Limited participation of 5-HT(1A) and 5-HT(2A/2C) receptors in the clozapine-induced Fos-protein expression in rat forebrain regions.

Through the development of tolerance following long-term clozapine treatment, we investigated whether 5-HT(1A) and 5-HT(2A/2C) receptors participate in the clozapine-induced Fos-protein expression in the rat forebrain. Tolerance exists when the acutely increased Fos responses to a challenge dose of the 5-HT(1A) and 5-HT(2A/2C) agonists 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane-hydrochloride (DOI) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), respectively, given simultaneously to rats, are attenuated after 3-week clozapine (20 mg kg(-1) day(-1) i.p.) pretreatment. As compared to the acute effects of clozapine, the Fos responses to concomitant administration of the 5-HT receptor agonists DOI (2.5 mg kg(-1) i.p. ) and 8-OH-DPAT (2.5 mg kg(-1) i.p.) were more pronounced in the prefrontal cortex, the nucleus accumbens core and the dorsomedial and ventromedial striatum, areas in which clozapine (20 mg kg(-1) i. p.) exhibited marginal effects. In the hypothalamic paraventricular nucleus, both clozapine and DOI/8-OH-DPAT induced a remarkably high number of Fos-positive nuclei. Long-term clozapine pretreatment attenuated the acutely induced Fos expression of the 5-HT receptor agonists in the nucleus accumbens core, the dorsomedial and ventromedial parts of the striatum and the lateral septum, indicating (partial) common sites of action of the agents in these brain regions. No tolerance was found in the nucleus accumbens shell and the hypothalamic paraventricular nucleus and the central amygdala, suggesting that the clozapine-induced Fos responses, though distinct in these regions, are independent of 5-HT receptors. The prefrontal cortex and the dorsolateral striatum indicated only a tendency towards tolerance. In addition, the involvement of the tested 5-HT receptor agonists in the clozapine-enhanced release of plasma corticosterone became apparent. The present results indicate that the clozapine-induced patterns of Fos expression in the rat forebrain can only be in part attributed to an interaction with 5-HT(1A/2A/2C) receptors.