The Effect of Serotonin 5-HT_2C Receptor Modulation on Binge Drinking and Alcohol-Seeking in Female Mice

Alcohol misuse remains a leading cause of preventable death worldwide, prompting research into novel pharmacotherapies for alcohol use disorder (AUD). This study investigated the therapeutic potential of full agonism or positive allosteric modulation of the serotonin 2C receptor (5-HT_2CR) in addressing alcohol binge drinking and seeking behaviours in mice. Using a drinking-in-the-dark paradigm and a context-induced reinstatement model following punishment-imposed abstinence, we assessed the acute effects of 5-HT_2CR ligands lorcaserin, CYD-1-79, VA012 and CTW0415 on alcohol intake and seeking behaviours in mice. Results showed that while lorcaserin effectively reduced both alcohol consumption and seeking behaviours, the 5-HT_2CR positive allosteric modulators (PAMs) did not significantly alter these behaviours over the range of doses examined. These findings suggest that 5-HT_2CR PAMs, at the tested doses, may lack intrinsic efficacy in modulating alcohol use. However, our lorcaserin data demonstrate that targeting 5-HT_2CR remains a valid approach to reduce behaviours associated with AUD.