An investigation of the role of 5-HT(2C) receptors in modifying ethanol self-administration behaviour

We have previously reported that the 5-HT uptake blocker and releaser, dexfenfluramine, attenuates ethanol intake, and that this may be mediated via a 5-HT(2C) receptor mechanism. Our goals were to further determine the contribution made by this receptor subtype in mediating the reduction in ethanol self-administration induced by dexfenfluramine using the selective 5-HT(2C) antagonist, SB242,084. Additionally, we wanted to compare dexfenfluramine's effects on ethanol motivated responding with those elicited by the 5-HT(2C) receptor agonist Ro60-0175. In male Wistar rats trained to self-administer a 12% w/v ethanol solution on an FR-4 schedule, both dexfenfluramine (0.05--2.5 mg/kg ip) and Ro60-0175 (0.1--1 mg/kg sc) produced a significant dose-dependent reduction in ethanol self-administration, which was reversed by SB242,084 (0.5 mg/kg ip). Interestingly, SB242,084 alone (0.1--1 mg/kg ip) significantly increased ethanol motivated responding in both high and low ethanol drinking animals. While dexfenfluramine had no effect on ethanol's kinetic profile, the selective 5-HT(2C) agents used had opposing effects, with the agonist Ro60-0175 decreasing and the antagonist SB242,084 increasing blood ethanol levels. Since there were incongruent drug effects on ethanol self-administration and blood ethanol levels, these data support a role for 5-HT(2C) receptors in modifying ethanol intake independent of their effects on blood ethanol kinetics. Furthermore, 5-HT(2C) receptors may exert a tonic control over ethanol self-administration behaviour, since agonist and antagonist administration had opposing effects on this behaviour.