Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

Aug 16, 2000Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

How (-)Pindolol may increase activation of serotonin 1A receptors triggered by venlafaxine

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Abstract

Acute administration of venlafaxine resulted in a 90% suppression of the firing activity of serotonin neurons in the dorsal raphe nucleus.

Coadministration of (-)pindolol significantly enhanced the suppression of neuronal firing caused by venlafaxine.
The effect of venlafaxine on neuron activity was completely reversed by the 5-HT(1A) antagonist WAY 100635.
Pretreatment with (-)pindolol blocked the acute suppression of serotonin neuron firing induced by venlafaxine.
Venlafaxine and paroxetine both suppressed the firing activity of dorsal hippocampus CA(3) pyramidal neurons.
These findings suggest that (-)pindolol may block somatodendritic 5-HT(1A) autoreceptors, enhancing the effects of serotonin reuptake inhibitors.

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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-HT(1A) 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-HT(1A) 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 CA(3) pyramidal neurons. This effect of venlafaxine was markedly 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 postsynaptic 5-HT(1A) receptors was suggested by its complete reversal by the 5-HT(1A) antagonist WAY 100635 (100 microg/kg, i.v.). A short-term treatment with VLX (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 together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT(1A) receptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT(1A) 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.

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

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