Potentiation of fluoxetine-induced penile erections by combined blockade of 5-HT1A and 5-HT1B receptors.

The serotonin reuptake inhibitor, fluoxetine (10.0 mg/kg, s.c.), elicited penile erections in rats. Selective blockade of 5-HT1A autoreceptors with WAY 100,635 ((N-(2-[4-(2-methoxyphenyl)-1- piperazinyl]ethyl)-N-(2-pyridinyl) cyclo-hexanecarboxamide) (0.16 mg/kg, s.c.), or of 5-HT1B autoreceptors with GR 127,935 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-me thyl- 1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide) (2.5 mg/kg, s.c.), slightly (1.5- to 2-fold) increased fluoxetine-induced penile erections. However, conjoint administration of WAY 100,635 and GR 127,935 markedly (5-fold) potentiated induction of penile erections by fluoxetine. Penile erections were abolished by the novel 5-HT2C receptor antagonist, SB 206,553 (5 methyl-1-(3-pyridil-carbamoyl)-1,2,3,5- tetrahydropyrrolo[2,3-f]indole). These data provide functional evidence for redundancy in autoreceptor control of 5-HT release. Combined blockade of 5-HT1A and 5-HT1B autoreceptors markedly enhances the actions of serotonin reuptake inhibitors.