Using an in vivo electrophysiological paradigm, venlafaxine and paroxetine displayed similar potency for suppressing the firing activity of dorsal raphe 5-HT neurons (ED 50 : 233 and 211 µg/kg i.v., respectively), while venlafaxine was three times less potent than desipramine (ED 50 : 727 and 241 µg/kg i.v., respectively) to suppress the firing activity of locus coeruleus NE neurons. The selective 5-HT 1A receptor antagonist WAY 100635 (100 µg/kg, i.v.) reversed the suppressant effect of venlafaxine and paroxetine on the firing activity of 5-HT neurons and the ␣ 2 -adrenoceptor antagonist piperoxane (1 mg/kg, i.v.) reversed those of venlafaxine and desipramine on the firing activity of NE neurons. The ED 50 of venlafaxine on the firing activity of 5-HT neurons was not altered (ED 50 : 264 µg/kg) in noradrenergic-lesioned rats, while the suppressant effect of venlafaxine on the firing activity of NE neurons was greater in serotonergiclesioned rats (ED 50 : 285 µg/kg). Taken together, these results suggest that, in vivo, venlafaxine blocks both reuptake processes, its potency to block the 5-HT reuptake process being greater than that for NE. Since the affinities of venlafaxine for the 5-HT and NE reuptake carriers are not in keeping with its potencies for suppressing the firing activity of 5-HT and NE neurons, the suppressant effect of venlafaxine on the firing activity of 5-HT and NE neurons observed in vivo may not be mediated solely by its action on the [ 3 H]cyanoimipramine and [ 3 H]nisoxetine binding sites. In an attempt to unravel the mechanism responsible for this peculiarity, in vitro superfusion experiments were carried out in rat brain slices to assess a putative monoamine releasing property for venlafaxine. (Ϯ)Fenfluramine and tyramine substantially increased the spontaneous outflow of [ 3 H]5-HT and [ 3 H]NE, respectively, while venlafaxine was devoid of such releasing properties.