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: 7.05). 10/2000; 23(3):294-306. DOI: 10.1016/S0893-133X(00)00112-3
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 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. Because pindolol augments fluoxetine or paroxetine, but not sertraline, mechanisms other than pharmacodynamics may be involved. "
ABSTRACT: This study was designed to study potentiation of fluoxetine's antidepressant effect by curcumin or pindolol. Twenty eight groups of mice (n=8) were used in three sets of experiments. In the first set, 9 groups were subjected to the forced swimming test after being treated intraperitoneally with three vehicles, fluoxetine (5 and 20 mg/kg), curcumin (20 mg/kg), pindolol (32 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg). One hour after the test, serum and brain fluoxetine and norfluoxetine levels were measured in mice receiving fluoxetine (5 and 20 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg). In the second set, the test was done after pretreatment with p-chlorophenylalanine. In the third set, the locomotor activity was measured. The immobility duration was significantly decreased in fluoxetine (20 mg/kg), curcumin (20 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg) groups. These decreases were reversed with p-chlorophenylalanine. Fluoxetine and norfluoxetine levels were significantly higher in fluoxetine (20 mg/kg) group with no differences in fluoxetine (5 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg) groups. Moreover, drugs failed to alter the locomotor activity indicating absence of central stimulation. In conclusion, curcumin, more than pindolol enhanced the antidepressant effect of a subeffective dose of fluoxetine in mice without increasing its serum or brain levels excluding any pharmacokinetic interaction. Reversal of this potentiation with p-chlorophenylalanine suggests a pharmacodynamic interaction through involvement of presynaptic 5-HT1A receptors.Indian Journal of Pharmaceutical Sciences 05/2014; 76(3):203-10. · 0.48 Impact Factor
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- "Serotonergic modulation—The therapeutic effects of chronic administration of antidepressant drugs are associated with an enhancement of serotonin neurotransmission (Blier and Bouchard, 1994; Blier and de Montigny, 1994; Owens, 1996). Acute administration of antidepressant drugs, such as SSRIs, causes a reduction in the firing of serotonergic neurons, which recover with long term administration (Chaput et al., 1986; Beique et al., 2000). This recovery in firing of serotonin neurons is thought to develop after desensitization of somatodendritic 5-HT 1A autoreceptors, activated in response to serotonin released from axon collaterals (Blier and de Montigny, 1994). "
ABSTRACT: Despite the widespread and devastating impact of depression on society, our current understanding of its pathogenesis is limited. Likewise, existing treatments are inadequate, providing relief to only a subset of people suffering from depression. The search for more effective antidepressant drugs includes the investigation of new molecular targets. Among them, current data suggests that sigma receptors are involved in multiple processes effecting antidepressant-like actions in vivo and in vitro. This review summarizes accumulated evidence supporting a role for sigma receptors in antidepressant effects and provides a conceptual framework for delineating their potential roles over the course of antidepressant treatment.Pharmacology [?] Therapeutics 05/2010; 127(3):271-82. DOI:10.1016/j.pharmthera.2010.04.003 · 9.72 Impact Factor
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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 . 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 –. 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 . "
ABSTRACT: We have recently reported that serotonin(4) (5-HT(4)) receptor agonists have a promising potential as fast-acting antidepressants. Here, we assess the extent to which this property may be optimized by the concomitant use of conventional antidepressants. We found that, in acute conditions, the 5-HT(4) agonist prucalopride was able to counteract the inhibitory effect of the selective serotonin reuptake inhibitors (SSRI) fluvoxamine and citalopram on 5-HT neuron impulse flow, in Dorsal Raphé Nucleus (DRN) cells selected for their high (>1.8 Hz) basal discharge. The co-administration of both prucalopride and RS 67333 with citalopram for 3 days elicited an enhancement of DRN 5-HT neuron average firing rate, very similar to what was observed with either 5-HT(4) agonist alone. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT(1A) receptors, that was two to three times stronger when the 5-HT(4) agonist was combined with citalopram. Similarly, co-administration of citalopram synergistically potentiated the enhancing effect of RS 67333 on CREB protein phosphorylation within the hippocampus. Finally, in the Forced Swimming Test, the combination of RS 67333 with various SSRIs (fluvoxamine, citalopram and fluoxetine) was more effective to reduce time of immobility than the separate administration of each compound. These findings strongly suggest that the adjunction of an SSRI to a 5-HT(4) agonist may help to optimize the fast-acting antidepressant efficacy of the latter.PLoS ONE 02/2010; 5(2):e9253. DOI:10.1371/journal.pone.0009253 · 3.23 Impact Factor
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