Dose-dependence in the effect of chronic venlafaxine on the sensitivity of 5-HT4 receptors in rat hippocampus

Abstract

Venlafaxine is a serotonin and noradrenaline reuptake inhibitor (NSRI) antidepressant drug for which clinical studies have suggested a high level efficacy and a possible early action onset compared to the classical anti-depressants. It also shows efficacy in treatment-resistant depression. It has been proposed that its therapeutic effects might be due, at least in part, to adaptive changes in serotonergic neurotransmission, through the activation of the different 5-HT receptor subtypes. In this regard, 5-HT4 receptors, mainly located in several areas of central nervous system, mediate neuronal excitability of hippocampal CA1 pyramidal cells. However, the information about the involvement of this subtype in the mechanism of action of venlafaxine is unknown. We have evaluated the effects of a 21 day treatment with venlafaxine at doses of 10 and 40 mg/kg/day (p.o.) in the sensitivity of 5-HT4 receptors in rat hippocampus. The density of 5-HT4 receptors (autoradiography, [3H]GR113808) was significantly decreased in the CA1 field of hippocampus after chronic treatment with 40 mg/kg/day of venlafaxine (41.5 ± 3.9%; P < 0.05 unpaired t test), but it was unchanged after chronic treatment with 10 mg/kg/day. We also tested the effect of venlafaxine in the neuronal excitability of CA1 pyramidal cells of hippocampus after zacopride application. For the concentration of 10 lM, there was a significant reduction in the zacopride-mediated excitatory effect from rats treated with both doses of the drug, more marked for the 40 mg/kg/day dose (red = 39.5 ± 9.0% and 55.5 ± 12.2%, for 10 and 40 mg/kg/day respectively; P < 0.05). In conclusion, our results demonstrate the existence of a dose-dependent, 5-HT4 receptor desensitization following chronic administration of venlafaxine. Taking into account that a high dose is required to obtain a complete desensitization pattern, it is suggested that the noradrenergic component may play a relevant role in the regulation of 5-HT4 receptors by chronic NSRI drugs.