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 (RT(50)) of the firing activity of dorsal 
hippocampus CA(3) pyramidal neurons from the suppression induced by 
microiontophoretic applications of 5-HT and NE. The RT(50) values for 5-HT were 
increased by both 10 and 40 mg/kg/day regimens of venlafaxine, whereas those for 
NE were increased only by the 40 mg/kg/day regimen, indicative of a greater 
potency of venlafaxine in blocking 5-HT reuptake. The sensitivity of the 
postsynaptic 5-HT(1A) and alpha(2)-adrenergic receptors was altered by neither 
regimen of venlafaxine. Using a paradigm by which the 5-HT(1A) antagonist WAY 
100635 can induce a disinhibition of firing activity of CA(3) pyramidal neurons, 
it was demonstrated that the high, but not the low, dose of venlafaxine led to 
an enhanced tonic activation of postsynaptic 5-HT(1A) receptors in the dorsal 
hippocampus. The duration of the suppressant effect of the firing activity of 
CA(3) hippocampus pyramidal neurons produced by the electrical stimulation of 
the ascending 5-HT pathway was significantly reduced when the frequency 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 venlafaxine. Hence, venlafaxine 
induced a desensitization of the terminal 5-HT(1B) autoreceptor only at the high 
dose. A 2-day treatment with 10 mg/kg/day of venlafaxine 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 venlafaxine. The suppressant effect of the i.v. 
administration of the 5-HT autoreceptor 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 venlafaxine. 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 neurons did not recover their firing activity after a 21-day 
treatment. Taken together, the results from this study indicate that the low 
dose of venlafaxine blocked selectively the reuptake of 5-HT, whereas the high 
dose blocked the reuptake of both 5-HT and NE. Moreover, an enhancement of 
serotonergic neurotransmission by venlafaxine was only achieved under conditions 
whereby the desensitization of the terminal 5-HT(1B) autoreceptor is appended to 
that of the somatodendritic 5-HT(1A) receptor.