Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: I. In vivo electrophysiological studies in the rat

The effect of a 21-day treatment with the dual 5-HT and NE reuptake blocker venlafaxine (delivered s.c. by osmotic minipumps) was assessed on the time required for a 50% recovery (RT50) of the firing activity of dorsal hippoc ampus CA, pyramidal neurons from the suppression induced by microiontophore tic applications of 5-HT and NE. The RT50 values for 5-HT were increased by both 10 and 40 mg/kg/day regimens of venlafaxine, whereas those for NE wer e increased only by the 40 mg/kg/day regimen, indicative of a greater poten cy of venlafaxine in blocking 5-HT reuptake. The sensitivity of the postsyn aptic 5-HT1A and alpha(2)-adrenergic receptors was altered by neither regim en of venlafaxine. Using a paradigm by which the 5-HT1A antagonist WAY 1006 35 can induce a dishinbition of firing activity of CA(3) pyramidal neurons, it was demonstrated that the high, but not the low, dose of venlafaxine le d to an enhanced tonic activation of postsynaptic 5-HT1A receptors in the d orsal hippocampus. The duration of the suppressant effect of the firing act ivity of CA(3) hippocampus pyramidal neurons produced by the electrical sti mulation of the ascending 5-HT pathway was significantly reduced when the f requency of the stimulation was enhanced from 1 Hz to 5 Hz in control rats and in rats treated with 10 mg/kg/day, but not with 40 mg/kg/day of venlafa xine. Hence, venlafaxine induced a desensitization of the terminal 5-HT1B a utoreceptor only at the high dose. A 2-day treatment with 10 mg/kg/day of v enlafaxine induced a suppression of the firing activity of 5-HT neurons of the dorsal raphe. The firing activity of these neurons was back to control level in rats that had been treated for 21 days with the same dose of venla faxine. The suppressant effect of the i.v. administration of the 5-HT autor eceptor agonist LSD on the firing activity of dorsal raphe 5-HT neurons was reduced in rats that had been treated for 21 days with 10 mg/kg/day of ven lafaxine. A 2-day treatment with 40 mg/kg/day of venlafaxine, unlike the 10 mg/kg/day regimen, induced a marked suppression of the firing activity of locus coeruleus NE neurons. However, in contrast to 5-HT neurons, NE neuron s did not recover their firing activity after a 21-day treatment. Taken tog ether, the results from this study indicate that the low dose of venlafaxin e blocked selectively the reuptake of 5-HT, whereas the high dose blocked t he reuptake of both 5-HT and NE. Moreover, an enhancement of serotonergic n eurotransmission by venlafaxine was only achieved under conditions whereby the desensitization of the terminal 5-HT1B autoreceptor is appended to that of the somatodendritic 5-HT1A receptor. (C) 2000 Elsevier Science Ltd. All rights reserved.