5-HT(3A) receptor subunit is required for 5-HT3 antagonist-induced reductions in alcohol drinking.

The ionotropic serotonin subtype-3 (5-HT3) receptor has emerged as a potential therapeutic target in the treatment of alcohol abuse and alcoholism because selective pharmacological antagonists reduce alcohol consumption in preclinical and clinical models. 5-HT binds to the extracellular N-terminus of the 5-HT(3A) receptor subunit but receptor activation is also enhanced by distinct allosteric sites, which indicates the presence of other receptor subunits. It is not known if specific molecular subunits of the 5-HT3 receptor modulate alcohol drinking. To address this issue, we characterized acute locomotor response to alcohol and alcohol consumption in a two-bottle home-cage procedure by congenic C57BL/6J mice with a targeted deletion of the 5-HT(3A) receptor subunit gene. 5-HT(3A)-null mice did not differ from wild-type littermate controls on measures of spontaneous locomotor activity, habituation to a novel environment, or locomotor response to ethanol (0, 0.5, 1, or 2 g/kg). Moreover, null mice did not differ from controls on measures of ethanol (2-10%) intake and preference during or after a two-bottle home-cage sucrose fading procedure. Systemic administration of the 5-HT3 antagonist LY-278,584 (0-10 mg/kg) decreased intake of both sweetened (2% sucrose+10% ethanol) and unsweetened (10% ethanol) ethanol in wild-type mice only. These findings indicate that reduction of alcohol drinking produced by 5-HT3 antagonism is dependent on the presence of 5-HT(3A)-containing receptors.

Neuropeptide-Y Y5 receptors modulate the onset and maintenance of operant ethanol self-administration.

BACKGROUND: Neuropeptide Y (NPY) is the most abundant and widely distributed peptide in the mammalian central nervous system and increases feeding behavior at NPY Y1 or Y5 receptor subtypes. Recent pharmacological and mutant mouse data indicate that NPY activity at its receptors can influence ethanol self-administration, although the direction and strength of this influence are not clear. METHODS: Effects of the novel NPY Y5 receptor antagonist L-152,804 on the onset and maintenance of operant self-administration were examined in male C57BL/6J mice, which were trained to self-administer ethanol (10% v/v) versus water via the sucrose substitution method during 16 hr overnight sessions. After 4 months of baseline responding, mice were injected with L-152,804 (0, 10, 30, or 60 mg/kg, intraperitoneally) before operant sessions. Potential locomotor effects of L-152,804 and possible interaction with the sedative properties of ethanol also were examined. RESULTS: All three doses of L-152,804 significantly delayed the onset of ethanol-reinforced responding relative to vehicle injection. L-152,804 produced no effect on the total number of ethanol- or water-reinforced responses per 16 hr session. However, L-152,804 selectively modulated the temporal distribution of ethanol-reinforced responding depending on the dose (10 and 60 mg/kg) and time point measured in a manner consistent with blockade of ethanol reinforcement. Additional experiments determined that L-152,804 (10 or 60 mg/kg) did not alter spontaneous locomotor activity or influence the sedative effects of ethanol (4 g/kg). CONCLUSIONS: These results indicate that blockade NPY Y5 receptor activity modulates the onset and maintenance of ethanol self-administration. For this reason, NPY-Y5 receptor antagonists may be useful in medical management of alcohol abuse and alcoholism.