Role of serotonin 5-HT1A receptors in the antidepressant-like effect and the antinociceptive effect of venlafaxine in mice.
The present study was undertaken to evaluate the potential role of 5-HT1A receptors in the antidepressant-like effect and antinociceptive effect of venlafaxine. With this aim, the effect of either a selective 5-HT1A receptor antagonist (WAY-100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT1A receptor agonist (8-OH-DPAT; 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) was investigated in mice in combination with venlafaxine by means of the forced swimming test, a paradigm aimed at screening potential antidepressants, and the hot-plate test, a phasic pain model. Surprisingly, the results showed that WAY-100635 produced a large decrease in the antidepressant-like effect of venlafaxine, while 8-OH-DPAT rendered effective a non-effective dose of this antidepressant. However, in the hot-plate test WAY-100635 significantly enhanced the antinociceptive effect of venlafaxine, whereas 8-OH-DPAT counteracted its antinociceptive effect. These findings show that 5-HT1A receptors play differing roles in modulating the antidepressant-like and antinociceptive effects of venlafaxine in the models investigated. The results imply that blockade of the 5-HT1A receptors in the forebrain will counteract the favourable (antidepressant-like) effect at raphe nuclei level, and consequently, the overall effect evidenced is an antagonism. This suggests a predominant role of 5-HT1A receptors located in the forebrain area for the antidepressant-like effect. In contrast, the antinociceptive effect of venlafaxine is probably potentiated due to the blockade of somatodendritic 5-HT1A receptors in the same raphe nuclei, facilitating the descending monoaminergic pain control system.
Berrocoso
Esther
E
Pharmacology and Neuroscience Research Group, Department of Neuroscience (Pharmacology and Psychiatry), School of Medicine, University of Cádiz, Cádiz, Spain.
Mico
Juan A
JA
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000493:pharmacokinetics / Q000494:pharmacology*; D003511:Cyclohexanols / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013550:Swimming / Q000523:psychology; D000069470:Venlafaxine Hydrochloride
D000700:Analgesics; D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000069470:Venlafaxine Hydrochloride