passive and active medium spiny neuron (MSN) electrophysiological properties in prepubertal rat dorsal striatum differ by sex. We made whole cell recordings from male and females MSNs from acute brain slices. The slope of the evoked firing rate to current injection curve was increased in MSNs recorded from females compared with males. The initial action potential firing rate was increased in MSNs recorded from females compared with males. Action potential after-hyperpolarization peak was decreased, and threshold was hyperpolarized in MSNs recorded from females compared with males. No sex differences in passive electrophysiological properties or miniature excitatory synaptic currents were detected. These findings indicate that MSN excitability is increased in prepubertal females compared with males, providing a new mechanism that potentially contributes to generating sex differences in striatal-mediated processes. Broadly, these findings demonstrate that sex differences in neuron electrophysiological properties can exist prepuberty in brain regions not directly related to reproduction. PMID:25376786

  14. Brain Remodelling following Endothelin-1 Induced Stroke in Conscious Rats

    PubMed Central

    Abeysinghe, Hima C. S.; Bokhari, Laita; Dusting, Gregory J.; Roulston, Carli L.

    2014-01-01

    The extent of stroke damage in patients affects the range of subsequent pathophysiological responses that influence recovery. Here we investigate the effect of lesion size on development of new blood vessels as well as inflammation and scar formation and cellular responses within the subventricular zone (SVZ) following transient focal ischemia in rats (n = 34). Endothelin-1-induced stroke resulted in neurological deficits detected between 1 and 7 days (P<0.001), but significant recovery was observed beyond this time. MCID image analysis revealed varying degrees of damage in the ipsilateral cortex and striatum with infarct volumes ranging from 0.76–77 mm3 after 14 days, where larger infarct volumes correlated with greater functional deficits up to 7 days (r = 0.53, P<0.05). Point counting of blood vessels within consistent sample regions revealed that increased vessel numbers correlated significantly with larger infarct volumes 14 days post-stroke in the core cortical infarct (r = 0.81, P<0.0001), core striatal infarct (r = 0.91, P<0.005) and surrounding border zones (r = 0.66, P<0.005; and r = 0.73, P<0.05). Cell proliferation within the SVZ also increased with infarct size (P<0.01) with a greater number of Nestin/GFAP positive cells observed extending towards the border zone in rats with larger infarcts. Lesion size correlated with both increased microglia and astrocyte activation, with severely diffuse astrocyte transition, the formation of the glial scar being more pronounced in rats with larger infarcts. Thus stroke severity affects cell proliferation within the SVZ in response to injury, which may ultimately make a further contribution to glial scar formation, an important factor to consider when developing treatment strategies that promote neurogenesis. PMID:24809543

  15. Brain remodelling following endothelin-1 induced stroke in conscious rats.

    PubMed

    Abeysinghe, Hima C S; Bokhari, Laita; Dusting, Gregory J; Roulston, Carli L

    2014-01-01

    The extent of stroke damage in patients affects the range of subsequent pathophysiological responses that influence recovery. Here we investigate the effect of lesion size on development of new blood vessels as well as inflammation and scar formation and cellular responses within the subventricular zone (SVZ) following transient focal ischemia in rats (n = 34). Endothelin-1-induced stroke resulted in neurological deficits detected between 1 and 7 days (P<0.001), but significant recovery was observed beyond this time. MCID image analysis revealed varying degrees of damage in the ipsilateral cortex and striatum with infarct volumes ranging from 0.76-77 mm3 after 14 days, where larger infarct volumes correlated with greater functional deficits up to 7 days (r = 0.53, P<0.05). Point counting of blood vessels within consistent sample regions revealed that increased vessel numbers correlated significantly with larger infarct volumes 14 days post-stroke in the core cortical infarct (r = 0.81, P<0.0001), core striatal infarct (r = 0.91, P<0.005) and surrounding border zones (r = 0.66, P<0.005; and r = 0.73, P<0.05). Cell proliferation within the SVZ also increased with infarct size (P<0.01) with a greater number of Nestin/GFAP positive cells observed extending towards the border zone in rats with larger infarcts. Lesion size correlated with both increased microglia and astrocyte activation, with severely diffuse astrocyte transition, the formation of the glial scar being more pronounced in rats with larger infarcts. Thus stroke severity affects cell proliferation within the SVZ in response to injury, which may ultimately make a further contribution to glial scar formation, an important factor to consider when developing treatment strategies that promote neurogenesis.

  16. Intraneuronal accumulation and persistence of radiolabel in rat brain following in vivo administration of [3H]-chlorisondamine.

    PubMed Central

    el-Bizri, H.; Rigdon, M. G.; Clarke, P. B.

    1995-01-01

    1. Chlorisondamine (CHL), a bisquaternary amine, produces a remarkably long-lasting blockade of central responses to nicotine. The mechanism underlying this blockade is not known. The main aim of this study was to test for possible accumulation of [3H]-CHL in rat brain during the period of chronic blockade. 2. Rats received CHL, either systemically (10 mg kg-1) or centrally (10 micrograms i.c.v.). Seven days later, striatal synaptosomes prepared from these animals were tested for nicotine-induced [3H]-dopamine release. This experiment showed that i.c.v. administration of CHL was as effective as systemic administration in producing ex vivo blockade of central nicotinic receptors. 3. Rats received bilateral i.c.v. infusions of [3H]-CHL (10 micrograms) and radioactivity was subsequently quantified in dissected cerebral cortex, striatum, hippocampus, midbrain and cerebellum. Radiolabel was detected at all three survival times (1, 7, and 21 days). Regional heterogeneity was apparent at 7 and 21 days survival. Radiolabel was almost exclusively confined to the insoluble subcellular fraction in all areas sampled. 4. The anatomical distribution of radiolabel was also visualized in brain sections. Rats received bilateral i.c.v. infusions of [3H]-CHL (10 micrograms) and were killed at 1, 7, 21 or 84 days. Immediately before they were killed, all rats were tested behaviourally, and central nicotinic blockade was demonstrated at 1, 7 and 21 days; partial recovery was observed at 84 days. Particularly at longer survival times, tritium was found to be heavily concentrated in the substantia nigra pars compacta, ventral tegmental area, dorsal raphé nucleus, and the granular layer of the cerebellum. 5. The possibility of retrograde axonal transport of radiolabel was then examined. Rats received a unilateral intrastriatal infusion of [3H]-CHL (0.34 or 0.034 micrograms) one week before they were killed. Autoradiographic labelling was largely confined to the site of infusion and to

  17. Waxholm Space atlas of the Sprague Dawley rat brain

    PubMed Central

    Papp, Eszter A.; Leergaard, Trygve B.; Calabrese, Evan; Johnson, G. Allan; Bjaalie, Jan G.

    2014-01-01

    Three-dimensional digital brain atlases represent an important new generation of neuroinformatics tools for understanding complex brain anatomy, assigning location to experimental data, and planning of experiments. We have acquired a microscopic resolution isotropic MRI and DTI atlasing template for the Sprague Dawley rat brain with 39 µm isotropic voxels for the MRI volume and 78 µm isotropic voxels for the DTI. Building on this template, we have delineated 76 major anatomical structures in the brain. Delineation criteria are provided for each structure. We have applied a spatial reference system based on internal brain landmarks according to the Waxholm Space standard, previously developed for the mouse brain, and furthermore connected this spatial reference system to the widely used stereotaxic coordinate system by identifying cranial sutures and related stereotaxic landmarks in the template using contrast given by the active staining technique applied to the tissue. With the release of the present atlasing template and anatomical delineations, we provide a new tool for spatial orientation analysis of neuroanatomical location, and planning and guidance of experimental procedures in the rat brain. The use of Waxholm Space and related infrastructures will connect the atlas to interoperable resources and services for multilevel data integration and analysis across reference spaces. PMID:24726336

  18. Waxholm Space atlas of the Sprague Dawley rat brain.

    PubMed

    Papp, Eszter A; Leergaard, Trygve B; Calabrese, Evan; Johnson, G Allan; Bjaalie, Jan G

    2014-08-15

    Three-dimensional digital brain atlases represent an important new generation of neuroinformatics tools for understanding complex brain anatomy, assigning location to experimental data, and planning of experiments. We have acquired a microscopic resolution isotropic MRI and DTI atlasing template for the Sprague Dawley rat brain with 39 μm isotropic voxels for the MRI volume and 78 μm isotropic voxels for the DTI. Building on this template, we have delineated 76 major anatomical structures in the brain. Delineation criteria are provided for each structure. We have applied a spatial reference system based on internal brain landmarks according to the Waxholm Space standard, previously developed for the mouse brain, and furthermore connected this spatial reference system to the widely used stereotaxic coordinate system by identifying cranial sutures and related stereotaxic landmarks in the template using contrast given by the active staining technique applied to the tissue. With the release of the present atlasing template and anatomical delineations, we provide a new tool for spatial orientation analysis of neuroanatomical location, and planning and guidance of experimental procedures in the rat brain. The use of Waxholm Space and related infrastructures will connect the atlas to interoperable resources and services for multi-level data integration and analysis across reference spaces. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Experimental induction of corpora amylacea in adult rat brain.

    PubMed

    Schipper, H M

    1998-10-01

    Corpora amylacea (CA) are glycoproteinaceous inclusions that accumulate in astroglia and other brain cells as a function of advancing age and, to an even greater extent, in several human neurodegenerative conditions. The mechanisms responsible for their biogenesis and their subcellular origin(s) remain unclear. We previously demonstrated that the sulfhydryl agent, cysteamine (CSH), promotes the accumulation of CA-like inclusions in cultured rat astroglia. In the present study, we show that subcutaneous administration of CSH to adult rats (150 mg/kg for 6 weeks followed by a 5-week drug-washout period) elicits the accumulation of CA in many cortical and subcortical brain regions. As in the aging human brain and in CSH-treated rat astrocyte cultures, the inclusions are periodic acid-Schiff -positive and are consistently immunostained with antibodies directed against mitochondrial epitopes and ubiquitin. Our findings support our contention that mitochondria are important structural precursors of CA, and that CSH accelerates aging-like processes in rat astroglia both in vitro and in the intact brain.

  20. Thyroid insufficiency in developing rat brain: A genomic analysis.

    EPA Science Inventory

    Thyroid Insufficiency in the Developing Rat Brain: A Genomic Analysis. JE Royland and ME Gilbert, Neurotox. Div., U.S. EPA, RTP, NC, USA. Endocrine disruption (ED) is an area of major concern in environmental neurotoxicity. Severe deficits in thyroid hormone (TH) levels have bee...

  1. EVALUATION OF PERFLUOROOCTANE SULFONATE IN THE RAT BRAIN

    EPA Science Inventory

    Perfluorooctane Sulfonate (PFOS) is an environmentally persistent chemical that has been detected in humans and wildlife. PFOS is primarily distributed in liver and blood. The current study evaluated the level of PFOS in the adult and neonatal rat brain and determined whether t...

  2. EVALUATION OF PERFLUOROOCTANE SULFONATE IN THE RAT BRAIN

    EPA Science Inventory

    Perfluorooctane Sulfonate (PFOS) is an environmentally persistent chemical that has been detected in humans and wildlife. PFOS is primarily distributed in liver and blood. The current study evaluated the level of PFOS in the adult and neonatal rat brain and determined whether t...

  3. Effects of protein malnutrition on oxidative status in rat brain.

    PubMed

    Feoli, Ana M; Siqueira, Ionara R; Almeida, Lúcia; Tramontina, Ana C; Vanzella, Cláudia; Sbaraini, Sabrina; Schweigert, Ingrid D; Netto, Carlos A; Perry, Marcos L S; Gonçalves, Carlos A

    2006-02-01

    This study evaluated the effects of protein malnutrition on oxidative status in rat brain areas. We investigated various parameters of oxidative status, free radical content (dichlorofluorescein formation), indexes of damage to lipid (thiobarbituric acid-reactive substances assay), and protein damage (tryptophan and tyrosine content) in addition to total antioxidant reactivity levels and antioxidant enzyme activities of superoxide dismutase, glutathione peroxidase, and catalase in different cerebral regions (cortex, hippocampus, and cerebellum) from rats subjected to prenatal and postnatal protein malnutrition (control 25% casein and protein malnutrition 7% casein). Protein malnutrition altered various parameters of oxidative stress, especially damage to macromolecules. Free radical content was unchanged by protein malnutrition. There was an increase in levels of thiobarbituric acid-reactive substances, the index of lipid peroxidation, in the cerebellum and cerebral cortex (P < 0.05) from protein-malnourished rats. Moreover, significant decreases in tryptophan and tyrosine in all tested brain structures (P < 0.05) were observed. Catalase activity was significantly decreased in the cerebellum (P < 0.05). In addition, a significant decrease in total antioxidant reactivity levels (P < 0.05) was observed in the cerebral cortex from protein-malnourished rats. The present data indicated that protein malnutrition increased oxidative damage to lipids and proteins from the studied brain areas. These results may be an indication of an important mechanism for changes in brain development that are caused by protein malnutrition.

  4. Autoradiographic localization of relaxin binding sites in rat brain

    SciTech Connect

    Osheroff, P.L.; Phillips, H.S. )

    1991-08-01

    Relaxin is a member of the insulin family of polypeptide hormones and exerts its best understood actions in the mammalian reproductive system. Using a biologically active 32P-labeled human relaxin, the authors have previously shown by in vitro autoradiography specific relaxin binding sites in rat uterus, cervix, and brain tissues. Using the same approach, they describe here a detailed localization of human relaxin binding sites in the rat brain. Displaceable relaxin binding sites are distributed in discrete regions of the olfactory system, neocortex, hypothalamus, hippocampus, thalamus, amygdala, midbrain, and medulla of the male and female rat brain. Characterization of the relaxin binding sites in the subfornical organ and neocortex reveals a single class of high-affinity sites (Kd = 1.4 nM) in both regions. The binding of relaxin to two of the circumventricular organs (subfornical organ and organum vasculosum of the lamina terminalis) and the neurosecretory magnocellular hypothalamic nuclei (i.e., paraventricular and supraoptic nuclei) provides the anatomical and biochemical basis for emerging physiological evidence suggesting a central role for relaxin in the control of blood pressure and hormone release. They conclude that specific, high-affinity relaxin binding sites are present in discrete regions of the rat brain and that the distribution of some of these sites may be consistent with a role for relaxin in control of vascular volume and blood pressure.

  5. Thyroid insufficiency in developing rat brain: A genomic analysis.

    EPA Science Inventory

    Thyroid Insufficiency in the Developing Rat Brain: A Genomic Analysis. JE Royland and ME Gilbert, Neurotox. Div., U.S. EPA, RTP, NC, USA. Endocrine disruption (ED) is an area of major concern in environmental neurotoxicity. Severe deficits in thyroid hormone (TH) levels have bee...

  6. FACS purification of immunolabeled cell types from adult rat brain.

    PubMed

    Guez-Barber, Danielle; Fanous, Sanya; Harvey, Brandon K; Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G; Picciotto, Marina R; Hope, Bruce T

    2012-01-15

    Molecular analysis of brain tissue is greatly complicated by having many different classes of neurons and glia interspersed throughout the brain. Fluorescence-activated cell sorting (FACS) has been used to purify selected cell types from brain tissue. However, its use has been limited to brain tissue from embryos or transgenic mice with promoter-driven reporter genes. To overcome these limitations, we developed a FACS procedure for dissociating intact cell bodies from adult wild-type rat brains and sorting them using commercially available antibodies against intracellular and extracellular proteins. As an example, we isolated neurons using a NeuN antibody and confirmed their identity using microarray and real time PCR of mRNA from the sorted cells. Our FACS procedure allows rapid, high-throughput, quantitative assays of molecular alterations in identified cell types with widespread applications in neuroscience. Published by Elsevier B.V.

  7. FACS purification of immunolabeled cell types from adult rat brain

    PubMed Central

    Guez-Barber, Danielle; Fanous, Sanya; Harvey, Brandon K; Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G; Picciotto, Marina R; Hope, Bruce T

    2011-01-01

    Molecular analysis of brain tissue is greatly complicated by having many different classes of neurons and glia interspersed throughout the brain. Fluorescence-activated cell sorting (FACS) has been used to purify selected cell types from brain tissue. However, its use has been limited to brain tissue from embryos or transgenic mice with promoter-driven reporter genes. To overcome these limitations, we developed a FACS procedure for dissociating intact cell bodies from adult wild-type rat brains and sorting them using commercially available antibodies against intracellular and extracellular proteins. As an example, we isolated neurons using a NeuN antibody and confirmed their identity using microarray and real time PCR of mRNA from the sorted cells. Our FACS procedure allows rapid, high-throughput, quantitative assays of molecular alterations in identified cell types with widespread applications in neuroscience. PMID:21911005

  8. Effects of magnesium sulfate on traumatic brain edema in rats.

    PubMed

    Feng, Dong-fu; Zhu, Zhi-an; Lu, Yi-cheng

    2004-06-01

    To investigate the effects of magnesium sulfate on traumatic brain edema and explore its possible mechanism. Forty-eight Sprague-Dawley (SD) rats were randomly divided into three groups: Control, Trauma and Treatment groups. In Treatment group, magnesium sulfate was intraperitoneally administered immediately after the induction of brain trauma. At 24 h after trauma, total tissue water content and Na(+), K(+), Ca(2+), Mg(2+) contents were measured. Permeability of blood-brain barrier (BBB) was assessed quantitatively by Evans Blue (EB) dye technique. The pathological changes were also studied. Water, Na(+), Ca(2+) and EB contents in Treatment group were significantly lower than those in Trauma group (P<0.05). Results of light microscopy and electron microscopy confirmed that magnesium sulfate can attenuate traumatic brain injury and relieve BBB injury. Treatment with MgSO4 in the early stage can attenuate traumatic brain edema and prevent BBB injury.

  9. Effects of magnesium administration on brain edema and blood-brain barrier breakdown after experimental traumatic brain injury in rats.

    PubMed

    Esen, Figen; Erdem, Tulin; Aktan, Damla; Kalayci, Rivaze; Cakar, Nahit; Kaya, Mehmet; Telci, Lutfi

    2003-04-01

    In this study, we examined the effects of magnesium sulfate administration on brain edema and blood-brain barrier breakdown after experimental traumatic brain injury in rats. Seventy-one adult male Sprague-Dawley rats were anesthetized, and experimental closed head trauma was induced by allowing a 450-g weight to fall from a 2-m height onto a metallic disk fixed to the intact skull. Sixty-eight surviving rats were randomly assigned to receive an intraperitoneal bolus of either 750 micromol/kg magnesium sulfate (group 4; n = 30) or 1 mL of saline (group 2; n = 30) 30 minutes after induction of traumatic brain injury; 39 nontraumatized animals received saline (group 1; n = 21) or magnesium sulfate (group 3; n = 18) with an identical protocol of administration. Brain water content and brain tissue specific gravity, as indicators of brain edema, were measured 24 hours after traumatic brain injury. Blood-brain barrier integrity was evaluated quantitatively 24 hours after injury by spectrophotometric assay of Evans blue dye extravasations. In the magnesium-treated injured group, brain water content was significantly reduced (left hemisphere: group 2, 83.2 +/- 0.8; group 4, 78.4 +/- 0.7 [P <.05]; right hemisphere: group 2, 83.1 +/- 0.7; group 4, 78.4 +/- 0.5. [P <.05]) and brain tissue specific gravity was significantly increased (left hemisphere: group 2, 1.0391 +/- 0.0008; group 4, 1.0437 +/- 0.001 [P <.05]; right hemisphere, group 2, 1.0384 +/- 0.001; group 4, 1.0442 +/- 0.005 [P <.05]) compared with the saline-treated injured group. Evans blue dye content in the brain tissue was significantly decreased in the magnesium-treated injured group (left hemisphere: group 2, 0.0204 +/- 0.03; group 4, 0.0013 +/- 0.0002 [P <.05]; right hemisphere: group 2, 0.0064 +/- 0.0009; group 4, 0.0013 +/- 0.0003 [P <.05]) compared with the saline-treated injured group. The findings of the present study support that beneficial effects of magnesium sulfate exist after severe traumatic brain

  10. Perinatal manganese exposure and hydroxyl radical formation in rat brain.

    PubMed

    Bałasz, Michał; Szkilnik, Ryszard; Brus, Ryszard; Malinowska-Borowska, Jolanta; Kasperczyk, Sławomir; Nowak, Damian; Kostrzewa, Richard M; Nowak, Przemysław

    2015-01-01

    The present study was designed to investigate the role of pre- and postnatal manganese (Mn) exposure on hydroxyl radical (HO(•)) formation in the brains of dopamine (DA) partially denervated rats (Parkinsonian rats). Wistar rats were given tap water containing 10,000 ppm manganese chloride during the duration of pregnancy and until the time of weaning. Control rat dams consumed tap water without added Mn. Three days after birth, rats of both groups were treated with 6-hydroxydopamine at one of three doses (15, 30, or 67 µg, intraventricular on each side), or saline vehicle. We found that Mn content in the brain, kidney, liver, and bone was significantly elevated in dams exposed to Mn during pregnancy. In neonates, the major organs that accumulated Mn were the femoral bone and liver. However, Mn was not elevated in tissues in adulthood. To determine the possible effect on generation of the reactive species, HO(•) in Mn-induced neurotoxicity, we analyzed the contents of 2.3- and 2.5-dihydroxybenzoic acid (spin trap products of salicylate; HO(•) being an index of in vivo HO(•) generation), as well as antioxidant enzyme activities of superoxide dismutase (SOD) isoenzymes and glutathione S-transferase (GST). 6-OHDA-depletion of DA produced enhanced HO(•) formation in the brain tissue of newborn and adulthood rats that had been exposed to Mn, and the latter effect did not depend on the extent of DA denervation. Additionally, the extraneuronal, microdialysate, content of HO(•) in neostriatum was likewise elevated in 6-OHDA-lesioned rats. Interestingly, there was no difference in extraneuronal HO(•) formation in the neostriatum of Mn-exposed versus control rats. In summary, findings in this study indicate that Mn crosses the placenta but in contrast to other heavy metals, Mn is not deposited long term in tissues. Also, damage to the dopaminergic system acts as a "trigger mechanism," initiating a cascade of adverse events leading to a protracted increase in

  11. Reward cues in space: commonalities and differences in neural coding by hippocampal and ventral striatal ensembles.

    PubMed

    Lansink, Carien S; Jackson, Jadin C; Lankelma, Jan V; Ito, Rutsuko; Robbins, Trevor W; Everitt, Barry J; Pennartz, Cyriel M A

    2012-09-05

    Forming place-reward associations critically depends on the integrity of the hippocampal-ventral striatal system. The ventral striatum (VS) receives a strong hippocampal input conveying spatial-contextual information, but it is unclear how this structure integrates this information to invigorate reward-directed behavior. Neuronal ensembles in rat hippocampus (HC) and VS were simultaneously recorded during a conditioning task in which navigation depended on path integration. In contrast to HC, ventral striatal neurons showed low spatial selectivity, but rather coded behavioral task phases toward reaching goal sites. Outcome-predicting cues induced a remapping of firing patterns in the HC, consistent with its role in episodic memory. VS remapped in conjunction with the HC, indicating that remapping can take place in multiple brain regions engaged in the same task. Subsets of ventral striatal neurons showed a "flip" from high activity when cue lights were illuminated to low activity in intertrial intervals, or vice versa. The cues induced an increase in spatial information transmission and sparsity in both structures. These effects were paralleled by an enhanced temporal specificity of ensemble coding and a more accurate reconstruction of the animal's position from population firing patterns. Altogether, the results reveal strong differences in spatial processing between hippocampal area CA1 and VS, but indicate similarities in how discrete cues impact on this processing.

  12. Reward cues in space: commonalities and differences in neural coding by hippocampal and ventral striatal ensembles

    PubMed Central

    Lansink, Carien S.; Jackson, Jadin; Lankelma, Jan V.; Ito, Rutsuko; Robbins, Trevor W.; Everitt, Barry J.; Pennartz, Cyriel M.A.

    2012-01-01

    Forming place-reward associations critically depends on the integrity of the hippocampal-ventral striatal system. The ventral striatum receives a strong hippocampal input conveying spatial-contextual information, but it is unclear how this structure integrates this information to invigorate reward-directed behavior. Neuronal ensembles in rat hippocampus and ventral striatum were simultaneously recorded during a conditioning task in which navigation depended on path integration. In contrast to hippocampus, ventral striatal neurons showed low spatial selectivity, but rather coded behavioral task phases towards reaching goal sites. Outcome-predicting cues induced a remapping of firing patterns in the hippocampus, consistent with its role in episodic memory. Ventral striatum remapped in conjunction with the hippocampus, indicating that remapping can take place in multiple brain regions engaged in the same task. Subsets of ventral striatal neurons showed a “flip” from high activity when cue lights were illuminated to low activity in intertrial intervals, or vice versa. The cues induced an increase in spatial information transmission and sparsity in both structures. These effects were paralleled by an enhanced temporal specificity of ensemble coding and a more accurate reconstruction of the animal’s position from population firing patterns. Altogether, the results reveal strong differences in spatial processing between hippocampal area CA1 and ventral striatum, but indicate similarities in how discrete cues impact on this processing. PMID:22956836

  13. Prenatal ethanol exposure increases brain cholesterol content in adult rats.

    PubMed

    Barceló-Coblijn, Gwendolyn; Wold, Loren E; Ren, Jun; Murphy, Eric J

    2013-11-01

    Fetal alcohol syndrome is the most severe expression of the fetal alcohol spectrum disorders (FASD). Although alterations in fetal and neonate brain fatty acid composition and cholesterol content are known to occur in animal models of FASD, the persistence of these alterations into adulthood is unknown. To address this question, we determined the effect of prenatal ethanol exposure on individual phospholipid class fatty acid composition, individual phospholipid class mass, and cholesterol mass in brains from 25-week-old rats that were exposed to ethanol during gestation beginning at gestational day 2. While total phospholipid mass was unaffected, phosphatidylinositol and cardiolipin mass was decreased 14 and 43 %, respectively. Exposure to prenatal ethanol modestly altered brain phospholipid fatty acid composition, and the most consistent change was a significant 1.1-fold increase in total polyunsaturated fatty acids (PUFA), in the n-3/n-6 ratio, and in the 22:6n-3 content in ethanolamine glycerophospholipids and in phosphatidylserine. In contrast, prenatal ethanol consumption significantly increased brain cholesterol mass 1.4-fold and the phospholipid to cholesterol ratio was significantly increased 1.3-fold. These results indicate that brain cholesterol mass was significantly increased in adult rats exposed prenatally to ethanol, but changes in phospholipid mass and phospholipid fatty acid composition were extremely limited. Importantly, suppression of postnatal ethanol consumption was not sufficient to reverse the large increase in cholesterol observed in the adult rats.

  14. Inducible Gene Manipulations in Brain Serotonergic Neurons of Transgenic Rats

    PubMed Central

    Tews, Björn; Bartsch, Dusan

    2011-01-01

    The serotonergic (5-HT) system has been implicated in various physiological processes and neuropsychiatric disorders, but in many aspects its role in normal and pathologic brain function is still unclear. One reason for this might be the lack of appropriate animal models which can address the complexity of physiological and pathophysiological 5-HT functioning. In this respect, rats offer many advantages over mice as they have been the animal of choice for sophisticated neurophysiological and behavioral studies. However, only recently technologies for the targeted and tissue specific modification of rat genes - a prerequisite for a detailed study of the 5-HT system - have been successfully developed. Here, we describe a rat transgenic system for inducible gene manipulations in 5-HT neurons. We generated a Cre driver line consisting of a tamoxifen-inducible CreERT2 recombinase under the control of mouse Tph2 regulatory sequences. Tissue-specific serotonergic Cre recombinase expression was detected in four transgenic TPH2-CreERT2 rat founder lines. For functional analysis of Cre-mediated recombination, we used a rat Cre reporter line (CAG-loxP.EGFP), in which EGFP is expressed after Cre-mediated removal of a loxP-flanked lacZ STOP cassette. We show an in-depth characterisation of this rat Cre reporter line and demonstrate its applicability for monitoring Cre-mediated recombination in all major neuronal subpopulations of the rat brain. Upon tamoxifen induction, double transgenic TPH2-CreERT2/CAG-loxP.EGFP rats show selective and efficient EGFP expression in 5-HT neurons. Without tamoxifen administration, EGFP is only expressed in few 5-HT neurons which confirms minimal background recombination. This 5-HT neuron specific CreERT2 line allows Cre-mediated, inducible gene deletion or gene overexpression in transgenic rats which provides new opportunities to decipher the complex functions of the mammalian serotonergic system. PMID:22140568

  15. Age-dependence of malonate-induced striatal toxicity.

    PubMed

    Meldrum, A; Page, K J; Everitt, B J; Dunnett, S B

    2000-10-01

    Malonate is an inhibitor of cellular metabolism, which, following intrastriatal injection, induces a striatal pathology similar to that seen in Huntington's disease. In two parallel studies, we have investigated the suggested relationship between the neuronal vulnerability to metabolic toxicity and the decline in metabolic function with increasing age. The first experiment investigated malonate-induced neuronal loss in animals aged from 6 weeks up to 27 months, and the second assessed the activities of two mitochondrial enzymes, succinate dehydrogenase and cytochrome oxidase (CYTOX) in animals aged 6 weeks, 3, 8 and 18 months. In the first study, male Lister-Hooded rats received intrastriatal stereotaxic injections of malonate (0.5 or 1.0 M). Animals were killed 10 days after surgery, and the brains were stained with cresyl violet and processed for NADPH-diaphorase activity and glial fibrillary-acidic-protein (GFAP) immunohistochemistry. Animals aged 6 months and older exhibited over 60% striatal neuronal loss. However, the degree of neuronal loss did not show any age-related increase in rats between 6 and 27 months of age, indicating that the extent of malonate-induced toxicity does not increase with age in animals older than 6 months. Infusion of 0.5 M malonate produced smaller lesions, which also demonstrated a consistent extent of neuronal loss from 6 months onwards. Metabolic enzyme activities were decreased in the striatum with increasing age, although this effect was only significant for CYTOX activity. Thus, the pattern of malonate-induced neuronal loss in aged animals partially reflects the changes in metabolic activity during ageing.

  16. Enzyme markers of maternal malnutrition in fetal rat brain.

    PubMed

    Shambaugh, G E; Mankad, B; Derecho, M L; Koehler, R R

    1987-01-01

    The impact of maternal starvation in late gestation on development of some enzymatic mechanisms concerned with neurotransmission and polyamine synthesis was studied in fetal rat brain. Between 17 and 20 d, acetylcholinesterase and choline acetyltransferase activity increased in fetal brains of fed dams, whereas maternal starvation from day 17 to day 20 resulted in heightened acetylcholinesterase but not choline acetyltransferase activity. Ornithine decarboxylase activity on a per-gram wet-weight basis fell between 17 and 20 d in fetal brain from fed dams. Increasing the duration of maternal starvation resulted in a progressive increase in fetal brain ornithine decarboxylase. Arginine and putrescine levels in the brain were lower in fetuses of starved mothers while spermidine and spermine concentrations were unchanged. Since the Km of ornithine decarboxylase for ornithine was found to vary directly with levels of putrescine in fetal brain, lower concentrations of putrescine and greater ornithine decarboxylase activity in fetal brains from starved mothers suggested that levels of this enzyme may be controlled in part by putrescine. Changes in the maternal nutritional state had no effect on the activity of glutamate decarboxylase in fetal brain, and tissue levels of the product, gamma-aminobutyric acid, were unchanged. Thus changes in ornithine decarboxylase and acetylcholinesterase activity in fetal brain may uniquely reflect biochemical alterations consequent to maternal starvation.

  17. Anesthesia-induced neurodegeneration in fetal rat brains

    PubMed Central

    Wang, Shouping; Peretich, Kelly; Zhao, Yifan; Liang, Ge; Meng, Qingcheng; Wei, Huafeng

    2011-01-01

    Summary We investigated the extent of isoflurane induced neurodegeneration on the fetuses of pregnant rats exposed in utero. Pregnant rats at gestational day 21 were divided into three experimental groups. Rats in the control group spontaneously breathed 100% oxygen for one hour. Rats in the treatment groups breathed either 1.3% or 3% isoflurane in 100% oxygen through an endotracheal tube with mechanical ventilation for one hour. Rat pups were delivered by Caesarian section six hours after treatment and fetal blood was sampled from the left ventricle of each fetal heart and evaluated for S100β. Fetal brains were then evaluated for apoptosis using caspase-3 immunohistochemistry in the CA1 region of the hippocampus and the retrosplenial cortex (RS). The 3% isoflurane treatment group showed significantly higher levels of S100β levels and significantly increased average densities of total caspase-3 positive cells in the CA1 hippocampus and RS cortex as compared to the control and 1.3% isoflurane groups. There were no differences in S100β levels or densities of caspase-3 positive cells between the control and 1.3% isoflurane groups. Isoflurane at a concentration of 3% for one hour increased neurodegeneration in the hippocampal CA1 area and the retrosplenial cortex in the developing brain of fetal rats. PMID:20016413

  18. Inadequate Antioxidative Responses in Kidneys of Brain-Dead Rats.

    PubMed

    Hoeksma, Dane; Rebolledo, Rolando A; Hottenrott, Maximilia; Bodar, Yves S; Wiersema-Buist, Janneke J; Van Goor, Harry; Leuvenink, Henri G D

    2017-04-01

    Brain death (BD)-related lipid peroxidation, measured as serum malondialdehyde (MDA) levels, correlates with delayed graft function in renal transplant recipients. How BD affects lipid peroxidation is not known. The extent of BD-induced organ damage is influenced by the speed at which intracranial pressure increases. To determine possible underlying causes of lipid peroxidation, we investigated the renal redox balance by assessing oxidative and antioxidative processes in kidneys of brain-dead rats after fast and slow BD induction. Brain death was induced in 64 ventilated male Fisher rats by inflating a 4.0F Fogarty catheter in the epidural space. Fast and slow inductions were achieved by an inflation speed of 0.45 and 0.015 mL/min, respectively, until BD confirmation. Healthy non-brain-dead rats served as reference values. Brain-dead rats were monitored for 0.5, 1, 2, or 4 hours, after which organs and blood were collected. Increased MDA levels became evident at 2 hours of slow BD induction at which increased superoxide levels, decreased glutathione peroxidase (GPx) activity, decreased glutathione levels, increased inducible nitric oxide synthase and heme-oxygenase 1 expression, and increased plasma creatinine levels were evident. At 4 hours after slow BD induction, superoxide, MDA, and plasma creatinine levels increased further, whereas GPx activity remained decreased. Increased MDA and plasma creatinine levels also became evident after 4 hours fast BD induction. Brain death leads to increased superoxide production, decreased GPx activity, decreased glutathione levels, increased inducible nitric oxide synthase and heme-oxygenase 1 expression, and increased MDA and plasma creatinine levels. These effects were more pronounced after slow BD induction. Modulation of these processes could lead to decreased incidence of delayed graft function.

  19. Pharmacological modulation of blood-brain barrier increases permeability of doxorubicin into the rat brain.

    PubMed

    Sardi, Iacopo; la Marca, Giancarlo; Cardellicchio, Stefania; Giunti, Laura; Malvagia, Sabrina; Genitori, Lorenzo; Massimino, Maura; de Martino, Maurizio; Giovannini, Maria G

    2013-01-01

    Our group recently demonstrated in a rat model that pretreatment with morphine facilitates doxorubicin delivery to the brain in the absence of signs of increased acute systemic toxicity. Morphine and other drugs such as dexamethasone or ondansetron seem to inhibit MDR proteins localized on blood-brain barrier, neurons and glial cells increasing the access of doxorubicin to the brain by efflux transporters competition. We explored the feasibility of active modification of the blood-brain barrier protection, by using morphine dexamethasone or ondansetron pretreatment, to allow doxorubicin accumulation into the brain in a rodent model. Rats were pretreated with morphine (10 mg/kg, i.p.), dexamethasone (2 mg/kg, i.p.) or ondansetron (2 mg/kg, i.p.) before injection of doxorubicin (12 mg/kg, i.p.). Quantitative analysis of doxorubicin was performed by mass spectrometry. Acute hearth and kidney damage was analyzed by measuring doxorubicin accumulation, LDH activity and malondialdehyde plasma levels. The concentration of doxorubicin was significantly higher in all brain areas of rats pretreated with morphine (P < 0.001) or ondansetron (P < 0.05) than in control tissues. The concentration of doxorubicin was significantly higher in cerebral hemispheres and brainstem (P < 0.05) but not in cerebellum of rats pretreated with dexamethasone than in control tissues. Pretreatment with any of these drugs did not increase LDH activity or lipid peroxidation compared to controls. Our data suggest that morphine, dexamethasone or ondansetron pretreatment is able to allow doxorubicin penetration inside the brain by modulating the BBB. This effect is not associated with acute cardiac or renal toxicity. This finding might provide the rationale for clinical applications in the treatment of refractory brain tumors and pave the way to novel applications of active but currently inapplicable chemotherapeutic drugs.

  20. Sex matters: repetitive mild traumatic brain injury in adolescent rats.

    PubMed

    Wright, David K; O'Brien, Terence J; Shultz, Sandy R; Mychasiuk, Richelle

    2017-09-01

    Whether sex differences contribute to the heterogeneity of mild traumatic brain injury (mTBI) and repeated mTBI (RmTBI) outcomes in adolescents is unknown. Therefore, this study examined changes in, and differences between, male and female rats following single mTBI and RmTBI. Rats were given a single mTBI, RmTBI (i.e., 3x), or sham injuries. Injuries were administered using a lateral impact model that mimics forces common in human mTBI. After the final injury, rats underwent extensive behavioral testing to examine cognition, motor function, and anxiety- and depressive-like behavior. Postmortem analyses investigated gene expression and structural changes in the brain. Many of the outcomes exhibited a sex-dependent response to RmTBI. While all rats given RmTBI had deficits in balance, motor coordination, locomotion, and anxiety-like behavior, only male rats given RmTBI had short-term working memory deficits, whereas only females given RmTBI had increased depressive-like behavior. Volumetric and diffusion weighted MRI analyses found that while RmTBI-induced atrophy of the prefrontal cortex was greater in female rats, only the male rats exhibited worse white matter integrity in the corpus callosum following RmTBI. Sex-dependent changes in brain expression of mRNA for glial fibrillary acidic protein, myelin basic protein, and tau protein were also observed following injury. These findings suggest that in adolescent mTBI, sex matters; and future studies incorporating both male and females are warranted to provide a greater understanding of injury prognosis and better inform clinical practice.

  1. Rat umbilical cord blood cells attenuate hypoxic–ischemic brain injury in neonatal rats

    PubMed Central

    Nakanishi, Keiko; Sato, Yoshiaki; Mizutani, Yuka; Ito, Miharu; Hirakawa, Akihiro; Higashi, Yujiro

    2017-01-01

    Increasing evidence has suggested that human umbilical cord blood cells (hUCBC) have a favorable effect on hypoxic–ischemic (HI) brain injury. However, the efficacy of using hUCBCs to treat this injury has been variable and the underlying mechanism remains elusive. Here, we investigated its effectiveness using stereological analysis in an allogeneic system to examine whether intraperitoneal injection of cells derived from UCBCs of green fluorescent protein (GFP)-transgenic rats could ameliorate brain injury in neonatal rats. Three weeks after the HI event, the estimated residual brain volume was larger and motor function improved more in the cell-injected rats than in the control (PBS-treated) rats. The GFP-positive cells were hardly detectable in the brain (0.0057% of injected cells) 9 days after injection. Although 60% of GFP-positive cells in the brain were Iba1-positive, none of these were positive for NeuroD or DCX. While the number of proliferating cells increased in the hippocampus, that of activated microglia/macrophages decreased and a proportion of M2 microglia/macrophages increased in the ipsilateral hemisphere of cell-injected rats. These results suggest that intraperitoneal injection of cells derived from UCBCs could ameliorate HI injury, possibly through an endogenous response and not by supplying differentiated neurons derived from the injected stem cells. PMID:28281676

  2. Effects of environmental tobacco smoke on adult rat brain biochemistry.

    PubMed

    Fuller, Brian F; Gold, Mark S; Wang, Kevin K W; Ottens, Andrew K

    2010-05-01

    Environmental tobacco smoke (ETS) has been linked to deleterious health effects, particularly pulmonary and cardiac disease; yet, the general public considers ETS benign to brain function in adults. In contrast, epidemiological data have suggested that ETS impacts the brain and potentially modulates neurodegenerative disease. The present study begins to examine yet unknown biochemical effects of ETS on the adult mammalian brain. In the developed animal model, adult male rats were exposed to ETS 3 h a day for 3 weeks. Biochemical data showed altered glial fibrillary acid protein levels as a main treatment effect of ETS, suggestive of reactive astrogliosis. Yet, markers of oxidative and cell stress were unaffected by ETS exposure in the brain regions examined. Increased proteolytic degradation of alphaII-spectrin by caspase-3 and the dephosphorylation of serine(116) on PEA-15 indicated greater apoptotic cell death modulated by the extrinsic pathway in the brains of ETS-exposed animals. Further, beta-synuclein was upregulated by ETS, a neuroprotective protein previously reported to exhibit anti-apoptotic and anti-fibrillogenic properties. These findings demonstrate that ETS exposure alters the neuroproteome of the adult rat brain, and suggest modulation of inflammatory and cell death processes.

  3. [Effect of oxythiamine and pyrithiamine on rat brain--morphological changes in the thiamine deficient rat brain (author's transl)].

    PubMed

    Oguchi, E; Okazaki, M; Hobara, R; Toyoshima, Y; Sakamoto, K

    1978-11-01

    We observed under light and electron microscopes morphological changes in the brains of rats in a thiamine deficient state as induced by an oxythiamine, pyrithiamine and thiamine deficient diet (OT, PT and TDD). We simultaneously determined thiamine levels in the whole brain of rats. The rats were separated into six groups-normal control, OT or PT treated rats (OT or PT group), OT or PT treated rats fed a TDD (OTD or PTD group), rats fed a TDD (TDD group)-. Microscopically, there were symmetrically distributed lesions containing spongy reticulation mainly in the vestibular nucleus. Electron microscopically, we found more advanced lesions in the OTD and PTD groups than in the TDD group. These ultrastructural changes were seen in the vicinity of capillaries and such consisted of abnormal endothelial cells and pericytes, excrescence of microglias, swelling or vacuolation of astrocytes, nerve cells containing distorted organelle and myelin degeneration, besides extracellular edema. The thiamine level in the TDD group decreased to 56% that of control. No effect of OT on the thiamine level was observed either in case of ingestion of a regular diet or when TDD was given. On the other hand, the thiamine level decreased to 43% in the PT group and to 17-23 in PTD. These results suggest that encephalopathy caused by the OT or PT-induced thiamine deficiency has the same selective vulnerable site as does the TDD-induced deficiency, however cellular sensitivity may differ slightly with the various ultrastructural changes.

  4. Rapamycin suppresses brain aging in senescence-accelerated OXYS rats.

    PubMed

    Kolosova, Nataliya G; Vitovtov, Anton O; Muraleva, Natalia A; Akulov, Andrey E; Stefanova, Natalia A; Blagosklonny, Mikhail V

    2013-06-01

    Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span inC elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wister rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging.

  5. Simultaneous quantification of nicotine and metabolites in rat brain by liquid chromatography-tandem mass spectrometry.

    PubMed

    Vieira-Brock, Paula L; Miller, Eleanor I; Nielsen, Shannon M; Fleckenstein, Annette E; Wilkins, Diana G

    2011-11-15

    A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of nicotine (NIC), cotinine (COT), nornicotine (NNIC), norcotinine (NCOT), nicotine-N-β-D-glucuronide (NIC GLUC), cotinine-N-β-D-glucuronide (COT GLUC), nicotine-1'-oxide (NNO), cotinine-N-oxide (CNO), trans-3'-hydroxycotinine (3-HC), anabasine (AB) and anatabine (AT) was modified and validated for quantification of these selected analytes in rat brain tissue. This analytical method provides support for preclinical NIC pharmacokinetic and toxicological studies after controlled dosing protocols. After brain homogenization and solid-phase extraction, target analytes and corresponding deuterated internal standards were chromatographically separated on a Discovery(®) HS F5 HPLC column with gradient elution and analyzed by LC-MS/MS in positive electrospray ionization (ESI) mode with multiple reaction monitoring (MRM) data acquisition. Method linearity was assessed and calibration curves were determined over the following ranges: 0.1-7.5 ng/mg for NIC, COT GLUC and AB; and 0.025-7.5 ng/mg for COT, NNIC, NCOT, NIC GLUC, NNO, CNO, 3-HC and AT (R(2)≥0.99 for all analytes). Extraction recoveries ranged from 64% to 115%, LC-MS/MS matrix effects were ≤21%, and overall process efficiency ranged from 57% to 93% at low and high quality control concentrations. Intra- and inter-assay imprecisions and accuracy for all analytes were ≤12.9% and ≥86%, respectively. The method was successfully applied to quantification of NIC and metabolites in the brain of post-natal day 90 rats that were sacrificed 2-h after a single 0.8 mg/kg s.c. administration of (-)NIC. In these tissues, striatal concentrations were 204.8±49.4, 138.2±14.2 and 36.1±6.1 pg/mg of NIC, COT and NNIC, respectively. Concentrations of NIC, COT and NNIC in the remaining whole brain (RWhB) were 183.3±68.0, 130.0±14.1 and 46.7±10.3 pg/mg, respectively. Quantification of these same analytes in plasma was also

  6. Magnetic resonance imaging as a tool to image neuroinflammation in a rat model of Parkinson's disease--phagocyte influx to the brain is promoted by bilberry-enriched diet.

    PubMed

    Virel, Ana; Rehnmark, Anna; Orädd, Greger; Olmedo-Díaz, Sonia; Faergemann, Erik; Strömberg, Ingrid

    2015-11-01

    Neuroinflammation is a chronic event in neurodegenerative disorders. In the rat model of Parkinson's disease, including a striatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA), antioxidant treatment affects the inflammatory process. Despite a heavy accumulation of microglia early after the injury, dopamine nerve fibre regeneration occurs. It remains unclear why this heavy accumulation of microglia is found early after the lesion in antioxidant-treated animals, or even more, what is the origin of these microglia. In this study magnetic resonance imaging (MRI) was used to elucidate whether the inflammatory response was generated from the blood or from activated brain microglia. Superparamagnetic iron oxide (SPIO) nanoparticles were injected intravenously prior to a striatal 6-OHDA injection to tag phagocytes in the blood. Rats were fed either with bilberry-enriched or control diet. T2*-weighted MRI scans were performed 1 week after the lesion, and hypointense areas were calculated from T2*-weighted images, to monitor the presence of SPIO particles. The results revealed that feeding the animals with bilberries significantly promoted accumulation of blood-derived immune cells. Gadolinium-enhanced MRI demonstrated no difference in leakage of the blood-brain barrier independent of diets. To conclude, bilberry-enriched diet promotes an influx of periphery-derived immune cells to the brain early after injury.

  7. Human and rat brain lipofuscin proteome

    USDA-ARS?s Scientific Manuscript database

    The accumulation of an autofluorescent pigment called lipofuscin in neurons is an invariable hallmark of brain aging. So far, this material has been considered to be waste material without particular relevance for cellular pathology. However, two lines of evidence argue that lipofuscin may have yet ...

  8. Alterations of amino Acid level in depressed rat brain.

    PubMed

    Yang, Pei; Li, Xuechun; Ni, Jian; Tian, Jingchen; Jing, Fu; Qu, Changhai; Lin, Longfei; Zhang, Hui

    2014-10-01

    Amino-acid neurotransmitter system dysfunction plays a major role in the pathophysiology of depression. Several studies have demonstrated the potential of amino acids as a source of neuro-specific biomarkers could be used in future diagnosis of depression. Only partial amino acids such as glycine and asparagine were determined from certain parts of rats' brain included hippocampi and cerebral cortex in previous studies. However, according to systematic biology, amino acids in different area of brain are interacted and interrelated. Hence, the determination of 34 amino acids through entire rats' brain was conducted in this study in order to demonstrate more possibilities for biomarkers of depression by discovering other potential amino acids in more areas of rats' brain. As a result, 4 amino acids (L-aspartic acid, L-glutamine, taurine and γ-amino-n-butyric acid) among 34 were typically identified as potentially primary biomarkers of depression by data statistics. Meanwhile, an antidepressant called Fluoxetine was employed to verify other potential amino acids which were not identified by data statistics. Eventually, we found L-α-amino-adipic acid could also become a new potentially secondary biomarker of depression after drug validation. In conclusion, we suggested that L-aspartic acid, L-glutamine, taurine, γ-amino-n-butyric acid and L-α-amino-adipic acid might become potential biomarkers for future diagnosis of depression and development of antidepressant.

  9. Alcohol induced changes in phosphoinositide signaling system in rat brain

    SciTech Connect

    Pandey, S.; Piano, M.; Schwertz, D.; Davis, J.; Pandey, G. )

    1991-03-11

    Agonist-induced phosphoinositide break down functions as a signal generating system in a manner similar to the C-AMP system. In order to examine if the changes produced by chronic ethanol treatment on membrane lipid composition and metabolism effect the cellular functions of the neuron, the authors have examined the effect of chronic ethanol exposure on norepinephrine (NE) serotonin (5HT) and calcium ionophore (CI) stimulated phosphoinositide (PI) hydrolysis in rat cortical slices. Rats were maintained on liber-decarli diet alcohol and control liquid diet containing isocaloric sucrose substitute for two months. They were then sacrificed and brain was removed for determination of PI turnover. 5HT stimulated {sup 3}H- inositol monophosphate ({sup 3}H-IPI) formation was significantly lower in the cortex of alcohol treated rats as compared to control rats. However, neither CI nor NE stimulated IP1 formation was significantly different from control rats. The results thus indicate that chronic exposure to ethanol decreases 5HT induced PI breakdown in rat cortex. In order to examine if this decrease is related to a decrease in 5HT2 receptors, or decreased in coupling of receptor to the effector pathway, the authors are currently determining the number and affinity of 5HT2 receptors in alcohol treated rats.

  10. The effect of striatal dopamine depletion on striatal and cortical glutamate: A mini-review

    PubMed Central

    Caravaggio, Fernando; Nakajima, Shinichiro; Plitman, Eric; Gerretsen, Philip; Chung, Jun Ku; Iwata, Yusuke; Graff-Guerrero, Ariel

    2017-01-01

    Understanding the interplay between the neurotransmitters dopamine and glutamate in the striatum has become the highlight of several theories of neuropsychiatric illnesses, such as schizophrenia. Using in vivo brain imaging in humans, alterations in dopamine and glutamate concentrations have been observed in several neuropsychiatric disorders. However, it is unclear a priori how alterations in striatal dopamine should modulate glutamate concentrations in the basal ganglia. In this selective mini-review, we examine the consequence of reducing striatal dopamine functioning on glutamate concentrations in the striatum and cortex; regions of interest heavily examined in the human brain imaging studies. We examine the predictions of the classical model of the basal ganglia, and contrast it with findings in humans and animals. The review concludes that chronic dopamine depletion (>4 months) produces decreases in striatal glutamate levels which are consistent with the classical model of the basal ganglia. However, acute alterations in striatal dopamine functioning, specifically at the D2 receptors, may produce opposite affects. This has important implications for models of the basal ganglia and theorizing about neurochemical alterations in neuropsychiatric diseases. Moreover, these findings may help guide a priori hypotheses for 1H-MRS studies measuring glutamate changes given alterations in dopaminergic functioning in humans. PMID:26334687

  11. Pituitary and brain D2 receptor density measured in vitro and in vivo in EEDQ treated male rats

    SciTech Connect

    Ekman, A.; Eriksson, E. )

    1991-01-01

    The effect of the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on dopamine D2 receptor density in rat pituitary and brain was measured using in vitro and in vivo radioligand binding techniques. In the in vitro radioligand binding experiments EEDQ was found to reduce the density (B{sub max}) of ({sup 3}H)-spiperone binding sites in the striatum by 86% while in the pituitary the corresponding decrease was only 37%. The affinity (K{sub D}) of the remaining striatal and pituitary D2 receptors was not different in EEDQ treated animals as compared to controls. When D2 receptor density was measured in vivo the effect of EEDQ was less pronounced. Thus, in rats given EEDQ the specific binding of either of the two D2 ligands ({sup 3}H)-raclopride or ({sup 3}H)-spiperone in striatum and in the limbic forebrain was reduced by 45-62%; moreover, no significant decrease in pituitary D2 receptor density was observed. The data are discussed in relation to the finding that the same dose of EEDQ that failed to influence pituitary D2 receptor density as measured in vivo effectively antagonizes the prolactin decreasing effect of the partial D2 agonist (-)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine ((-)-3-PPP).

  12. Suppressed Fat Appetite after Roux-en-Y Gastric Bypass Surgery Associates with Reduced Brain μ-opioid Receptor Availability in Diet-Induced Obese Male Rats.

    PubMed

    Hankir, Mohammed K; Patt, Marianne; Patt, Jörg T W; Becker, Georg A; Rullmann, Michael; Kranz, Mathias; Deuther-Conrad, Winnie; Schischke, Kristin; Seyfried, Florian; Brust, Peter; Hesse, Swen; Sabri, Osama; Krügel, Ute; Fenske, Wiebke K

    2016-01-01

    Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [(11)C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [(11)C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.

  13. Suppressed Fat Appetite after Roux-en-Y Gastric Bypass Surgery Associates with Reduced Brain μ-opioid Receptor Availability in Diet-Induced Obese Male Rats

    PubMed Central

    Hankir, Mohammed K.; Patt, Marianne; Patt, Jörg T. W.; Becker, Georg A.; Rullmann, Michael; Kranz, Mathias; Deuther-Conrad, Winnie; Schischke, Kristin; Seyfried, Florian; Brust, Peter; Hesse, Swen; Sabri, Osama; Krügel, Ute; Fenske, Wiebke K.

    2017-01-01

    Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [11C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [11C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting. PMID:28133443

  14. Neuropharmacological characterization of voltage-sensitive calcium channels: possible existence of neomycin-sensitive, omega-conotoxin GVIA- and dihydropyridines-resistant calcium channels in the rat brain.

    PubMed

    Yamada, K; Teraoka, T; Morita, S; Hasegawa, T; Nabeshima, T

    1993-12-01

    We attempted to characterize the functional roles of subtypes of voltage-sensitive calcium channels in the brain. The maximal number of [125I]omega-conotoxin GVIA (omega-CTX) binding sites in rat brain associated with N-type calcium channels (N-channels) was approximately 10 times more than that of [3H]-PN200-110 associated with L-type calcium channels (L-channels). [125I]omega-CTX binding was inhibited by aminoglycoside antibiotics, neomycin and dynorphin A(1-13), but not by various classes of L-channel antagonists. A 6-hydroxydopamine-induced lesion of the striatum resulted in a marked reduction of both [125I]-omega-CTX and [3H]PN200-110 binding. Kainic acid-induced lesion of the striatum reduced [3H]PN200-110 binding by 57%, but did not reduce [125I]omega-CTX binding. Omega-CTX produced a small (18%) but significant reduction of potassium-stimulated Ca2+ influx into rat brain synaptosomes, although it produced a concentration-dependent inhibition in chick brain synaptosomes. Neomycin inhibited Ca2+ influx in both preparations in a concentration-dependent manner. Both omega-CTX and neomycin inhibited potassium-stimulated [3H]dopamine (DA) release from rat striatal slices. The L-channel antagonists had no effect on either Ca2+ influx or [3H]DA release. These results suggest that DA release in the striatum is regulated by Ca2+ influx through N-channels located in presynaptic nerve terminals, and that the most of the Ca2+ influx in rat brain appears to be governed by neomycin-sensitive, omega-CTX- and DHP-resistant calcium channels.

  15. Effect of acute thioacetamide administration on rat brain phospholipid metabolism

    SciTech Connect

    Osada, J.; Aylagas, H.; Miro-Obradors, M.J.; Arce, C.; Palacios-Alaiz, E.; Cascales, M. )

    1990-09-01

    Brain phospholipid composition and the ({sup 32}P)orthophosphate incorporation into brain phospholipids of control and rats treated for 3 days with thioacetamide were studied. Brain phospholipid content, phosphatidylcholine, phosphatidylethanolamine, lysolecithin and phosphatidic acid did not show any significant change by the effect of thioacetamide. In contrast, thioacetamide induced a significant decrease in the levels of phosphatidylserine, sphingomyelin, phosphatidylinositol and diphosphatidylglycerol. After 75 minutes of intraperitoneal label injection, specific radioactivity of all the above phospholipids with the exception of phosphatidylethanolamine and phosphatidylcholine significantly increased. After 13 hours of isotope administration the specific radioactivity of almost all studied phospholipid classes was elevated, except for phosphatidic acid, the specific radioactivity of which did not change and for diphosphatidylglycerol which showed a decrease in specific radioactivity. These results suggest that under thioacetamide treatment brain phospholipids undergo metabolic transformations that may contribute to the hepatic encephalopathy induced by thioacetamide.