Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine.

The mechanisms by which the atypical neuroleptic clozapine produces its therapeutic effects in the treatment of schizophrenia without causing the extrapyramidal side effects that are characteristic of most antipsychotic drugs remain unclear. Recently, a single injection of the typical antipsychotic haloperidol has been shown to increase c-fos expression in the striatum [Dragunow et al. (1990) Neuroscience 37, 287-294]. C-fos is a proto-oncogene that encodes a 55,000 mol. wt phosphoprotein, Fos, which is thought to assist in the regulation of "target genes" containing an AP-1 binding site. Because a wide variety of physiological and pharmacological stimuli increase c-fos expression, it has been proposed that Fos immunohistochemistry might be useful in mapping functional pathways in the central nervous system. The present experiments examined some potential neuroanatomical differences in the actions of clozapine and haloperidol by comparing their effects on c-fos expression in the medial prefrontal cortex, nucleus accumbens, striatum and lateral septum. The effects of the selective dopamine receptor antagonists SCH 23390 (D1) and raclopride (D2) were also examined. Haloperidol (0.5, 1 mg/kg) and raclopride (1, 2 mg/kg) produced large increases in the number of Fos-containing neurons in the striatum and nucleus accumbens. SCH 23390 (0.5, 1 mg/kg) reduced the number of Fos-positive neurons in the nucleus accumbens and striatum, and had no effect in the other regions. Neither haloperidol nor raclopride increased the number of Fos-positive neurons in the medial prefrontal cortex. Haloperidol, but not raclopride, produced a modest increase in c-fos expression in the lateral septal nucleus. Clozapine (10, 20 mg/kg) was without effect in the striatum; however, it significantly increased the number of Fos-positive neurons in the nucleus accumbens, medial prefrontal cortex and lateral septal nucleus. Destruction of mesotelencephalic dopaminergic neurons with 6-hydroxydopamine abolished the increase in Fos expression in the nucleus accumbens and striatum produced by haloperidol and raclopride, and also blocked the clozapine-induced increase in the nucleus accumbens. However, the inductive effects of clozapine and haloperidol on c-fos expression in the lateral septal nucleus and of clozapine in the medial prefrontal cortex were not affected by the 6-hydroxydopamine lesions. These results suggest that clozapine's unique therapeutic profile may be related to its failure to induce Fos in the striatum as well as its idiosyncratic actions in the lateral septum and medial prefrontal cortex. The effects of clozapine in these latter regions do not appear to be mediated by dopaminergic mechanisms.     

Interactions between environmental stimulation and antipsychotic drug effects on forebrain c-fos activation.

The immediate-early gene product Fos is differentially induced in the rat brain by the antipsychotic drugs haloperidol and clozapine. It is often claimed that although both drugs induce Fos in the nucleus accumbens, haloperidol but not clozapine increases Fos-like immunoreactivity in the striatum, whereas clozapine but not haloperidol increases Fos-like immunoreactivity in prefrontal cortex. Investigations of antipsychotic drug effects on Fos have typically administered high doses with pronounced sedative effects to behaviorally naive animals. In the present study, we compared the effects of low doses of haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) on Fos-like immunoreactivity in rats which were either behaviorally naive, exposed to a novel environment or tested for two-way active avoidance. We determined that haloperidol increased Fos in the striatum and nucleus accumbens regardless of testing condition whereas clozapine markedly reduced the induction of Fos by behavioral testing in these regions; moreover, haloperidol dramatically increased prefrontal cortical Fos expression in animals placed in a novel environment, but not in testing-naive controls.From these results we suggest that antipsychotic drug-induced patterns of Fos expression in the rat are highly dependent on animals' concurrent behavioral status, perhaps reflecting neuroanatomically specific interactions between antipsychotic drugs and environmental stressors which also may occur in the schizophrenic condition.     

Lysergic acid diethylamide-induced Fos expression in rat brain: role of serotonin-2A receptors

Lysergic acid diethylamide (LSD) produces altered mood and hallucinations in humans and binds with high affinity to serotonin-2A (5-HT(2A)) receptors. Although LSD interacts with other receptors, the activation of 5-HT(2A) receptors is thought to mediate the hallucinogenic properties of LSD. The goal of this study was to identify the brain sites activated by LSD and to determine the influence of 5-HT(2A) receptors in this activation. Rats were pretreated with the 5-HT(2A) receptor antagonist MDL 100907 (0.3 mg/kg, i.p.) or vehicle 30 min prior to LSD (500 microg/kg, i.p.) administration and killed 3 h later. Brain tissue was examined for Fos protein expression by immunohistochemistry. LSD administration produced a five- to eight-fold increase in Fos-like immunoreactivity in medial prefrontal cortex, anterior cingulate cortex, and central nucleus of amygdala. However, in dorsal striatum and nucleus accumbens no increase in Fos-like immunoreactivity was observed. Pretreatment with MDL 100907 completely blocked LSD-induced Fos-like immunoreactivity in medial prefrontal cortex and anterior cingulate cortex, but only partially blocked LSD-induced Fos-like immunoreactivity in amygdala. Double-labeled immunohistochemistry revealed that LSD did not induce Fos-like immunoreactivity in cortical cells expressing 5-HT(2A) receptors, suggesting an indirect activation of cortical neurons. These results indicate that the LSD activation of medial prefrontal cortex and anterior cingulate cortex is mediated by 5-HT(2A) receptors, whereas in amygdala 5-HT(2A) receptor activation is a component of the response. These findings support the hypothesis that the medial prefrontal cortex, anterior cingulate cortex, and perhaps the amygdala, are important regions involved in the production of hallucinations.     

Medial prefrontal cortex depressor response: role of the solitary tract nucleus in the rat.

The depressor response elicited by unilateral low intensity electrical stimulation of the rat ventral medial prefrontal cortex may be mediated by a connection with the solitary tract nucleus. We tested this hypothesis by (i) examining the influence of medial prefrontal cortex stimulation on the induction of Fos-like immunoreactivity in neurons in the medulla oblongata, and (ii) by testing the effect of inhibition of solitary tract nucleus neurons on the medial prefrontal cortex stimulation-evoked depressor response. Depressor responses (>10 mmHg) were elicited by electrical stimulation of the medial prefrontal cortex every minute for 1 h ('Stimulated' group). Control animals were treated identically but did not receive electrical stimulation ('Unstimulated' group). Neurons exhibiting Fos-like immunoreactivity were abundant at the stimulation site which included the infralimbic area, and dorsal peduncular cortex. Medullary Fos-like immunoreactivity observed in the 'Stimulated' and 'Unstimulated' groups exceeded levels observed in untreated rats and was detected in the rostral, caudal and intermediate areas of the ventrolateral medulla, and the commissural, intermediate, medial and lateral regions of the solitary tract nucleus, as well as the medial vestibular nucleus, and the dorsal motor nucleus of the vagus. The number of neurons displaying Fos-like immunoreactivity in the ipsilateral solitary tract nucleus and caudal ventrolateral medulla of the 'Stimulated' group was found to be significantly elevated compared to the contralateral side (P<0.05), and the 'Unstimulated' group bilaterally. Inhibition of solitary tract nucleus neurons using bilateral injections of the GABA(A) receptor agonist muscimol (44 pmol/25 nl) inhibited the sympathetic vasomotor baroreflex and attenuated the depressor and sympathoinhibitory response to medial prefrontal cortex stimulation by 62% and 65%, respectively. These findings suggest that the projection from the medial prefrontal cortex to the solitary tract nucleus is excitatory and support the hypothesis that the depressor response elicited by medial prefrontal cortex stimulation is mediated, in part, by a cortico-solitary projection which activates the intramedullary baroreflex pathway.     

Renewal of an extinguished instrumental response: neural correlates and the role of D1 dopamine receptors

Contexts play an important role in controlling the expression of extinguished behaviors. We used an ABA renewal design to study the neural correlates, and role of D1 dopamine receptors, in contextual control over extinguished instrumental responding. Rats were trained to respond for a sucrose reward in one context (A). Responding was then extinguished in the same (A) or different (B) context. Rats were tested for responding in the original training context (A). Return to the original training context after extinction (group ABA) was associated with a return of responding. Three distinct patterns of Fos induction were detected on test: 1) ABA renewal was associated with selective increases in c-Fos protein induction in basolateral amygdala, ventral accumbens shell, and lateral hypothalamus (but not in orexin- or melanin-concentrating hormone (MCH)-hypothalamic neurons); 2) being placed in the same context as extinction training (AAA or ABB) was associated with a selective decrease in c-Fos induction in rostral agranular insular cortex; 3) being placed in any context on test was associated with the up-regulation of c-Fos induction in anterior cingulate, dorsomedial accumbens shell, accumbens core, lateral septum, and substantia nigra. The return of responding in ABA renewal was prevented by pre-treatment with the D1 dopamine receptor antagonist SCH23390 (10 microg/kg; s.c.). SCH23390 also suppressed basal and renewal-associated c-Fos protein induction throughout accumbens, and, selectively suppressed renewal-associated c-Fos induction in lateral hypothalamus. These results suggest that renewal of extinguished responding for a sucrose reward depends on a distributed neural circuit involving basolateral amygdala, ventral accumbens shell, and lateral hypothalamus. D1 dopamine receptors within this circuit are essential for renewal. The results also suggest that rostral agranular insular cortex may play an important role in suppressing reward-seeking after extinction training.     

Sites of action of thyrotropin-releasing hormone on central nervous system neurons revealed by expression of the immediate-early gene c-fos in the rat

Centrally administered thyrotropin-releasing hormone produces a number of physiological and behavioral changes, e.g., a general antidepressant effect, increasing body temperature, and elevated blood pressure. However, the specific brain sites of action responsible for the centrally activating property of thyrotropin-releasing hormone have not been precisely determined. Using chloral hydrate-anesthetized adult Sprague–Dawley rats, we compared the distribution of Fos-like immunoreactivity after intracerebroventricular administration of thyrotropin-releasing hormone with the results after intracerebroventricular injection of vehicle alone. Some rats were paralysed and artificially ventilated to avoid possible Fos expression secondarily induced by autonomic (e.g., respiratory) disturbances. In thyrotropin-releasing hormone administered rats, selective Fos-like immunoreactivity was observed in V/VI layers of the pre- and infralimbic areas of the medial prefrontal cortex, the ventral midline thalamus, and the nucleus of the solitary tract as well as in the adjacent reticular formation. Fos-like immunoreactivity was significantly reduced in most areas of the cerebral cortex (II/III layers), the shell of the nucleus accumbens, the medial amygdaloid nucleus, parts of the hypothalamus, and the periaqueductal gray.These data suggest that various behavioral and autonomic responses induced by centrally administered thyrotropin-releasing hormone might be produced through the complex neural circuitry comprising the above structures, which are presumed to be implicated in limbic and/or autonomic functions.     

Subsets of neurotensin-immunoreactive neurons revealed following antagonism of the dopamine-mediated suppression of neurotensin immunoreactivity in the rat striatum.

The distribution of neurotensin-immunoreactive structures in the rat striatum was evaluated after blockade of dopamine neurotransmission by drugs that act presynaptically (6-hydroxydopamine, reserpine) and postsynaptically, preferentially at the D2 (eticlopride, haloperidol) and D1 [(R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepi n-7-ol, SCH-23390] receptor sites. Calbindin-D (mol. wt 28,000) immunoreactivity was used to delineate patch (striosome) and matrix in the caudate-putamen and core and shell in the nucleus accumbens. Antagonism at the D2 dopamine receptor and 6-hydroxydopamine lesions caused dense axonal immunoreactivity and moderate numbers of neurotensin-immunoreactive neurons to be distributed preferentially in the matrix of the caudate-putamen. D1 receptor antagonism was significantly less effective at eliciting neurotensin-immunoreactive neurons in the caudate-putamen. Reserpine or co-administration of the D1 and D2 receptor antagonists produced many neurotensin-immunoreactive neurons in both striatal compartments throughout the caudate-putamen and dense axonal neurotensin immunoreactivity in the medial patch compartment. To varying degrees, with SCH-23390 being least effective and reserpine most effective, all of the drug treatments elicited neurotensin immunoreactivity in neurons in the olfactory tubercle, rostral nucleus accumbens, accumbal shell and ventrolateral caudate-putamen, i.e. most of the ventral striatum.     

Sites of action of thyrotropin-releasing hormone on central nervous system neurons revealed by expression of the immediate-early gene c-fos in the rat

Centrally administered thyrotropin-releasing hormone produces a number of physiological and behavioral changes, e.g., a general antidepressant effect, increasing body temperature, and elevated blood pressure. However, the specific brain sites of action responsible for the centrally activating property of thyrotropin-releasing hormone have not been precisely determined. Using chloral hydrate-anesthetized adult Sprague-Dawley rats, we compared the distribution of Fos-like immunoreactivity after intracerebroventricular administration of thyrotropin-releasing hormone with the results after intracerebroventricular injection of vehicle alone. Some rats were paralysed and artificially ventilated to avoid possible Fos expression secondarily induced by autonomic (e.g., respiratory) disturbances. In thyrotropin-releasing hormone administered rats, selective Fos-like immunoreactivity was observed in V/VI layers of the pre- and infralimbic areas of the medial prefrontal cortex, the ventral midline thalamus, and the nucleus of the solitary tract as well as in the adjacent reticular formation. Fos-like immunoreactivity was significantly reduced in most areas of the cerebral cortex (II/III layers), the shell of the nucleus accumbens, the medial amygdaloid nucleus, parts of the hypothalamus, and the periaqueductal gray. These data suggest that various behavioral and autonomic responses induced by centrally administered thyrotropin-releasing hormone might be produced through the complex neural circuitry comprising the above structures, which are presumed to be implicated in limbic and/or autonomic functions.     

大鼠胃肠道伤害性刺激引起的中枢神经系统c-fos表达

本文应用Fos免疫组织化学(ABC法)对大鼠胃肠道伤害性刺激后中枢神经系统内的c-fos表达进行了观察,结果表明:(1)多数核团或部位的c-fos表达于伤害性刺激后的30min开始,2h达高峰,4h后逐渐降低,12h基本恢复正常。(2)Fos免疫反应阳性神经元呈双侧性分布,定位于胸髓(Rexed Ⅰ、Ⅱ、Ⅴ和Ⅹ层)、孤束核、延髓腹外侧区、臂旁外侧核、脑桥室周灰质、中脑导水管周围灰质、楔形核、中缝背核、下丘、丘脑(中线核团、背内侧核、腹后内侧核小细胞部)、外侧缰核、内侧膝状体大细胞部、下丘脑(背内侧核、腹内侧核、室周核等)、中央杏仁核、终纹床核、伏核、外侧隔核、梨状区皮质等。本文对以上部位的c-fos表达规律及其意义进行了初步探讨。     

Dopaminergic regulation of striatal proenkephalin mRNA and prodynorphin mRNA: contrasting effects of D1 and D2 antagonists

In situ hybridization was used to measure the levels of proenkephalin mRNA and prodynorphin mRNA in regions of rat striatum and nucleus accumbens. Chronic administration of haloperidol (2.4 mg/kg/day for 7 days) increased the levels of proenkephalin mRNA in both striatum and nucleus accumbens. In contrast, the levels of prodynorphin mRNA were not significantly affected in any region. Chronic administration of the D1 antagonist SCH 23390 (2.4 mg/kg/day for 7 days) decreased the striatal content of proenkephalin mRNA. A similar effect was seen in the lateral nucleus accumbens. The levels of prodynorphin mRNA were unaffected by SCH 23390 treatment in all regions examined. These results suggest that there is no major tonic dopaminergic regulation of prodynorphin synthesis in the basal ganglia. However, it appears that there is a tonic suppression, via D2 receptors, and a tonic enhancement, via D1 receptors, of proenkephalin synthesis, in the striatum and nucleus accumbens.     

Differential psychostimulant-induced activation of neural circuits in dopamine transporter knockout and wild type mice

Dopamine (DA) is a neurotransmitter that has been implicated in a wide variety of psychiatric disorders that include attention deficit-hyperactivity disorder (ADHD), schizophrenia, and drug abuse. Recently, we have been working with a mouse in which the gene for the DA transporter (DAT) has been disrupted. This mouse is hyperactive in the open field, displays an inability to inhibit ongoing behaviors, and is deficient on learning and memory tasks. Psychostimulants such as amphetamine and methylphenidate attenuate the hyperlocomotion of the mutants, but stimulate activity of the wild type (WT) controls. The objective of the present study is to examine the neural basis for the differential responses to psychostimulants in these mice. WT and DAT knockout (KO) animals were given vehicle or methylphenidate, amphetamine, or cocaine and brain sections were immunostained for Fos. In WT mice, methylphenidate induced Fos-like immunoreactivity (Fos-LI) in the mesostriatal and mesolimbocortical DA pathways that included the anterior olfactory nucleus, frontal association cortex, orbitofrontal cortex, cingulate cortex, caudate-putamen, globus pallidus, claustrum, lateral septum, nucleus accumbens, basolateral and central nuclei of the amygdala, bed nucleus of stria terminalis, subthalamic nucleus, substantia nigra, ventral tegmental area, and dorsal raphe. Additional areas of activation included the granular dentate gyrus, Edinger-Westphal nucleus, and periaqueductal gray. While the mutants showed little response in most of these same areas, the anterior olfactory nucleus, caudal caudate-putamen, lateral septum, basolateral and central nuclei of the amygdala, and bed nucleus of stria terminalis were activated. Amphetamine and cocaine produced similar changes to that for methylphenidate, except these psychostimulants also induced Fos-LI in the nucleus accumbens of the KO animals. Since the DAT gene is disrupted in the KO mouse, these findings suggest that dopaminergic mechanisms may mediate the WT responses, whereas non-dopaminergic systems predominate in the mutant. In the mutants, it appears that limbic areas and non-dopaminergic transmitter systems within these brain regions may mediate responses to psychostimulants. Inasmuch as the KO mouse may represent a useful animal model for ADHD and because psychostimulants such as cocaine are reinforcing to these animals, our results may provide some useful insights into the neural mechanisms-other than DA-that may contribute to the symptoms of ADHD and/or drug abuse in human patients.     

Role of accumbens and cortical dopamine receptors in the regulation of cortical acetylcholine release.

Cortical acetylcholine, under resting and stimulated conditions, was measured in frontoparietal and prefrontal cortex using in vivo microdialysis in freely-moving rats. Cortical acetylcholine efflux was stimulated by systemic administration of the benzodiazepine receptor partial inverse agonist FG 7142. Administration of FG 7142 (8.0 mg/kg; i.p.) significantly elevated acetylcholine efflux in both cortical regions (150-250% relative to baseline) for 30 min after drug administration. The ability of endogenous dopamine to regulate cortical acetylcholine efflux under resting or stimulated conditions and the relative contributions of D1- and D2-like dopamine receptor activation was also assessed. In a first series of experiments, systemic administration of the antipsychotic drug haloperidol (0.15, 0.9 mg/kg, i.p.) blocked FG 7142-stimulated acetylcholine efflux in frontoparietal, cortex while the D1-like antagonist, SCH 23390 (0.1, 0.3 mg/kg), was less effective in attenuating stimulated acetylcholine efflux. In a second series of experiments, the effects of infusions of these antagonists and of the D2-like antagonist sulpiride (10, 100 microM) into the nucleus accumbens were assessed. Infusions of haloperidol and sulpiride significantly blocked FG 7142-stimulated acetylcholine efflux while SCH 23390 did not. By contrast, a third series of experiments demonstrated that perfusion of these antagonists (100 microM) locally into the cortex (through the probe) did not affect FG 7142-stimulated acetylcholine efflux. Moreover, none of these dopamine receptor antagonists, whether administered systemically or perfused into the nucleus accumbens or cortex, affected basal cortical acetylcholine efflux. These results reveal similarities in stimulated cortical acetylcholine release across frontal cortical regions and suggest a prominent role for D2-mediated accumbens dopamine transmission in the regulation of cortical acetylcholine release. The findings provide evidence in support of a neural substrate that links dysregulation of mesolimbic dopaminergic transmission to changes in cortical cholinergic transmission. Dysregulation within this circuit is hypothesized to contribute to the etiology of disorders such as schizophrenia, dementia and drug abuse.     

D1-receptor antagonists: comparison of [3H]SCH39166 to [3H]SCH23390.

A radiolabeled form of the benzonaphthazephine, SCH39166 was used to characterize the binding of this D1 antagonist in cortex, and an autoradiographic comparison of the localization of [3H]SCH39166 to [3H]SCH23390 (D1 antagonist and forerunner of SCH39166) binding was performed. The Kd for [3H]SCH39166, calculated from dissociation and association rate constants (1.09 nM), was comparable to the Kd value derived from Scatchard analyses of saturation data (1.74 nM). [3H]SCH39166 binds to brain tissue in a saturable manner with high affinity and low non-specific binding. Inhibition of [3H]SCH39166 binding by dopaminergic and serotonergic agents supports the hypothesis that this is indeed a D1-specific compound with little overlap onto serotonin (5-HT) receptors. The affinity of [3H]SCH39166 for 5-HT2 and 5-HT1c receptors is at least an order of magnitude lower than the affinity of [3H]SCH23390 for these same receptor sites. Quantitative autoradiographic analysis of [3H]SCH39166 and [3H]SCH23390 binding indicates high D1-receptor density in the caudate-putamen, nucleus accumbens, olfactory tubercle, substantia nigra and entopeduncular nucleus. Low levels of binding (not significantly above background) were detected with [3H]SCH39166 in lamina IV of the cortex and in choroid plexus; areas which had significant [3H]SCH23390 binding and are known to have a high density of 5-HT (5-HT2 and 5-HT1c respectively) receptors.     

Chronic use of marijuana decreases cannabinoid receptor binding and mRNA expression in the human brain

Chronic exposure to Cannabis sativa (marijuana) produced a significant down-regulation of cannabinoid receptor in the postmortem human brain. The significant decrease in maximal binding capacity was not accompanied by changes in the affinity constant. [3H]SR141716A binding was reduced in the caudate nucleus, putamen and in the accumbens nucleus. A significant decrease of binding sites was seen in the globus pallidus. Also in the ventral tegmental area and substantia nigra pars reticulata quantitative analysis of the density of receptors shows a significant reduction in [3H]SR141716A binding. In Cannabis sativa user brains, compared with normal brains [3H]SR141716A binding was reduced only in the hippocampus. The density of cannabinoid receptor 1 mRNA-positive neurons was significantly lower in Cannabis sativa users than in control brains for the caudate nucleus, putamen, accumbens nucleus and hippocampal region (CA1-CA4, areas of Ammon's horn). No hybridization was seen in the mesencephalon and globus pallidus.     

Dopaminergic transplants normalize amphetamine- and apomorphine-induced Fos expression in the 6-hydroxydopamine-lesioned striatum.

Dopamine receptor-mediated Fos protein expression in the striatum has been used to monitor dopamine receptor activation at the cellular level after dopaminergic denervation and reinnervation by fetal nigral transplants. The pattern of striatal Fos expression after systemic administration of either the dopamine receptor agonist, apomorphine, or the dopamine-releasing agent, amphetamine, was studied in rats which had received cell suspension grafts of fetal ventral mesencephalic neurons into the striatum after a complete 6-hydroxydopamine lesion of mesostriatal dopaminergic projection. Grafted animals, and normal and lesioned controls were killed 2 h after administration of either D-amphetamine (5 mg/kg, i.p.) or apomorphine (0.25 mg/kg, s.c.). Fos protein was detected immunohistochemically, and the density of Fos-immunoreactive cell nuclei was measured in 12 selected areas of caudate-putamen, nucleus accumbens and globus pallidus by computerized image analysis. Consistent with previous studies, amphetamine induced high Fos expression in the medial and dorsal parts of the intact caudate-putamen and significantly lower expression in the denervated caudate-putamen. A significant difference between lesioned and intact striata was present also in globus pallidus, but not in nucleus accumbens. In grafted rats, amphetamine-induced Fos activation was restored to normal or supranormal levels in the anterior and central caudate-putamen (i.e. close to the graft deposits), whereas in the tail of caudate-putamen Fos expression was significantly lower than normal. The side-to-side difference in globus pallidus seen in lesioned rats was no longer present in the grafted animals. Apomorphine led to high Fos activation throughout the dopamine-depleted caudate-putamen, whereas only very few immunopositive cells were observed in the intact caudate-putamen. Also in globus pallidus and nucleus accumbens, a significantly higher number of Fos-immunoreactive cells was detected on the denervated side. In the grafted rats, apomorphine-induced Fos activation was similar to normal in all striatal areas sampled, as well as in the globus pallidus. The graft-induced effect extended over a considerably larger area than that covered by the graft-derived tyrosine hydroxylase-immunoreactive innervation. These findings indicate that fetal ventral mesencephalic transplants normalize dopamine receptor-mediated function in the 6-hydroxydopamine-lesioned caudate-putamen and nucleus accumbens, as well as in a primary target of the striatal output neurons, the globus pallidus. The results support the idea that dopamine released from the grafted neurons, both under baseline conditions and after amphetamine administration, exerts functional effects over a larger volume of the striatum than that reached by the graft-derived fibers.     

The cannabinoid antagonist SR 141716A (Rimonabant) reduces the increase of extra-cellular dopamine release in the rat nucleus accumbens induced by a novel high palatable food

The assumption of a novel high palatable food (a candied cherry) occurs concomitantly with an increase in the concentration of extra-cellular dopamine and its main metabolite 3,4-dihydroxy-phenylacetic acid (DOPAC) by about 45% in the dialysate obtained by intracerebral microdialysis from the shell of the nucleus accumbens of male rats. Such increase was reversed by SR 141716A (Rimonabant), a selective cannabinoid CB1 receptor antagonist (0.3 mg/kg i.p. and 1 mg/kg i.p.), which also reduces the assumption of the high palatable food, when given 15 min before exposure to the candied cherry. SR 141716A effects on extracellular dopamine and DOPAC were prevented by WIN 55,212-2 (0.3 mg/kg i.p.) or HU 210 (0.1 mg/kg i.p.) given 15 min before SR 141716A. The present results show for the first time that SR 141716A reduces the increase in extra-cellular dopamine induced by a novel high palatable food in the nucleus accumbens. This confirms that cannabinoid CB1 receptors play a key role in food intake and/or appetite and suggests that the mesolimbic dopaminergic system is involved at least in part, in the effects of cannabinoid receptor agonists and antagonists on food intake and/or appetite.     

Different sensitivity of in vivo acetylcholine transmission to D1 receptor stimulation in shell and core of nucleus accumbens.

We investigated whether D1 dopaminergic receptors modulate in vivo acetylcholine output in the shell and core areas of rat nucleus accumbens using the microdialysis technique. Subcutaneous injection (1, 2 and 3 mg/kg) of the D1 agonist SKF 82958 enhanced acetylcholine output in both areas of the nucleus accumbens while the selective D1 antagonist SCH 39166 (0.15 and 0.30 mg/kg, s.c.) lowered it. Both SKF 82958 and SCH 39166 were more effective in the shell than in the core region. The increase in acetylcholine release induced by SKF 82958 in the shell was tetrodotoxin-sensitive. The dopamine release inducer d-amphetamine (1 and 2mg/kg, s.c.) and the dopamine uptake inhibitor cocaine (10 and 20 mg/kg, i.p.) dose-dependently raised acetylcholine release in the shell and core areas. The dopaminergic stimulants, like the direct-acting D1 compounds, were more effective in the shell than in the core compartment of the nucleus accumbens. The acetylcholine increases in the shell induced by d-amphetamine (2 mg/kg), cocaine (20 mg/kg) and SKF 82958 (3 mg/kg) were antagonized by the D1 antagonists SCH 39166 (5 microM) and SCH 23390 (10 microM), applied locally by reverse dialysis. The results suggest that dopamine acting at the D1 receptors exerts a tonic stimulatory control over the cholinergic function of the shell and core compartments of the nucleus accumbens with the shell being more strongly influenced.     

Forebrain D1 function and sensorimotor gating in rats: effects of D1 blockade, frontal lesions and dopamine denervation

Prefrontal D1 hypoactivity is implicated in the pathophysiology of schizophrenia, and might contribute to sensorimotor gating deficits in schizophrenia patients, based on evidence that D1 blockade in the medial prefrontal cortex (MPFC) reduces prepulse inhibition of startle (PPI) in animal models. PPI is disrupted by systemic and intra-MPFC infusion of the D1 antagonist, SCH23390. We investigated the role of the MPFC in the PPI-disruptive effects of systemic SCH23390 administration, and more generally, in the dopaminergic regulation of PPI. PPI was measured in rats after forebrain manipulations, including systemic administration of SCH23390, ibotenic acid lesions of the MPFC, and 6OHDA-induced dopamine (DA) depletion from MPFC or nucleus accumbens. Systemic SCH23390 disrupted PPI; these effects were not opposed by ibotenic acid lesions of the MPFC. PPI remained intact after MPFC DA depletion, but--as predicted by Bubser and Koch [M. Bubser, M. Koch, Prepulse inhibition of the acoustic startle response of rats is reduced by 6 hydroxydopamine lesions of the medial prefrontal cortex, Psychopharmacology 113 (1994) 487-492]--a reduction in PPI from pre- to post-surgery correlated significantly with MPFC DA loss. The effects of systemic SCH23390 were not opposed by NAC DA depletion. D1 receptors regulate PPI in rats, but this effect does not appear to be mediated either by the MPFC or by increased mesolimbic DA activity.     

Kappa opioid receptor immunoreactivity in the nucleus accumbens and caudate-putamen is primarily associated with synaptic vesicles in axons

A rabbit polyclonal antiserum, raised against a C-terminal oligopeptide of the mouse kappa opioid receptor, was used to localize the cellular distribution of kappa receptors in the dorsal and ventral striatum of rats with light and electron microscopic immunocytochemistry. Prominent, diffuse kappa receptor immunoreactivity was present in the nucleus accumbens, particularly in the shell, ventral caudate-putamen and olfactory tubercle. The density of receptor immunoreactivity decreased in more dorsal areas of the caudate-putamen. In contrast, neuronal cell bodies stained clearly in the dorsal endopiriform nucleus, claustrum and layer VI of the adjacent cerebral cortex. Observations at the electron microscopic level in the dorsomedial shell of the nucleus accumbens and caudate-putamen revealed that the kappa receptor immunoreactivity was predominantly located in axons, often associated with synaptic vesicles, remote from the terminal or preterminal area. The few terminals which were labeled made slightly more asymmetrical than symmetrical contacts and the percentage of asymmetrical contacts observed was greater in the caudate than in the accumbens. A small number of postsynaptic spines was labeled; most of them were contacted by asymmetrical terminals. No labeling was observed in dendritic shafts.Thus, the predominant localization of kappa receptor immunoreactivity in axons is consistent with its role as a major inhibitor of glutamate and dopamine release in the dorsal and ventral striatum.     

Effects of cortical and striatal dopamine D1 receptor blockade on cued versus noncued behavioral responses

Various lines of evidence suggest that disruptions in brain dopamine (DA) transmission produce behavioral impairments that can be overcome by salient response-eliciting environmental stimuli. We examined here whether D1 receptor blockade within striatal or frontal cortical DA target regions would differentially affect head entry responses elicited by an auditory cue compared with those occurring during noncued intertrial intervals. Rats received 2 drug-free 28-trial daily sessions in which an auditory cue was immediately followed by food delivery. On the following day, separate groups of rats received bilateral infusions of D1 antagonist SCH23390 to the dorsomedial striatum (DMS), nucleus accumbens (NAcc) core, or the medial prefrontal cortex (mPFC). SCH23390 infused into the DMS and NAcc core suppressed noncued head entries but had no effect on head entries in response to the auditory cue. SCH23390 infused to the mPFC did not reduce either cued or noncued approach responses. Systemic administration of the drug, in contrast, reduced the frequency of both cued and noncued approaches. The results are consistent with the notion that has emerged from the Parkinson's literature that reduced DA transmission produces behavioral suppression that can be overcome by salient environmental response elicitors, and extends this notion by showing that D1 receptor transmission within the striatum strongly suppresses noncued responses while leaving the identical behavior intact when cued by an environmental stimulus.