sb-242084 and Alcoholism

This study aims to assess the therapeutic potentials of novel serotonergic compounds in treating alcohol use disorders by investigating the effects of SB242084 and buspirone on intermittent and continuous alcohol consumption in male and female mice. Adult male and female C57BL/6J mice were given two-bottle choice to 20% ethanol and water on an intermittent or continuous availability schedule. Drug testing consisted of intraperitoneal injections of 0.3, 1, 3 mg/kg SB242084 or 1, 3, 10 mg/kg buspirone, and subsequent alcohol and water consumption were measured. To monitor the drug effects on anxiety-like and locomotor behavior, the highest dose of each compound was administered before free activity in an open field. SB242084 dose-dependently attenuated alcohol drinking for intermittent alcohol drinking in male mice but did not significantly alter alcohol drinking in mice given continuous access. Two-hour and four-hour female drinking behavior was unaffected by SB242084. In comparison, buspirone not only suppressed intermittent and continuous alcohol drinking in both males and females but also reduced distance traveled in the open field test. Observed differences in responses to SB242084 between drinking groups may imply differing neural mechanisms between episodic and continuous drinking driven by serotonin. Reductions in drinking after buspirone treatment may be related to non-specific properties. These findings suggest the therapeutic potential of compounds blocking the 5-HT2C receptor for alcohol use disorders.

Topics: Alcohol Drinking; Alcoholism; Animals; Buspirone; Ethanol; Female; Male; Mice; Mice, Inbred C57BL; Serotonin

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.

Topics: Alcohol Drinking; Alcoholism; Aminopyridines; Animals; Behavior, Animal; Central Nervous System Depressants; Conditioning, Operant; Dexfenfluramine; Ethanol; Ethylamines; Indoles; Male; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists