AUTHOR=Simões Sandy C. , Amorim Livia N. , Serra Yasmim A. , Abreu Camila S. , Santana Maria Clara E. , Leite João P. C. , Kaneto Carla M. , Costa Roberta C. A. , Ferreira Kaio R. , de Oliveira Isabelle C. S. , Oliveira-Lima Alexandre J. , Sulima Agnieszka , Rice Kenner C. , Marinho Eduardo A. V. , Berro Lais F. 

TITLE=Serotonin 5-HT2A and 5-HT2C receptors differentially modulate the acquisition and expression of voluntary alcohol drinking in male mice

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 19 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1639344

DOI=10.3389/fnins.2025.1639344

ISSN=1662-453X

ABSTRACT=IntroductionStudies suggest that serotonin (5-HT) plays an important role in alcohol use disorder (AUD). While several receptor subtypes modulate the role of 5-HT in AUD, evidence suggests that 5-HT2A and 5-HT2C receptors may be directly involved in alcohol drinking due to their interaction with the mesolimbic dopaminergic system. The aim of the present study was to investigate the effects of 5-HT2A and 5-HT2C antagonists, alone or in combination, on the acquisition and expression (i.e., return to alcohol drinking after a period of abstinence/treatment) of voluntary alcohol drinking in male mice.MethodsAnimals had intermittent access to alcohol (10% v/v) in a two-bottle choice procedure for 30 days (acquisition), and were then submitted to alcohol re-exposure sessions after periods of abstinence. Vehicle, the 5-HT2A receptor antagonist M100907 (M100, 1 mg/kg) and/or the 5-HT2C receptor antagonist SB242084 (SB, 1 mg/kg) were administered either prior to acquisition (Experiment 1) or during the abstinence period preceding re-exposure sessions (Experiment 2). During re-exposure tests, animals were submitted to the same conditions as during acquisition, with no treatments prior to those sessions.ResultsOur findings show that combined treatment with 5-HT2A and 5-HT2C antagonists, but not treatment with the antagonists separately, reduced alcohol drinking and preference when administered immediately before acquisition (Experiment 1). Combined treatment with 5-HT2A and 5-HT2C antagonists after the establishment of voluntary alcohol drinking did not alter the expression of drinking behavior (Experiment 2). On the other hand, while post-acquisition treatment with a 5-HT2A antagonist alone decreased alcohol intake and preference during re-exposure, co-administration of a 5-HT2C antagonist blocked these effects.DiscussionOur findings suggest that 5-HT2A and 5-HT2C receptors differentially modulate the acquisition and expression of voluntary alcohol drinking in mice.