Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: II. In vitro studies in the rat.
The effects of long-term administrations of a low (10 mg/kg/day) and a high (40 mg/kg/day) dose of the dual 5-HT and NE reuptake inhibitor venlafaxine (delivered s.c. by osmotic minipumps for 21 days) were assessed on the electrically-evoked release of tritium from hippocampal slices preloaded with either [(3)H]5-HT or [(3)H]NE, 48 h after the removal of the minipump. The high, but not the low, dose regimen of venlafaxine enhanced the electrically-evoked release of [(3)H]5-HT while treatment with the high dose of venlafaxine failed to alter the electrically-evoked release of [(3)H]NE. The inhibitory effect of the 5-HT(1B) agonist CP 93,129 on the electrically evoked release of [(3)H]5-HT was unaltered by the low dose regimen of venlafaxine while it was attenuated in rats treated with the high dose of venlafaxine, indicative of a functional desensitization of the terminal 5-HT(1B) autoreceptor. Unexpectedly, neither regimen of venlafaxine altered the inhibitory effect of UK 14,304 on the electrically evoked release of both [(3)H]5-HT and [(3)H]NE, indicating that neither the alpha(2)-adrenergic auto- nor heteroreceptors were desensitized. Finally, the functions of the 5-HT and NE reuptake process were assessed. None of the treatment regimens altered the basal uptake of [(3)H]5-HT from hippocampal or mesencephalic slices nor that of [(3)H]NE from hippocampal slices. Finally, the enhancing effect of 1 microM of paroxetine in the perfusion medium on the electrical release of [(3)H]5-HT was unaltered in hippocampal slices prepared from rats that had been treated for 21 days with 40 mg/kg/day of venlafaxine. Taken together, these results indicate that, in terms of alteration of the sensitivity of the terminal 5-HT(1B) autoreceptor, alpha(2)-adrenergic auto-and heteroreceptors, the effects of long-term administration of venlafaxine are no different than those observed with classical SSRI's.
Béïque
J
J
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, H3A 1A1, Quebec, Canada.
de Montigny
C
C
Blier
P
P
Debonnel
G
G
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D017660:Autoreceptors / Q000187:drug effects / Q000502:physiology; D000068438:Brimonidine Tartrate; D002352:Carrier Proteins / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003511:Cyclohexanols / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D027981:Symporters; D013997:Time Factors; D014316:Tritium; D000069470:Venlafaxine Hydrochloride
D000316:Adrenergic alpha-Agonists; D017660:Autoreceptors; D000068438:Brimonidine Tartrate; D002352:Carrier Proteins; D003511:Cyclohexanols; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011725:Pyridines; D011758:Pyrroles; D011810:Quinoxalines; D044302:Receptor, Serotonin, 5-HT1B; D018341:Receptors, Adrenergic, alpha-2; D011985:Receptors, Serotonin; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; D014316:Tritium; D000069470:Venlafaxine Hydrochloride; C493226:Slc6a2 protein, rat; C493232:Slc6a4 protein, rat; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one