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-HT1A autoreceptors, which mediate feedback inhibit ion of serotonergic neuronal activity. In this study, we examined the effec ts of venlafaxine, a dual 5-HT/noradrenaline reuptake inhibitor, alone and in combination with the selective 5-HT1A receptor antagonist N-[2-[4-(2-met hoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WA Y 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 fi ring rate (ED50 = 0.19 mg/kg), with virtually complete inhibition of neuron al discharge at the highest dose tested. The subsequent administration of W AY 100635 (0.1 mg/kg, i.v.) rapidly reversed the neuronal suppression produ ced by venlafaxine and significantly elevated the firing rate above baselin e levels. The overshoot. in neuronal activity was associated with the onset of an adverse behavioral reaction resembling the 5-HT syndrome resulting f rom excessive levels of brain 5-HT. The intensity of this reaction parallel ed the degree of neuronal restoration induced by WAY 100635, suggesting a c ausal relationship. Such behavioral responses were either not observed prev iously, or of a low intensity, when WAY 100635 was combined with selective 5-HT reuptake inhibitors. Overall, these results suggest that the risk of i nducing adverse effects, such as the 5-HT syndrome, may be higher with dual 5-HT/noradrenaline reuptake inhibitors than with selective 5-HT reuptake i nhibitors, when these agents are combined with a potent 5-HT1A autoreceptor antagonist. Possible mechanisms that might account for these differences i n drug interaction are discussed. (C) 2000 Elsevier Science B.V. All rights reserved.