M100907, a selective 5-HT2A receptor antagonist, attenuates phencyclidine-induced Fos expression in discrete regions of rat brain

Abstract 5-HT and dopamine receptor antagonists have become widely used as atypical antipsychotics. Although 5-HT 2A receptor antagonistic activity is thought to contribute to the atypical aspects of these agents, the precise mechanism remains unknown. M100907 ( R (+)-alpha(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine –methanol), a selective 5-HT 2A receptor antagonist, is reported to attenuate phencyclidine (PCP)-induced locomotion in rodents. For the purpose of identifying regions in which M100907 exerts its effect, we investigated the effects of M100907 on PCP-induced Fos expression in rat brain. PCP (5 mg/kg, subcutaneously, s.c.) induced Fos expression in the cingulate cortex area 3, the agranular insular cortex, the piriform cortex, the nucleus accumbens, the anterior paraventricular thalamic nucleus and the ventral lateral septal nucleus. Pretreatment with M100907 (0.5 mg/kg, s.c.) attenuated Fos expression induced by PCP in the nucleus accumbens core, the shell, the agranular insular cortex and the piriform cortex. M100907 did not induce Fos expression in any of the regions investigated including the dorsolateral caudate/putamen when given alone. These results indicate that 5-HT 2A receptor antagonism attenuates Fos expression in a regionally specific manner in rat brain in the PCP model of psychosis.