Effects of chronic treatment with acetylcholine receptor agonists on ethanol self-administration in male cynomolgus monkeys

Abstract

Alcohol use disorder (AUD) affects 400 million individuals over age 15 worldwide but <3% of AUD patients receive medication-assisted treatment, highlighting the need for novel pharmacotherapies. Repurposing drugs already approved by the Food and Drug Administration to treat other conditions could be a productive approach. For example, the smoking cessation medication varenicline, a partial agonist at α4β2 nicotinic acetylcholine receptors, has been shown to reduce alcohol craving and moderately reduce alcohol drinking in clinical trials. Additionally, the muscarinic acetylcholine receptor agonist xanomeline, approved for managing schizophrenia when given in combination with the peripherally-restricted muscarinic acetylcholine receptor antagonist trospium (Cobenfy™), can attenuate cocaine self-administration in laboratory animals. Its mechanism of action, stimulation of M1 and M4 receptors, suggests that it could reduce alcohol drinking. Six adult male cynomolgus monkeys with 3 yrs of ethanol self-administration experience had access to ethanol 22 h/day, 5 days/week; food pellets were self-administered during the first 5 h of the session. Once ethanol intakes were stable, monkeys received varenicline (0.03-0.3 mg/kg), xanomeline (0.3-1.0 mg/kg) or a combination of xanomeline (0.56-1.7 mg/kg) plus 0.3 mg/kg trospium intramuscularly (IM) twice daily. Varenicline and xanomeline only reduced ethanol intake in the absence of moderate-to-severe adverse effects in one of six monkeys. When co-administered with the peripheral muscarinic acetylcholine receptor antagonist trospium, however, higher xanomeline doses could be administered without adverse effects and ethanol intake was decreased in three of four monkeys. Xanomeline and other acetylcholine receptor agonists have potential as alcohol use disorder pharmacotherapies but peripherally mediated adverse effects must be effectively managed.