Venlafaxine: Discrepancy between in vivo 5-HT and NE reuptake blockade andaffinity for reuptake sites

Using an in vivo electrophysiological paradigm, venlafaxine and paroxetine displayed similar potency for suppressing the firing activity of dorsal rap he 5-HT neurons (ED50: 233 and 211 mu g/kg i.v., respectively), while venla faxine was three times less potent than desipramine (ED50: 727 and 241 mu g /kg i.v., respectively) to suppress the firing activity of locus coeruleus NE neurons. The selective 5-HT1A receptor antagonist WAY 100635 (100 mu g/k g, i.v.) reversed the suppressant effect of venlafaxine and paroxetine on t he firing activity of 5-HT neurons and the alpha(2)-adrenoceptor antagonist piperoxane (1 mg/kg, i.v.) reversed those of venlafaxine and desipramine o n the firing activity of NE neurons. The ED50 Of venlafaxine on the firing activity of 5-HT neurons was not altered (ED50: 264 pg/kg) in noradrenergic -lesioned rats, while the suppressant effect of venlafaxine on the firing a ctivity of NE neurons was greater in serotonergic lesioned rats (ED50: 285 pg/kg). Taken together, these results suggest that, in vivo, venlafaxine bl ocks both reuptake processes, its potency to block the 5-HT reuptake proces s being greater than that for NE. Since the affinities of venlafaxine for t he 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 eff ect of venlafaxine on the firing activity of 5-HT and NE neurons observed i n vivo may not be mediated solely by its action on the [H-3]cyanoimipramine and [H-3]nisoxetine binding sites. In an attempt to unravel the mechanism responsible for this peculiarity, in vitro superfusion experiments were car ried out in rat brain slices to assess a putative monoamine releasing prope rty for venlafaxine. (+/-)Fenfluramine and tyramine substantially increased the spontaneous outflow of [H-3]5-HT and [H-3]NE, respectively, while venl afaxine was devoid of such releasing properties. (C) 1999 Wiley-Liss, Inc.