Reduced signal transduction by 5-HT 4 receptors after long-term venlafaxine treatment in rats

Abstract

BACKGROUND AND PURPOSE The 5-HT 4 receptor may be a target for antidepressant drugs. Here we have examined the effects of the dual antidepressant, venlafaxine, on 5-HT 4 receptor-mediated signalling events. EXPERIMENTAL APPROACH The effects of 21 days treatment (p.o.) with high (40 mg·kg -1) and low (10 mg·kg -1) doses of venlafaxine, were evaluated at different levels of 5-HT 4 receptor-mediated neurotransmission by using in situ hybridization, receptor autoradiography, adenylate cyclase assays and electrophysiological recordings in rat brain. The selective noradrenaline reuptake inhibitor, reboxetine (10 mg·kg -1, 21 days) was also evaluated on 5-HT 4 receptor density. KEY RESULTS Treatment with a high dose (40 mg·kg -1) of venlafaxine did not alter 5-HT 4 mRNA expression, but decreased the density of 5-HT 4 receptors in caudate-putamen (% reduction = 26 ± 6), hippocampus (% reduction = 39 ± 7 and 39 ± 8 for CA1 and CA3 respectively) and substantia nigra (% reduction = 49 ± 5). Zacopride-stimulated adenylate cyclase activation was unaltered following low-dose treatment (10 mg·kg -1) while it was attenuated in rats treated with 40 mg·kg -1 of venlafaxine (% reduction = 51 ± 2). Furthermore, the amplitude of population spike in pyramidal cells of CA1 of hippocampus induced by zacopride was significantly attenuated in rats receiving either dose of venlafaxine. Chronic reboxetine did not modify 5-HT 4 receptor density. CONCLUSIONS AND IMPLICATIONS Our data indicate a functional desensitization of 5-HT 4 receptors after chronic venlafaxine, similar to that observed after treatment with the classical selective inhibitors of 5-HT reuptake. © 2010 The British Pharmacological Society.