Dysregulation of gene induction in corticostriatal circuits after repeated methylphenidate treatment in adolescent rats: differential effects on zif 268 and homer 1a

Psychostimulants and other dopamine agonists produce molecular changes in neurons of cortico-basal ganglia-cortical circuits, and such neuronal changes are implicated in behavioural disorders. Methylphenidate, a psychostimulant that causes dopamine overflow (among other effects), alters gene regulation in neurons of the striatum. The present study compared the effects of acute and repeated methylphenidate treatment on cortical and striatal gene regulation in adolescent rats. Changes in the expression of the immediate-early genes zif 268 and homer 1a were mapped in 23 striatal sectors and 22 cortical areas that provide input to these striatal sectors, in order to determine whether specific corticostriatal circuits were affected by these treatments. Acute administration of methylphenidate (5 mg/kg, i.p.) produced modest zif 268 induction in cortical areas. These cortical zif 268 responses were correlated in magnitude with zif 268 induction in functionally related striatal sectors. In contrast, after repeated methylphenidate treatment (10 mg/kg, 7 days), cortical and striatal gene induction were dissociated. In these animals, the methylphenidate challenge (5 mg/kg) produced significantly greater gene induction (zif 268 and homer 1a) in the cortex. This enhanced response was widespread but regionally selective, as it occurred predominantly in premotor, motor and somatosensory cortical areas. At the same time, striatal gene induction was partly suppressed (zif 268) or unchanged (homer 1a). Thus, repeated methylphenidate treatment disrupted the normally coordinated gene activation patterns in cortical and striatal nodes of corticostriatal circuits. This drug-induced dissociation in cortical and striatal functioning was associated with enhanced levels of behavioural stereotypies, suggesting disrupted motor switching function.     

Repeated methylphenidate treatment in adolescent rats alters gene regulation in the striatum

Methylphenidate is a psychostimulant which inhibits the dopamine transporter and produces dopamine overflow in the striatum, similar to the effects of cocaine. Excessive dopamine action is often associated with changes in gene expression in dopamine-receptive neurons. Little is known about methylphenidate's effects on gene regulation. We investigated whether a methylphenidate treatment regimen known to produce behavioural changes would alter gene expression in the striatum. Using in situ hybridization histochemistry, we assessed the effects of acute and repeated methylphenidate treatment on the expression of immediate-early genes (c-fos, zif 268) and neuropeptides (dynorphin, substance P, enkephalin) in adolescent rats. Acute methylphenidate treatment (0-10 mg/kg, i.p.) produced a dose-dependent increase in the expression of c-fos and zif 268. These effects were most pronounced in the dorsal striatum at middle to caudal striatal levels, and were found for doses as low as 2 mg/kg. Repeated treatment with methylphenidate (10 mg/kg/day, 7 days) increased the expression of dynorphin, which was highly correlated with the acute immediate-early gene response across different striatal regions. Moreover, after repeated methylphenidate treatment, cocaine-induced expression of c-fos and zif 268, as well as of substance P, was significantly attenuated throughout the striatum. These effects of repeated methylphenidate treatment mirror those produced by repeated treatment with cocaine or other psychostimulants and are considered to reflect drug-induced neuroadaptations. Thus, our findings demonstrate that acute and repeated methylphenidate treatment can produce molecular alterations similar to other psychostimulants.     

Cocaine-induced locomotor activity and Fos expression in nucleus accumbens are sensitized for 6 months after repeated cocaine administration outside the home cage

Induction of the immediate early gene protein product Fos has been used extensively to assess neural activation in the striatum after repeated cocaine administration to rats in their home cages but rarely after repeated administration outside the home cage, which produces more robust locomotor sensitization. In the present study, we found cocaine-induced Fos expression in nucleus accumbens, but not caudate-putamen, was enhanced 1 and 6 months after repeated drug administration in locomotor activity chambers. Double-labelling of Fos protein and enkephalin mRNA indicated that Fos expression in nucleus accumbens was enhanced in enkephalin-positive, but not enkephalin-negative, medium spiny neurons. In contrast, cocaine-induced Fos expression was absent altogether in nucleus accumbens and unaltered in caudate-putamen 1 month after repeated cocaine administration in the home cage. As cocaine-induced locomotor activity was also enhanced 1 and 6 months after repeated cocaine administration in locomotor activity chambers, we wanted to confirm that neuronal activity in nucleus accumbens mediates cocaine-induced locomotor activity using our particular treatment regimen. Bilateral infusions of the GABA agonists baclofen and muscimol (1 microg/side) into nucleus accumbens of sensitized rats blocked cocaine-induced Fos expression and locomotor activity. Thus, while neuronal activity in both D1- and D2-type neurons in nucleus accumbens can mediate acute cocaine-induced locomotor activity, the enhanced activation of enkephalinergic D2-type neurons suggests that these latter neurons mediate the enhancement of cocaine-induced locomotor activity for up to 6 months after repeated drug administration outside the home cage.     

Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease

Summary The dopaminergic innervation of the prefrontal cortex is able to transsynaptically regulate the activity of subcortical dopamine innervations. Disruption of the prefrontal cortical DA innervation results in the enhanced biochemical responsiveness of the dopamine innervation of the nucleus accumbens. We present recent data indicating that distinct prefrontal cortical dopamine innervations can be functionally dissociated on the basis of responsiveness to stress. The ventral striatal projection target (nucleus accumbens shell) of the prefrontal cortical region that is stress sensitive is also responsive to stress. In this manner interconnected cortico-striato-pallido-mesencephalic loops can be defined on the basis of the biochemical responsive of local dopamine systems to stress and on the basis of responsiveness to antipsychotic drugs. These data suggest the functional derangement of a distinct corticofugal loops in schizophrenia and in certain aspects of Parkinson's disease.     

Topography of cocaine-induced gene regulation in the rat striatum: relationship to cortical inputs and role of behavioural context

Psychostimulants alter gene expression in projection neurons of the striatum, and such neuroplasticity is implicated in drug addiction and dependence. Evidence indicates that excitatory inputs from the cortex and thalamus are critical for these molecular changes. In the present study, we determined the topography of cocaine-induced changes in gene expression in the rat striatum and investigated whether these molecular alterations are associated with particular cortical inputs. Acute induction of c-fos (by 25 mg/kg of cocaine), and the c-fos response and dynorphin expression after repeated cocaine treatment (25 mg/kg, 4 days) were assessed as examples for short-term and longer-term molecular changes, respectively. In addition, we examined whether these molecular effects were influenced by the behaviour performed during cocaine action (running-wheel training vs. open field). Our results demonstrate that the overall topography of cocaine-induced gene regulation in the striatum is remarkably stable. Both acute and longer-term molecular changes were maximal in caudal dorsal striatal sectors that receive convergent inputs from the medial agranular and the sensorimotor cortex. In contrast, relatively minor or no effects were found in rostral and ventral striatal sectors. However, running-wheel training under the influence of cocaine enhanced the c-fos response to a subsequent cocaine challenge selectively in parts of the caudal sensorimotor striatum. These results indicate that cocaine produces molecular adaptations preferentially in cortico-basal ganglia circuits through the sensorimotor striatum, and that some of these neuronal changes are influenced by the behaviour performed during drug exposure.     

Cadherin‐8 expression,synaptic localization,and molecular control of neuronal form in prefrontal corticostriatal circuits

Neocortical interactions with the dorsal striatum support many motor and executive functions, and such underlying functional networks are particularly vulnerable to a variety of developmental, neurological, and psychiatric brain disorders, including autism spectrum disorders, Parkinson's disease, and Huntington's disease. Relatively little is known about the development of functional corticostriatal interactions, and in particular, virtually nothing is known of the molecular mechanisms that control generation of prefrontal cortex–striatal circuits. Here, we used regional and cellular in situ hybridization techniques coupled with neuronal tract tracing to show that Cadherin‐8 (Cdh8), a homophilic adhesion protein encoded by a gene associated with autism spectrum disorders and learning disability susceptibility, is enriched within striatal projection neurons in the medial prefrontal cortex and in striatal medium spiny neurons forming the direct or indirect pathways. Developmental analysis of quantitative real‐time polymerase chain reaction and western blot data show that Cdh8 expression peaks in the prefrontal cortex and striatum at P10, when cortical projections start to form synapses in the striatum. High‐resolution immunoelectron microscopy shows that Cdh8 is concentrated at excitatory synapses in the dorsal striatum, and Cdh8 knockdown in cortical neurons impairs dendritic arborization and dendrite self‐avoidance. Taken together, our findings indicate that Cdh8 delineates developing corticostriatal circuits where it is a strong candidate for regulating the generation of normal cortical projections, neuronal morphology, and corticostriatal synapses. J. Comp. Neurol. 523:75–92, 2015. © 2014 Wiley Periodicals, Inc.     

Cocaine induces the expression of homer 1b/c, homer 3a/b, and hsp 27 proteins in rat cerebellum

The long homer proteins 1b/c, 2a/b, and 3a/b play an important role in postsynaptic neurons by clustering glutamate receptors and by coupling the receptors with various intracellular effectors. Using immunohistochemistry and Western-blot analysis, this study shows that the expression of the long homer isoforms 1b/c and 3a/b was induced in rat cerebellum in response to cocaine administration. Acute treatment produced a very robust induction of both constitutive isoforms, whereas repeated treatment for 10 days induced a large expression of homer 1b/c and a more modest increase in the expression of the 3a/b isoform. The heat shock protein hsp 27 was also considerably induced in the cerebellum of cocaine-treated rats, suggesting that it participates in assisting the correct folding of proteins, and by counteracting oxidative stress mechanisms triggered by the psychostimulant. In addition of being expressed in Purkinje neurons, homer 3a/b and hsp 27, but not homer 1b/c, were localized within Bergmann glial cells and in their extensions, which surround Purkinje cells, as assessed by coimmunoreactivity with glial fibrillary acidic protein. Cocaine was also found to induce both proteins in the Bergmann glial cells. Since we found that homer 3a/b colocalized with the mGluR1 receptor in Purkinje cells, the data suggest that the long homer isoforms are involved in the cocaine-induced neuroplasticity that takes place in the cerebellum, by reshaping postsynaptic densities in Purkinje cell dendrites.     

Caffeine-mediated induction of c-fos, zif-268 and arc expression through A1 receptors in the striatum: different interactions with the dopaminergic system

Adenosine and the adenosine receptor antagonist, caffeine, modulate locomotor activity and striatal neuropeptide expression through interactions with the dopaminergic system by mechanisms which remain partially undetermined. We addressed this question by using quantitative immunocytochemistry and in situ hybridization, combined with retrograde tracing of striatal neurons, to characterize the mechanism(s) leading to the striatal increase in the immediate early genes (IEG), c-fos, zif-268 and arc, following a single injection of caffeine or the A1 antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). Caffeine and DPCPX induced c-fos, zif-268 and arc expression, both at mRNA and protein levels, in large proportions of striatonigral and striatopallidal neurons. The involvement of dopamine systems was evaluated by manipulations of the dopaminergic transmission. Quinpirole, a D2 agonist, almost completely blocked the caffeine-induced IEG increase in both striatopallidal and striatonigral neurons. Conversely, the lesion of the nigrostriatal pathway and the D1 antagonist SCH23390 abolished the caffeine effects in striatonigral neurons but had no or slight effect, respectively, on its action in striatopallidal neurons. These observations demonstrate that caffeine- and DPCPX-mediated IEG inductions involved different mechanisms in striatonigral and striatopallidal neurons through blockade of A1 receptors. Immediate early gene inductions result from a stimulation of dopamine release in striatonigral neurons and from activation of glutamate release and probably also acetylcholine release in striatopallidal neurons. These results also support the idea that, besides A2A receptors, adenosine acting at the A1 receptor plays pivotal functions in the basal ganglia physiology and that blockade of these receptors by specific or nonspecific antagonists, DPCPX and caffeine, may influence a broad range of neuronal functions in the striatum.     

Granular and dysgranular retrosplenial cortices provide qualitatively different contributions to spatial working memory: evidence from immediate-early gene imaging in rats

The present study revealed striking task-dependent differences in immediate-early gene activity in the two main subregions (granular and dysgranular) of the retrosplenial cortex. In addition, there were activity differences along the rostro-caudal axis of both subregions. Two groups of rats were trained on a working memory task in a radial-arm maze, one group in the light, the other in the dark. Each working memory group had two sets of yoked controls. Working memory consistently increased retrosplenial immediate-early gene activity ( c-fos and zif268 ), although systematic differences occurred in the granular and dysgranular subregions. Both c-fos and zif268 expression increased in granular cortex irrespective of whether the spatial memory task was in the light or dark. In contrast, only in the light did spatial memory increase dysgranular cortex activation. Correlations based on the counts of Fos-positive cells helped to reinforce the particular association between the dysgranular retrosplenial cortex and radial-arm maze performance in the light. These results provide clear evidence for proposed functional differences between the major retrosplenial subregions: the granular cortex contributes to spatial learning and navigation based on both internal and external cues (light and dark), while dysgranular cortex is more selectively involved when distal visual cues control performance (light only).     

Differential regulation of psychostimulant-induced gene expression of brain derived neurotrophic factor and the immediate-early gene Arc in the juvenile and adult brain

Psychostimulant drugs are widely used in children for the treatment of attention-deficit/hyperactivity disorder. Recent animal studies have suggested that exposure to these agents in early life could be detrimental to brain development. Here, for the first time, the effect of methylphenidate (MPH) and d -amphetamine (AMPH) on the expression of two key genes for neuronal development and plasticity, brain-derived neurotrophic factor ( bdnf ) and the effector immediate early gene activity-regulated, cytoskeletal-associated protein ( Arc ), was examined in both juvenile and adult rats. Both MPH [2 mg/kg, intraperitoneal (i.p.)] and AMPH (0.5 mg/kg, i.p.) induced marked decreases of bdnf mRNA in hippocampal and cortical brain regions of juveniles, whereas effects in adults were significantly less (hippocampus) or opposite (frontal cortex). In comparison, Arc mRNA was decreased (hippocampus and parietal cortex), largely unaffected (frontal cortex) or increased (striatum) in juveniles, whereas in adults, Arc mRNA increased in most brain regions. MPH-induced locomotion was also measured, and showed a much smaller increase in juveniles than in adults. In summary, our data show that the effects of MPH and AMPH on expression of the neurodevelopmentally important genes, bdnf and Arc , differ markedly in juvenile and adult rats, with juveniles showing evidence of brain region-specific decreases in both genes. These age-dependent effects on gene expression may be linked with the reported long-term harmful effects of psychostimulants in animal models.     

Prenatal cocaine exposure decreases nigrostriatal dopamine release in vitro: effects of age and sex

The present study examined the effects of prenatal cocaine (PCOC) exposure, age, sex, and estrous phase on the functional development of nigrostriatal dopamine (DA) neurons. Striatal tissue was obtained from prepubescent and adult rats of both sexes after bidaily exposure to saline (1 ml/kg) or cocaine (20 mg/kg/ml saline) from embryonic days 15-21. Tissue levels, basal release, and electrically evoked (1 or 8 Hz) overflow of endogenous DA and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), as well as their efflux in response to superfusion with the DA transport blocker, nomifensine (10 microM), were measured from superfused striatal slices. Generally, these measures were highest in tissue from males and adults. Tissue DA and DOPAC levels and the rate of DA turnover were unaffected by PCOC exposure. Slices from PCOC-exposed juvenile and adult male rats exhibited significantly reduced basal and electrically evoked DA release at both stimulation intensities, in conjunction with higher levels of presynaptic DA reuptake. Female rats were largely spared from the effects of PCOC exposure, and measures did not vary with estrous phase. These findings demonstrate that the effects of PCOC exposure on various parameters of nigrostriatal DA neuronal function are not uniform across age, sex, or phases of the estrous cycle. These novel alterations in nigrostriatal DA transmission are in need of independent replication, but they may have profound implications for behavioral activities regulated by these neurons and, thus, may provide a basis for sex-selective effects of PCOC in exposed humans. Possible mechanisms of deleterious effects of PCOC exposure in select groups are discussed.     

热损伤对大鼠纹状体多巴胺受体基因表达的影响

目的：研究热损伤对纹状体多巴胺受体D1R，D2R基因表达水平以及D2R前体mRNA剪接的影响。方法：采用RT—PCR的方法分析43℃热损伤对大鼠纹状体多巴胺受体D1R，D2R基因表达的影响；用RNA酶保护实验检测43℃热损伤后D2RmRNA剪接的变化。结果：43℃热损伤30min后，D1R表达量显著降低，D2R表达量升高。D2R长短片段D2RL／D2RS的比值较对照组明显升高，D2RL的转录占优势。结论：D1R，D2R及D2R长短片段比值变化结果为阐明热损伤的分子机制提供了实验依据。     

Developmentally regulated and evolutionarily conserved expression of SLITRK1 in brain circuits implicated in Tourette syndrome

Tourette syndrome (TS) is an inherited developmental neuropsychiatric disorder characterized by vocal and motor tics. Multiple lines of neurophysiological evidence implicate dysfunction in the corticostriatal‐thalamocortical circuits in the etiology of TS. We recently identified rare sequence variants in the Slit and Trk‐like family member 1 (SLITRK1) gene associated with TS. SLITRK1, a single‐pass transmembrane protein, displays similarities to the SLIT family of secreted ligands, which have roles in axonal repulsion and dendritic patterning, but its function and developmental expression remain largely unknown. Here we provide evidence that SLITRK1 has a developmentally regulated expression pattern in projection neurons of the corticostriatal‐thalamocortical circuits. SLITRK1 is further enriched in the somatodendritic compartment and cytoplasmic vesicles of cortical pyramidal neurons in mouse, monkey, and human brain, observations suggestive of an evolutionarily conserved function in mammals. SLITRK1 is transiently expressed in the striosomal/patch compartment of the mammalian striatum and moreover is associated with the direct output pathway; adult striatal expression is confined to cholinergic interneurons. These analyses demonstrate that the expression of SLITRK1 is dynamic and specifically associated with the circuits most commonly implicated in TS and related disorders, suggesting that SLITRK1 contributes to the development of corticostriatal‐thalamocortical circuits. J. Comp. Neurol. 513:21–37, 2009. © 2008 Wiley‐Liss, Inc.     

Decreased haloperidol-induced potentiation of zif268 mRNA expression in the nucleus accumbens shell and the dorsal lateral striatum of rats lacking cholecystokinin-A receptors.

Evidence suggests that endogenous cholecystokinin (CCK), a neuropeptide that modulates brain dopamine function, may contribute to the therapeutic and motor effects of antipsychotic drugs via activation of CCK-A receptors in the mesolimbic and nigrostriatal pathways, respectively. To determine if CCK modulates the effects of antipsychotic drugs through CCK-A receptors, we measured the haloperidol-induced zif268 mRNA response in the nucleus accumbens (NA) shell, NA core, and dorsal lateral striatum (DLS) in Otsuka Long Evans Tokushima Fatty (OLETF) rats that lack CCK-A receptors due to a spontaneous mutation. OLETF rats and normal Long Evans rats were treated with subcutaneous (s.c.) injections of saline or haloperidol (2 mg/kg). In situ hybridization was performed and zif268 mRNA expression was quantified. The haloperidol-induced expression of zif268 mRNA was significantly decreased in the DLS (P < 0.01) and the NA shell (P < 0.05), but not in the NA core, in OLETF rats compared to LETO rats. These data suggest that CCK-A receptor mechanisms may contribute to the therapeutic and the extrapyramidal motor effects associated with antipsychotic drug treatment.     

Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats

Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine‐related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a 5‐day withdrawal period. In addition, c‐Fos, FosB/ΔFosB, DAT, and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c‐Fos expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FosB/ΔFosB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+, and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction. Synapse 67:553–567, 2013. © 2013 Wiley Periodicals, Inc.     

Long-lasting effects of a PEGylated mutant cocaine esterase (CocE) on the reinforcing and discriminative stimulus effects of cocaine in rats

Recent mutagenesis studies have identified a mutant G4C/S10C/T172R/G173Q cocaine esterase (CCRQ CocE) with an in vitro duration of action of >40 days. Although the in vivo duration of CCRQ CocE's action was <24 h, modification of this enzyme with polyethylene glycol (PEG) polymers resulted in a CocE (PEG-CCRQ CocE) capable of preventing cocaine-induced lethality for up to 72 h. The current studies were aimed at providing a detailed characterization of the effectiveness, selectivity, and duration of PEG-CCRQ CocE's actions in cocaine self-administration and discrimination assays in rats. Pretreatment with PEG-CCRQ CocE produced dose-dependent rightward shifts in the dose-response curves for cocaine self-administration and discrimination, with the highest dose of PEG-CCRQ CocE capable of producing an initial shift of cocaine's reinforcing and interoceptive effects of >30-fold to the right, with significant inhibition of these effects observed for up to 72 h. Although PEG-CCRQ CocE also produced slight reductions in the rates of methylphenidate- and food-reinforced responding, these effects were short-lived, lasting <24 h. Finally, when taken together with the finding that PEG-CCRQ CocE failed to alter the cocaine-like interoceptive effects of either methylphenidate or d-amphetamine, these results suggest that PEG-CCRQ CocE possesses a high degree of pharmacologic specificity for cocaine and a prolonged in vivo duration of action. In conclusion, these studies provide strong evidence to support the further development of long-lasting, highly efficient CocEs, such as PEG-CCRQ CocE, as a potential therapeutic option for the treatment of cocaine abuse in humans.     

Aggression and defeat: persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits

The question of how ostensibly aversive social stress experiences in an aggressive confrontation can persistently increase intense drug taking such as cocaine ‘bingeing’ needs to be resolved. The biology of social conflict highlights distinctive behavioral, cardiovascular and endocrine profiles of dominant and subordinate animals, as seen also in rodents and primates under laboratory conditions. In contrast to continuous subordination stress that produces chronic pathophysiological consequences and often is fatal, animals adapt to brief episodes of social defeat stress, but show enduring functional activation in mesocorticolimbic microcircuits. Uncontrollable episodes of social defeat stress produce long-lasting tolerance to opiate analgesia and, concurrently, behavioral sensitization to challenges with either amphetamine or cocaine. One week after a single social defeat stress, cross-sensitization to cocaine is evident in terms of enhanced motor activity as well as in terms of increased Fos labeling in the periaqueductal grey area, the locus coeruleus, and the dorsal raphe nuclei. When challenged with a low amphetamine dose, the behavioral and neural effects of repeated brief episodes of social defeat stress persist for months. Previous exposure to social defeat stress can (1) significantly shorten the latency to acquire cocaine self-administration, (2) maintain this behavior at low cocaine unit doses, (3) significantly increase the levels of cocaine taking during a 24 h binge of continuous drug availability, (4) dysregulate the timing of consecutive infusions, and (5) abolish the circadian pattern of self-administration. Amygdaloid modulation, especially originating from central and basolateral nuclei, of dopaminergic pathways via peptidergic and glutamatergic neurons appears to be a key mechanism by which social defeat stress affects cocaine self-administration. Social stress alters the feedback from prefrontal cortex and thereby may contribute to the dysregulation of dopaminergic activity that is necessary for cocaine self-administration.     

Differentially altered mGluR1 and mGluR5 mRNA expression in rat caudate nucleus and nucleus accumbens in the development and expression of behavioral sensitization to repeated amphetamine administration.

Altered glutamatergic transmission in the striatum may be implicated in behavioral sensitization to repeated amphetamine (AMPH) administration. Quantitative in situ hybridization histochemistry was performed to define the effects of acute and chronic AMPH exposures on mRNA expression of Group I metabotropic glutamate receptors (mGluRs) in the striatum. Behavioral ratings indicated that the motor activity of rats was significantly higher after the final of five daily AMPH injections (4 mg/kg, i.p.) than that after the first of five daily AMPH, indicative of the development of behavioral sensitization. Moreover, the motor activity of rats treated with five daily AMPH was significantly greater than that of rats treated with five daily saline in response to a 2 mg/kg challenge dose of AMPH 7, 14, 28, and 60 days after the discontinuation of drug treatments, indicative of the persistent expression of behavioral sensitization. Three hours after acute administration of AMPH to naive rats, mGluR1 and mGluR5 mRNA expression in the dorsal (caudatoputamen) and ventral (nucleus accumbens) striatum showed no change as compared to acute saline injection. In rats that developed behavioral sensitization to repeated AMPH, mGluR1 levels in the dorsal and ventral striatum were increased by 53% and 43%, respectively, 3 h after the final AMPH treatment. However, this change did not persist during withdrawal since it was not observed 7, 14, and 28 days after the discontinuation of AMPH treatment. Conversely, mGluR5 levels were markedly reduced 3 h after the final of five daily AMPH treatments in the entire striatum of sensitized rats (34% and 77% of controls in the dorsal and ventral striatum, respectively). The reduction persisted at 7, 14, and 28 days of withdrawal. These results reveal a close linkage between striatal Group I mGluR gene expression and behavioral sensitization to AMPH. This may indicate functional implications of the two subtypes of Group I mGluRs in the regulation of behavioral sensitization to the dopamine stimulant.