Contrasting effects of SM-9018, a potential atypical antipsychotic, and haloperidol on c-fos mRNA expression in the rat striatum

SM-9018 (cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)hexahydro-1H-isoindole-1,3(2H)-dione HCl) is a potential atypical antipsychotic with high affinity for 5-HT2, dopamine D-2 and 5-HT1A receptors. Northern blot analysis was performed to compare the effects of SM-9018 and of haloperidol on the striatal c-fos mRNA expression in rats. Haloperidol (0.3-30 mg/kg, p.o.) markedly increased the striatal c-fos mRNA levels (about eight-fold at 30 mg/kg), the increase being abolished by lesioning of dopamine neurons with 6-hydroxydopamine. In contrast, SM-9018 produced only a slight increase (about two-fold) in c-fos mRNA expression at doses up to 30 mg/kg (p.o.). The 5-HT2 receptor antagonist, ritanserin (0.1-3 mg/kg, i.p.), dose-dependently attenuated the haloperidol-induced c-fos expression, but the putative 5-HT,A receptor antagonist, NAN-190 (1-(2-methoxyphenyl)-4-(4-(2-phethalimmido)butyl)piperazine HBr; 1-10 mg/kg, i.p.), did not. These findings suggest that SM-9018 is weaker than haloperidol for induction of striatal c-fos mRNA expression, to which the 5-HT2 receptor blocking activity of SM-9018 seems to contribute.