Frontiers in neuroscience · 2025
Serotonin 5-HT2A and 5-HT2C receptors differentially modulate the acquisition and expression of voluntary alcohol drinking in male mice.
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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
Аннотация
INTRODUCTION: 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.
METHODS: 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.
RESULTS: 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 re-exposure, co-administration of a 5-HT2C antagonist blocked these effects.
DISCUSSION: Our findings suggest that 5-HT2A and 5-HT2C receptors differentially modulate the acquisition and expression of voluntary alcohol drinking in mice.
METHODS: 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.
RESULTS: 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 re-exposure, co-administration of a 5-HT2C antagonist blocked these effects.
DISCUSSION: Our findings suggest that 5-HT2A and 5-HT2C receptors differentially modulate the acquisition and expression of voluntary alcohol drinking in mice.