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.