Venlafaxine: discrepancy between in vivo 5-HT and NE reuptake blockade and affinity for reuptake sites.
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 microg/kg i.v., respectively), while venlafaxine was three times less potent than desipramine (ED50: 727 and 241 microg/kg i.v., respectively) to suppress the firing activity of locus coeruleus NE neurons. The selective 5-HT1A receptor antagonist WAY 100635 (100 microg/kg, i.v.) reversed the suppressant effect of venlafaxine and paroxetine on the firing activity of 5-HT neurons and the alpha2-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 microg/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 microg/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.
Béïque
J C
JC
Department of Psychiatry, McGill University, Montréal, Québec, Canada.
de Montigny
C
C
Blier
P
P
Debonnel
G
G
D000200:Action Potentials / Q000187:drug effects; D018759:Adrenergic Uptake Inhibitors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D003511:Cyclohexanols / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D003891:Desipramine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D005277:Fenfluramine / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism*; D017374:Paroxetine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010883:Piperoxan / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D014439:Tyramine / Q000378:metabolism / Q000494:pharmacology; D000069470:Venlafaxine Hydrochloride
D018759:Adrenergic Uptake Inhibitors; D003511:Cyclohexanols; D003891:Desipramine; D005277:Fenfluramine; D009638:Norepinephrine; D017374:Paroxetine; D010879:Piperazines; D010883:Piperoxan; D011725:Pyridines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014439:Tyramine; D000069470:Venlafaxine Hydrochloride; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide