TY - JOUR T1 - RTICBM-74 is a Brain-Penetrant CB<sub>1</sub> Receptor Allosteric Modulator that Reduces Alcohol Intake in Rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.121.000919 SP - JPET-AR-2021-000919 AU - Dennis Lovelock AU - Thuy Nguyen AU - Kalynn Van Voorhies AU - Yanan Zhang AU - Joyce Besheer Y1 - 2021/01/01 UR - http://jpet.aspetjournals.org/content/early/2021/12/20/jpet.121.000919.abstract N2 - The endocannabinoid system is implicated in the neuronal mechanisms of alcohol use disorder (AUD), with the cannabinoid receptor subtype 1 (CB1) representing a promising target for AUD therapeutic interventions. We have previously shown negative allosteric modulators (NAMs) of the CB1 receptor attenuated the reinstatement of other drugs of abuse including cocaine and methamphetamine in rats; however, their effects on alcohol-related behaviors have not been investigated. Here, we tested the pharmacokinetic properties of one such CB1 NAM, RTICBM-74, and its effects on alcohol self-administration in rats. RTICBM-74 showed low aqueous solubility and high protein binding but had excellent half-life and low clearance against rat liver microsomes and hepatocytes, and excellent brain penetrance in rats. RTICBM-74 pretreatment specifically reduced alcohol intake across a range of doses in male or female Wistar or Long-Evans rats that were trained to self-administer alcohol. These effects were similar to the CB1 antagonist/inverse agonist rimonabant which was tested as a positive control. Importantly, RTICBM-74 was effective at reducing alcohol intake at doses that did not affect locomotion or sucrose self-administration. Our findings suggest that CB1 NAMs such as RTICBM-74 have promising therapeutic potential in treatment of AUD. Significance Statement The present works shows that a newly developed CB1 NAM with an excellent pharmacokinetic profile reduces alcohol self-administration in rats, suggesting potential therapeutic relevance for the treatment of AUD. ER -