P.1.023 - Synergistic increases of noradrenaline and 5-HT neurotransmission induced by milnacipran with pindolo

Abstract

The increase of extracellular 5-HT in brain terminal regions produced by the 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 rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre- and postsynaptic 5-HT1A receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA3 pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective β-adrenoceptor antagonist metoprolol (15 mg/kg, i.p.). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT1A receptors was suggested by its complete reversal by the 5-HT1A antagonist WAY 100635 (100 μg/kg, i.v.). A short-term treatment with VLX (20 mg/kg/day × 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 × 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT1A receptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT1A autoreceptor, but not its postsynaptic congener. These results support and extend previous findings providing a biological substratum for the efficacy of pindolol as an accelerating strategy in major depression.