Potentiation by (-)pindolol of the activation of postsynaptic 5-HT1A receptors induced by venlafaxine

The increase of extracellular 5-HT in brain terminal regions produced by th e acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT1A autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the r at, to assess the effects of the coadministration of venlafaxine, a dual 5- HT/NE reuptake inhibitor, and (-)pindolol on pre- and postsynaptic 5-HT1A r eceptor function. The acute administration of venlafaxine and of the SSRI p aroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of d orsal hippocampus CA(3) pyramidal neurons. This effect of venlafaxine was m arkedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective beta-adrenoceptor antagonist metoprolol (15 mg/kg, i. p.). That this effect of venlafaxine was mediated by an activation of posts ynaptic 5-HT1A receptors was suggested by its complete reversal by the 5-HT 1A antagonist WAY 100635 (100 mu g/kg, i.v.). A short-term treatment with V LX (20 mg/kg/day x 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day x 2 days). Taken togethe r, these results indicate that (-)pindolol potentiated the activation of po stsynaptic 5-HT1A receptors resulting from 5-HT reuptake inhibition probabl y by blocking the somatodendritic 5-HT1A autoreceptor, but not its postsyna ptic congener. These results support and extend previous findings providing a biological substratum for the efficacy of pindolol as an accelerating st rategy in major depression. (C) 2000 American College of Neuropsychopharmac ology. Published by Elsevier Science Inc. All rights reserved.