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.
Hodge
Clyde W
CW
Department of Psychiatry and Bowles Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. chodge@md.unc.edu
Kelley
Stephen P
SP
Bratt
Alison M
AM
Iller
Kimberly
K
Schroeder
Jason P
JP
Besheer
Joyce
J
D000428:Alcohol Drinking / Q000523:psychology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007191:Indazoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects* / Q000235:genetics; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013549:Sweetening Agents / Q000494:pharmacology; D013649:Taste / Q000187:drug effects; D014326:Tropanes / Q000494:pharmacology
D007191:Indazoles; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D013549:Sweetening Agents; D014326:Tropanes; C061531:LY 278584