Potentiation by (-)Pindolol of the activation of postsynaptic 5-HT(1A) receptors induced by venlafaxine.
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.
Article: A subfamily of 5HT1D receptor genesTrends in Pharmacological Sciences - TRENDS PHARMACOL SCI. 01/1992; 13:152-159.
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ABSTRACT: Flesinoxan is a high affinity and selective 5-hydroxytryptamine1A (5-HT1A) ligand which, unlike the 5-HT1A agonists of the azapirone class, does not generate 1-(2-pyrimidinyl)piperazine, an alpha 2-adrenoreceptor antagonist. In view of potential antidepressant effects of flesinoxan, this study was undertaken to characterize its 5-HT1A properties in the rat brain using in vivo electrophysiology and hypothermia paradigms. The suppressant effect of microiontophoretic applications of flesinoxan on the firing activity of CA3 pyramidal neurons was blocked by concomitant application of the 5-HT1A antagonist BMY 7378. Compared to gepirone, the efficacy of flesinoxan to suppress the firing activity of CA3 pyramidal neurons was significantly greater. While the coapplication of flesinoxan antagonized the suppressant effect of 5-HT on CA3 pyramidal neurons, it failed to do so on dorsal raphe 5-HT neurons, indicating that flesinoxan acts as a partial agonist at postsynaptic and as a full agonist at presynaptic 5-HT1A receptors. The capacity of flesinoxan to antagonize the effect of 5-HT on CA3 pyramidal neurons was similar to that of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and significantly greater than that of gepirone. The intravenous administration of flesinoxan suppressed the firing activity of both CA3 pyramidal neurons and dorsal raphe 5-HT neurons. However, when compared to 8-OH-DPAT, significantly higher doses of flesinoxan were required. The acute brain penetration of [3H]flesinoxan and [3H]8-OH-DPAT was, therefore, determined. Nine minutes after intravenous administration, [3H]8-OH-DPAT reached significantly greater brain concentration than [3H]flesinoxan. Subcutaneous administration of flesinoxan and 8-OH-DPAT produced a dose-dependent hypothermia. The flesinoxan-induced hypothermia was significantly attenuated by prior administration of the non-selective 5-HT1A antagonist pindolol and the 5-HT1/2 antagonist methysergide. Similar degrees of hypothermia were achieved with 3 mg/kg of flesinoxan and 0.5 mg/kg of 8-OH-DPAT. The maximal effect of flesinoxan occurred 30 min later than that of 8-OH-DPAT and faded more slowly. The 5-HT1A properties of flesinoxan suggest that it may be an effective anxiolytic/antidepressant agent.Neuropharmacology 11/1995; 34(10):1311-26. · 4.11 Impact Factor
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ABSTRACT: 1. Venlafaxine is an antidepressant agent which blocks in vitro the reuptake of both 5-HT and NA. The present in vivo electrophysiological studies were undertaken, in the rat, to compare the effects of venlafaxine on 5-HT and NA reuptake to those of the selective 5-HT reuptake inhibitor paroxetine and the selective NA reuptake inhibitor desipramine. 2. Administered acutely, venlafaxine dose-dependently prolonged the time required for a 50% recovery (RT50) of the firing activity of dorsal hippocampus CA3 pyramidal neurons from the suppression induced by microiontophoretic applications of 5-HT and NA. Venlafaxine and paroxetine increased with a similar potency the RT50 values for 5-HT, while desipramine was more potent than venlafaxine at increasing the RT50 values for NA. Moreover, venlafaxine demonstrated a greater potency at increasing the RT50 values for 5-HT compared to that of NA. 3. A two-day treatment with venlafaxine (delivered s.c. by osmotic minipumps) increased the RT50 values for both 5-HT and NA applications. The RT50 values for 5-HT were significantly increased at a dose of 10 mg kg(-1) day(-1), whereas those for NA were increased at a dose of 20 mg kg(-1) day(-1), consistent with the data obtained following the acute administration of venlafaxine. 4. Taken together, these results indicate that, in vivo, venlafaxine blocks both reuptake processes, with a potency greater for the 5-HT than for the NA reuptake process. This dual action, combined with the differential potency of venlafaxine, might constitute the biological substratum responsible for its apparent unique clinical efficacy in major depression.British Journal of Pharmacology 11/1998; 125(3):526-32. · 5.07 Impact Factor