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.