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Potentiation by (-)Pindolol of the activation of postsynaptic 5-HT(1A) receptors induced by venlafaxine.

Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montréal, Québec, Canada.
Neuropsychopharmacology (Impact Factor: 7.83). 10/2000; 23(3):294-306. DOI: 10.1016/S0893-133X(00)00112-3
Source: PubMed

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-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.

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    • "It completely blocks central β-adrenoreceptors at clinically relevant plasma levels[7] while, at plasma levels in patients after 2.5 mg three times a day, it only partially blocks presynaptic 5-HT1A autoreceptors and does not augment the SSRI-induced 5-HT increase in the guinea pig brain. Therefore, it is unlikely that the favorable effects of combining pindolol with SSRIs are due to 5-HT1A antagonism[8]. Because pindolol augments fluoxetine or paroxetine, but not sertraline, mechanisms other than pharmacodynamics may be involved. "
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    • "It had previously been reported that in acute conditions, the dose of a given SSRI required to observe an inhibition of hippocampal pyramidal neurons is at least 5 to 10 times higher than that able to suppress the activity of DRN 5-HT neurons [21]. This difference is thought to be related to the fact that, at lower doses, 5-HT reuptake blockade concerns essentially the somatodendritic area, hence the suppression of firing, and that only a massive occupation of terminal sites produced by a high dose of the SSRI can elicit an elevation of extracellular 5-HT levels consistent enough to stimulate the inhibitory hippocampal 5-HT1A postsynaptic receptors [21]–[22]. Based on this, we used citalopram at 500 µg/kg, i.v. This dose actually corresponds to no more than 3–4 times the ED50 we previously found for this drug, regarding its abolishing action on 5-HT neuron activity [14]. "
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    • "Arc expression and 5-HT 1485 in hippocampal cell firing in animals pre-treated with a 5-HT 1A antagonist (Beique et al. 2000). Expression of c-fos also increased after the co-administration of paroxetine/WAY 100635, and the regions responding were similar to those showing increased Arc expression. "
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