Venlafaxine and its interaction with WAY 100635: effects on serotonergic unit activity and behavior in cats

The therapeutic efficacy of antidepressant drugs that inhibit the reuptake of serotonin (5-hydroxytryptamine, 5-HT) may be enhanced by blocking their indirect activation of 5-HT(1A) autoreceptors, which mediate feedback inhibition of serotonergic neuronal activity. In this study, we examined the effects of venlafaxine, a dual 5-HT/noradrenaline reuptake inhibitor, alone and in combination with the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY 100635), on the single-unit activity of serotonergic dorsal raphe neurons and concurrent behavior in freely moving cats. Systemic administration of venlafaxine (0.05-1.0 mg/kg, i.v.) produced a dose-dependent decrease in firing rate (ED(50)=0.19 mg/kg), with virtually complete inhibition of neuronal discharge at the highest dose tested. The subsequent administration of WAY 100635 (0.1 mg/kg, i.v.) rapidly reversed the neuronal suppression produced by venlafaxine and significantly elevated the firing rate above baseline levels. The overshoot in neuronal activity was associated with the onset of an adverse behavioral reaction resembling the 5-HT syndrome resulting from excessive levels of brain 5-HT. The intensity of this reaction paralleled the degree of neuronal restoration induced by WAY 100635, suggesting a causal relationship. Such behavioral responses were either not observed previously, or of a low intensity, when WAY 100635 was combined with selective 5-HT reuptake inhibitors. Overall, these results suggest that the risk of inducing adverse effects, such as the 5-HT syndrome, may be higher with dual 5-HT/noradrenaline reuptake inhibitors than with selective 5-HT reuptake inhibitors, when these agents are combined with a potent 5-HT(1A) autoreceptor antagonist. Possible mechanisms that might account for these differences in drug interaction are discussed.