CLOZAPINE INHIBITS SEROTONINERGIC TRANSMISSION BY AN ACTION AT ALPHA(1)-ADRENOCEPTORS NOT AT 5-HT1A RECEPTORS

This study examined the mechanism underlying the influence of clozapin e upon serotoninergic transmission in the rat. In vitro, clozapine man ifested weak affinity at 5-HT1A receptors (pK(i) = 6.5) as compared to the agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (9.0) , but high affinity at alpha(1)-adrenoceptors (8.2) as compared to the alpha(1)-adrenoceptor antagonist, prazosin (9.7). Ex vivo, clozapine (inhibitory dose (ID)(50) = 0.7 mg/kg s.c.) mimicked prazosin (0.5) in potently occupying central alpha(1)-adrenoceptors whereas, as compare d to 8-OH-DPAT (0.2), it failed to occupy 5-HT1A receptors (> 10.0). T he firing of serotoninergic neurones in the dorsal raphe nucleus was a bolished by 8-OH-DPAT, clozapine and prazosin with ID50 values of 0.00 6, 0.09 and 0.07 mg/kg i.v., respectively. At comparable doses, they r educed striatal turnover of 5-HT. While the 5-HT1A receptors antagonis ts, (-)-tertatolol (2.0 mg/kg i.v.) and spiperone (0.63 mg/kg i.v.), b locked the action of 8-OH-DPAT upon dorsal raphe nucleus firing, they failed to modify the effect of clozapine and prazosin. In contrast, th e alpha(1)-adrenoceptor agonist, cirazoline (0.005 mg/kg i.v.) prevent ed the actions of clozapine and prazosin, but not that of 8-OH-DPAT. I t is concluded that clozapine only weakly interacts with 5-HT1A recept ors and that its potent alpha(1)-adrenoceptor antagonist properties un derlie inhibition of serotoninergic transmission.