EFFECTS OF NOVEL LSD DERIVATIVES ON ALCOHOL CONSUMPTION AND MOTIVATIONAL REWARD IN MALE AND FEMALE RATS

Alcohol Use Disorder (AUD) is a chronically relapsing and heterogenous disorder, often marked by persistent anhedonia which is difficult to treat with currently available pharmacotherapies. We have recently synthesized novel LSD derivatives which lack 5-HT2b agonistic activity, including both full (2AB-3006) and partial (2AB-3007) 5-HT2a agonists. Here we compared the effects of these compounds on alcohol consumption and chronic alcohol-induced motivational anhedonia. Upon reaching stable levels of baseline drinking using a modified Drinking-in-the-Dark protocol, rats received either 2AB-3006, 2AB-3007, or vehicle in a separate context, and 1h later were allowed 4-h access to 20% ethanol. Motivational reward was subsequently assessed via operant responding under a progressive ratio (PR) schedule of reinforcement. Following task acquisition, daily PR sessions were conducted 5d/week either during drinking or abstinent periods. Following 3d of abstinence, rats received a single injection of either 2AB-3006, 2AB-3007, or vehicle and PR responding was assessed 2h later and for 4d following treatment. Interestingly, 2AB-3006 significantly reduced alcohol consumption acutely in female—but not male—rats, whereas 2AB-3007 was without effect. Likewise, 2AB-3006, but not 2AB-3007, significantly attenuated chronic alcohol-induced motivational anhedonia for up to 72h post-treatment during abstinence in female rats only. These findings support and warrant further investigation into the therapeutic potential of 2AB-3006 for reducing problematic alcohol consumption and use-related anhedonia, and indicate that hallucinogenic properties may play an important role in some of the therapeutic benefits of psychedelic compounds.