THE EFFECTS OF ANTIPSYCHOTIC-DRUGS ON FOS PROTEIN EXPRESSION IN THE PREFRONTAL CORTEX - CELLULAR-LOCALIZATION AND PHARMACOLOGICAL CHARACTERIZATION

The assessment of immediate-early gene induction has proven to be a us eful method for delineating the neural systems that subserve antipsych otic 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 media l prefrontal cortex. The atypical antipsychotic drug clozapine selecti vely increased the number of neurons that expressed Fos-like immunorea ctivity in the prefrontal cortex, targeting the deep layers of the inf ralimbic and prelimbic cortices. Pyramidal cells were the major cell t ype in which Fos was expressed. A small number of calbindin-like immun oreactive, but not parvalbumin- or reduced nicotinamide adenine dinucl eotide phosphate diaphorase-containing, interneurons also expressed Fo s after clozapine challenge. Immunoblot studies revealed that clozapin e induced Fos protein in the infralimbic and prelimbic cortices. Other antipsychotic drugs that are D-2 receptor antagonists, including halo peridol, raclopride, sulpiride, remoxipride and loxapine, did not alte r Fos expression. The clozapine-induced increase in Fos expression was also not attributable to actions at the D-1 dopamine receptor, nor to serotonin type 2a/2c receptor antagonism or combined serotonin type 2 -D-2 dopamine receptor antagonism. The ability of clozapine to block a lpha(1)-adrenergic or muscarinic cholinergic receptors did not contrib ute to the unique actions of clozapine. Despite the inability of dopam ine receptor antagonists other than clozapine to elicit an increase in Fos expression, both the mixed D-1-D-2 dopamine agonist apomorphine a nd the D-2-like agonist quinpirole increased Fos protein levels in the prefrontal cortex. However, neither pretreatment with sulpiride to bl ock D-2/3/4 dopamine receptors or SCH 23390 to block D-1/5 dopamine re ceptors modified the Fos response to clozapine. Since dopamine recepto r antagonist pretreatments did not attenuate the clozapine-elicited Fo s expression, but D-2 agonists increased cortical Fos expression, cloz apine may act in the prefrontal cortex on an as yet undefined dopamine receptor. In contrast to the nucleus accumbens shell, where all antip sychotic drugs increase Fos expression, only clozapine induced Fos in the medial prefrontal cortex. These observations suggest that the abil ity 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.