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

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.; Berro, Lais F. · 2025 · DOAJ

DOI: 10.3389/fnins.2025.1639344

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Summary

This study investigates the distinct roles of serotonin 5-HT2A and 5-HT2C receptors in the acquisition and expression of voluntary alcohol drinking in male mice. Motivated by the high relapse rates associated with alcohol use disorder (AUD) and contradictory evidence regarding serotonergic mechanisms, the researchers aimed to clarify how these specific receptor subtypes modulate alcohol consumption during initial learning versus relapse-like states. The study specifically examined whether 5-HT2A and 5-HT2C antagonists, administered alone or in combination, affect alcohol intake and preference during the acquisition phase and after periods of abstinence. The experimental design utilized Swiss male mice subjected to a two-bottle choice procedure with intermittent access to 10% alcohol. Experiment 1 assessed the effects of pre-acquisition treatment with the 5-HT2A antagonist M100907 (M100), the 5-HT2C antagonist SB242084 (SB), or their combination, administered intraperitoneally at 1 mg/kg prior to each of 30 acquisition sessions. Experiment 2 evaluated the effects of post-acquisition treatment, where mice with established drinking habits received the same drug regimens during abstinence periods preceding re-exposure sessions. Alcohol consumption and preference were measured across acquisition, abstinence, and re-exposure phases. Results from Experiment 1 demonstrated that combined treatment with M100 and SB significantly reduced both alcohol intake and preference during the acquisition phase compared to vehicle controls, whereas neither antagonist alone produced this effect. During re-exposure tests following abstinence, the combined treatment continued to suppress alcohol preference, while M100 alone significantly reduced alcohol intake. In contrast, Experiment 2 revealed that combined treatment administered after the establishment of drinking habits did not alter the expression of drinking behavior during re-exposure. However, post-acquisition treatment with M100 alone significantly decreased alcohol intake and preference during re-exposure. Notably, co-administration of SB blocked the suppressive effects of M100 on alcohol intake, indicating an antagonistic interaction between the two receptor pathways during the expression phase. These findings indicate that 5-HT2A and 5-HT2C receptors differentially modulate alcohol drinking depending on the stage of the drinking cycle. The synergistic effect of combined antagonism during acquisition suggests that both receptors contribute to the initial development of alcohol-seeking behavior. Conversely, the opposing effects observed during the expression phase imply that 5-HT2A and 5-HT2C mechanisms may function independently or competitively in maintaining established drinking habits. This distinction highlights the complexity of serotonergic involvement in AUD and suggests that pharmacological strategies targeting these receptors may need to be tailored to specific phases of alcohol use, such as prevention versus relapse prevention.

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