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

Sandy C Simões¹Livia N Amorim¹Yasmim A Serra¹Camila S Abreu¹Maria C E Santana¹João P C Leite¹Carla M Kaneto¹Roberta C A Costa¹Kaio R Ferreira¹Alexandre J Oliveira-Lima¹Agnieszka Sulima²Kenner C Rice²Eduardo Ary Villela Marinho¹Lais F Berro^3*

• ¹Universidade Estadual de Santa Cruz Departamento de Ciencias da Saude, Ilhéus, Brazil
• ²National Institute on Drug Abuse Molecular Targets and Medications Discovery Branch, Baltimore, United States
• ³University of Mississippi Medical Center, Jackson, United States

Studies 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. Animals 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. Our 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 reexposure, co-administration of a 5-HT2C antagonist blocked these effects. Our findings suggest that 5-HT2A and 5-HT2C receptors differentially modulate the acquisition and expression of voluntary alcohol drinking in mice.