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

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Abstract
Using an in vivo electrophysiological paradigm, venlafaxine and paroxetine displayed similar potency for suppressing the firing activity of dorsal raphe 5‐HT neurons (ED50: 233 and 211 μg/kg i.v., respectively), while venlafaxine was three times less potent than desipramine (ED50: 727 and 241 μg/kg i.v., respectively) to suppress the firing activity of locus coeruleus NE neurons. The selective 5‐HT1A 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 α2‐adrenoceptor antagonist piperoxane (1 mg/kg, i.v.) reversed those of venlafaxine and desipramine on the firing activity of NE neurons. The ED50 of venlafaxine on the firing activity of 5‐HT neurons was not altered (ED50: 264 μg/kg) in noradrenergic‐lesioned rats, while the suppressant effect of venlafaxine on the firing activity of NE neurons was greater in serotonergic‐lesioned rats (ED50: 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 [3H]cyanoimipramine and [3H]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. (±)Fenfluramine and tyramine substantially increased the spontaneous outflow of [3H]5‐HT and [3H]NE, respectively, while venlafaxine was devoid of such releasing properties. Synapse 32:198–211, 1999.

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