Jc. Beique et al., Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: II. In vitro studies in the rat, NEUROPHARM, 39(10), 2000, pp. 1813-1822
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 ele
ctrically-evoked release of tritium from hippocampal slices preloaded with
either [H-3]5-HT or [H-3]NE, 48 h after the removal of the minipump. The hi
gh, but not the low, dose regimen of venlafaxine enhanced the electrically-
evoked release of [H-3]5-HT while treatment with the high dose of venlafaxi
ne failed to alter the electrically-evoked release of [H-3]NE. The inhibito
ry effect of the 5-HT1B agonist CP 93,129 on the electrically evoked releas
e of [H-3]5-HT was unaltered by the low dose regimen of venlafaxine;while i
t was attenuated in rats treated with the high dose of venlafaxine, indicat
ive of a functional desensitization of the terminal 5-HT1B autoreceptor. Un
expectedly, neither regimen of venlafaxine altered the inhibitory effect of
UK 14,304 on the electrically evoked release of both [H-3]5-HT and [H-3]NE
, indicating that neither the alpha(2)-adrenergic auto- nor heteroreceptors
were desensitized. Finally, the functions of the 5-HT and NE reuptake proc
ess were assessed. None of the treatment regimens altered the basal uptake
of [H-3]5-HT from hippocampal or mesencephalic slices nor that of [H-3]NE f
rom hippocampal slices. Finally, the enhancing effect of 1 mu M of paroxeti
ne in the perfusion medium on the electrical release of [H-3]5-HT was unalt
ered in hippocampal slices prepared from rats that had been treated for 21
days with 40 mg/kg/day of venlafaxine. Taken together, these results indica
te that, in terms of alteration of the sensitivity of the terminal 5-HT1B a
utoreceptor, alpha(2)-adrenergic auto-and heteroreceptors, the effects of l
ong-term administration of venlafaxine are no different than those observed
with classical SSRI's. (C) 2000 Elsevier Science Ltd. All rights reserved.