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The assessment of immediate-early gene induction has proven to be a useful method for delineating the neural systems that subserve antipsychotic drug actions. In order to differentiate the sites and mechanisms of action of typical and atypical antipsychotic drugs, we examined the effects of antipsychotic drugs on Fos protein expression in the medial prefrontal cortex. The atypical antipsychotic drug clozapine selectively increased the number of neurons that expressed Fos-like immunoreactivity in the prefrontal cortex, targeting the deep layers of the infralimbic and prelimbic cortices. Pyramidal cells were the major cell type in which Fos was expressed. A small number of calbindin-like immunoreactive, but not parvalbumin- or reduced nicotinamide adenine dinucleotide phosphate diaphorase-containing, interneurons also expressed Fos after clozapine challenge. Immunoblot studies revealed that clozapine induced Fos protein in the infralimbic and prelimbic cortices. Other antipsychotic drugs that are D2 receptor antagonists, including haloperidol, raclopride, sulpiride, remoxipride and loxapine, did not alter Fos expression. The clozapine-induced increase in Fos expression was also not attributable to actions at the D1 dopamine receptor, nor to serotonin type 2a/2c receptor antagonism or combined serotonin type 2-D2 dopamine receptor antagonism. The ability of clozapine to block alpha 1-adrenergic or muscarinic cholinergic receptors did not contribute to the unique actions of clozapine. Despite the inability of dopamine receptor antagonists other than clozapine to elicit an increase in Fos expression, both the mixed D1-D2 dopamine agonist apomorphine and the D2-like agonist quinpirole increased Fos protein levels in the prefrontal cortex. However, neither pretreatment with sulpiride to block D2/3/4 dopamine receptors or SCH 23390 to block D1/5 dopamine receptors modified the Fos response to clozapine. Since dopamine receptor antagonist pretreatments did not attenuate the clozapine-elicited Fos expression, but D2 agonists increased cortical Fos expression, clozapine may act in the prefrontal cortex on an as yet undefined dopamine receptor. In contrast to the nucleus accumbens shell, where all antipsychotic drugs increase Fos expression, only clozapine induced Fos in the medial prefrontal cortex. These observations suggest that the ability of clozapine to treat schizophrenic patients who are resistant to the therapeutic benefits of conventional antipsychotic drugs may occur through actions in the prefrontal cortex.
Recent electrophysiological and pharmacological data indicate that dopamine enhances the activity of interneurons in the prefrontal cortex (PFC) and induces the release of GABA from these cells. We used in vivo microdialysis to examine the effects of two dopamine receptor antagonists on GABA release in the prefrontal cortex of awake, freely moving rats. Depolarization accomplished by local perfusion of potassium chloride or veratradine markedly increased extracellular GABA levels in the PFC. In contrast, local perfusion of TTX reduced extracellular GABA levels in the PFC. These data indicate that extracellular GABA is derived in part from neurons, and that extracellular levels of the inhibitory amino acid are impulse dependent. The acute administration of haloperidol weakly but significantly decreased extracellular GABA levels in the PFC; no effect of haloperidol on striatal extracellular GABA levels was observed. Systemic administration of the atypical antipsychotic drug clozapine markedly reduced extracellular GABA levels in the PFC, but did not alter striatal GABA levels. Thus, release of GABA from interneurons in the PFC is inhibited by two antipsychotic drugs. These data may suggest that different D2-like dopamine receptors are localized to pyramidal and nonpyramidal neurons in the cortex.
Studies of the mechanisms of action of antipsychotic drugs have focused on delineating the sites of action of these drugs and the receptors through which these drugs act. A number of methods have been used to approach these problems. Expression of immediate-early genes, such as c-fos, permits the detection of individual neurons that are metabolically activated by a particular drug challenge and thus opens the way to examining both the specific sites of action of drugs and their receptor mechanisms. We now report on studies defining corticostriatal circuits and the receptors that subserve the actions of antipsychotic drugs, using immunohistochemical and immunoblot methods to reveal immediate-early gene expression.
Because glutamate is an important modulator of subcortical dopamine (DA) function, and abnormal glutamate/DA interactions may be involved in the pathophysiology of schizophrenia, we examined the effect of chronically administered antipsychotic drugs (APDs) on the levels of specific glutamate receptor subunits in the terminal fields of nigrostriatal and mesocorticolimbic DA systems. By immunoblotting procedures using antibodies specific for the NMDAR1, GluR1, and GluR2 subunits, we found that haloperidol (predominantly a D2-like antagonist) increased NMDAR1 subunit immunoreactivity (and mRNA levels) in the striatum, while the D1-like antagonist SCH 23390 had the opposite effect. No effect was seen on GluR1 or GluR2 levels. The result that D1-like and D2-like receptor antagonism can reciprocally regulate NMDAR1 expression is consistent with our observation that complete unilateral destruction of the nigrostriatal DA pathway with 6-hydroxy-dopamine had no effect on striatal NMDAR1 subunit levels. Further examination of these striatal effects revealed that chronic treatment with the D2-like receptor antagonist raclopride significantly increased NMDAR1 levels in the striatum, while the 5-HT2a/2c antagonist mianserin tended to produce an increase that did not achieve statistical significance. These findings indicate that the dopaminergic antagonist properties of haloperidol are likely most responsible for its regulation of this subunit. In contrast, the atypical APD clozapine had no effect on striatal NMDAR1 levels, consistent with the relatively weaker influence of this drug on nigrostriatal DA function. The second major finding of the present study was the ability of haloperidol and clozapine to increase GluR1 levels in the medial prefrontal cortex (PFC), whereas chronic SCH 23390 treatment decreased GluR1 levels.
Monitoring expression of c-fos and other immediate-early genes has proven a useful method for determining potential sites of action of antipsychotic drugs. Most studies of the effects of antipsychotic drugs on immediate-early gene expression have focused on the basal ganglia and allied cortical regions. We now report that clozapine administration markedly increases both the number of cells expressing Fos protein-like immunoreactivity and the amount of Fos protein in the thalamic paraventricular nucleus, but not the contiguous mediodorsal thalamic nucleus. Comparable doses of several dopamine D2-like antagonists, including raclopride, sulpiride, remoxipride and haloperidol, did not induce Fos expression in the paraventricular nucleus. However, loxapine and very high doses of haloperidol resulted in a small but significant increase in paraventricular nucleus Fos expression. The dopamine D1 receptor antagonist SCH23390 did not induce Fos in the paraventricular nucleus or alter the magnitude of the clozapine-elicited increase in Fos expression. The serotonergic 5-hydroxytryptamine2a/2c antagonist ritanserin, alone or in combination with sulpiride, did not increase Fos expression in the paraventricular nucleus. Similarly, the 5-hydroxytryptamine2:D2 antagonist risperidone did not change the amount of Fos protein in the paraventricular nucleus. Neither the alpha 1 adrenergic antagonist prazosin nor the muscarinic cholinergic antagonist scopolamine mimicked the effect of clozapine. The key placement of the paraventricular nucleus as an interface between the reticular formation and forebrain dopamine systems suggests that this thalamic nucleus may be an important part of an extended neural network subserving certain actions of antipsychotic drugs.
To determine the effects of dopamine receptor blockade upon oxidizable components of striatal extracellular fluid, high-performance liquid chromatography (HPLC) with electrochemical detection was used to assay levels of ascorbic acid, dihydroxyphenylacetic acid (DOPAC) homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) in perfusates obtained from unanesthetized rats following i.p. administration of haloperiodol (1.0 mg/kg) or clozapine (20 mg/kg). Striatal push-pull perfusion was performed by passing artificial CSF between two pulled glass micropipets, encapsulated by a hollow, semipermeable cellulose fiber, thereby limiting recovery to compounds under mw 5000. Samples were directly injected into a C-18 column at half-hour intervals before and after neuroleptic administration. Haloperidol administration resulted in increases in extracellular DOPAC and HVA while failing to alter 5-HIAA or ascorbic acid levels. Similar results were found with clozapine, except for a more variable individual response to the drug; clozapine also produced a small increase in 5-HIAA levels. Animals given a saline injection did not show increases in any of these compounds. These data confirm the involvement of extracellular dopamine metabolites in the electrochemical signal increases observed in vivo following dopamine receptor blockade and provide evidence that extracellular ascorbic acid in the striatum is insensitive to peripheral neuroleptic administration.
Recent anatomical data suggest that the nucleus accumbens can be parcellated into a core region, related to the caudate-putamen, and a shell region, associated with the limbic system. We have used pharmacological methods to characterize the dopamine innervations of the nucleus accumbens core and shell in the rat. Concentrations of both dopamine and serotonin were significantly greater in the nucleus accumbens shell than the nucleus accumbens core. Metabolite: amine ratios suggested that both dopamine and serotonin utilization are greater in the core. However, dopamine turnover (as determined by measuring the rate of decline of dopamine after alpha-methyl-p-tyrosine treatment) was not significantly different in the two accumbal sectors. Dopamine concentrations in the two nucleus accumbens sectors were decreased to an equivalent degree at both 4 and 18 h after reserpine administration. In contrast, serotonin concentrations were decreased to a significantly greater degree in the nucleus accumbens core than nucleus accumbens shell at 4 h, but not 18 h, after reserpine administration. Administration of haloperidol increased dopamine utilization in both nucleus accumbens sectors, but augmented utilization to a significantly greater degree in the nucleus accumbens core. Clozapine increased dopamine utilization to an equivalent degree in both nucleus accumbens regions. Short duration immobilization stress selectively increased dopamine utilization in the nucleus accumbens shell. These data indicate that there are significant differences between the nucleus accumbens core and nucleus accumbens shell in basal dopamine metabolism, and indicate that the core and shell dopamine innervations can be distinguished on the basis of response to both pharmacological and environmental challenges.(ABSTRACT TRUNCATED AT 250 WORDS)