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.

Targeted gene deletion of the 5-HT3A receptor subunit produces an anxiolytic phenotype in mice.

Anxiety disorders are the most common psychiatric disorders. Typical medications used to treat patients are benzodiazepines or antidepressants that target serotonin (5-HT) activity. The ionotropic 5-HT(3) receptor has emerged as a potential therapeutic target because selective antagonist compounds reduce anxiety in rodents, primates, and humans. 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. It is not known if specific molecular subunits of the 5-HT(3) receptor modulate anxiety. To address this issue, we characterized anxiety-like behavior of mice with a targeted deletion of the 5-HT(3A) receptor subunit gene in the light/dark box, elevated plus maze, and novelty interaction animal models of anxiety. 5-HT(3A) null mice exhibited an anxiolytic behavioral phenotype that was highly correlated across behavioral measures. This evidence indicates that the 5-HT(3A) molecular subunit influences anxiety-like behavior. Pharmacotherapy that targets specifically the 5-HT(3A) receptor subunit may provide a novel treatment for anxiety disorders.