RECEPTOR MECHANISMS MEDIATING CLOZAPINE-INDUCED C-FOS EXPRESSION IN THE FOREBRAIN

The atypical antipsychotic clozapine produces distinctly different reg ional patterns of c-fos expression in rat forebrain than does the prot otypical neuroleptic haloperidol. While haloperidol-induced c-fos expr ession appears to be mediated by its D-2 dopamine receptor antagonist properties, the mechanisms by which clozapine increases c-fos expressi on remain uncertain. Using a combination of brain lesion, pharmacologi cal and immunohistochemical techniques, the present study sought to de termine the receptor mechanisms by which clozapine increases the numbe r of Fos-like immunoreactive neurons in various regions of the forebra in. To test whether serotonergic and/or noradrenergic systems are invo lved in clozapine-induced c-fos expression, rats received either 5,7-d ihydroxytryptamine lesions of the medial forebrain bundle or 6-hydroxy dopamine lesions of the dorsal noradrenergic bundle two weeks prior to clozapine (20 mg/kg) injections. Neither type of lesion affected cloz apine-induced c-fos expression in the rat forebrain, suggesting that n either serotonergic nor noradrenergic mechanisms are involved in this action of clozapine. In another experiment, the 5-hydroxytryptamine(2) receptor antagonist ritanserin (5 mg/kg), either alone or in combinat ion with haloperidol (1 mg/kg), failed to mimic the pattern of c-fos e xpression produced by clozapine. This suggests that clozapine's antago nist actions at 5-hydroxytryptamine, receptors cannot explain the uniq ue pattern of regional c-fos expression produced by this compound. To determine whether the blockade of subtypes of the D-2 dopamine recepto r family may contribute to clozapine's effects, the dopamine receptor agonists quinpirole and 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-O H-DPAT) were injected 15 min prior to clozapine. Quinpirole produced a small but significant decrease in clozapine-induced c-fos expression in the medial prefrontal cortex, had larger effects in the lateral sep tum, and blocked clozapine's actions in the nucleus accumbens and majo r island of Calleja. Pretreatment with 7-OH-DPAT attenuated clozapine- induced c-fos expression in the nucleus accumbens and lateral septum, completely blocked the expression in the major island of Calleja, but was without effect in the medial prefrontal cortex. Given the differen t affinities of quinpirole and 7-OH-DPAT for D-2, D-3 and D-4 receptor s, these data suggest that clozapine-induced increases in c-fos expres sion in the nucleus accumbens, major island of Cajella and lateral sep tal nucleus are due to antagonist actions of this antipsychotic at D-3 dopamine receptors. They also indicate that while antagonist actions at D-4 receptors may contribute, the primary mechanisms by which cloza pine increases c-fos expression in the medial prefrontal cortex remain to be determined.