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 clozapine upon serotoninergic transmission in the rat. In vitro, clozapine manifested 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 compared to 8-OH-DPAT (0.2), it failed to occupy 5-HT1A receptors (> 10.0). The firing of serotoninergic neurones in the dorsal raphe nucleus was abolished by 8-OH-DPAT, clozapine and prazosin with ID50 values of 0.006, 0.09 and 0.07 mg/kg i.v., respectively. At comparable doses, they reduced striatal turnover of 5-HT. While the 5-HT1A receptors antagonists, (-)-tertatolol (2.0 mg/kg i.v.) and spiperone (0.63 mg/kg i.v.), blocked the action of 8-OH-DPAT upon dorsal raphe nucleus firing, they failed to modify the effect of clozapine and prazosin. In contrast, the alpha(1)-adrenoceptor agonist, cirazoline (0.005 mg/kg i.v.) prevented the actions of clozapine and prazosin, but not that of 8-OH-DPAT. It is concluded that clozapine only weakly interacts with 5-HT1A receptors and that its potent alpha(1)-adrenoceptor antagonist properties underlie inhibition of serotoninergic transmission.