Selective inhibition of M5 muscarinic acetylcholine receptors attenuates cocaine self-administration in rats

Cocaine use disorder (CUD) remains a debilitating health problem in the United States for which there are no Food and Drug Administration-approved treatment options. Accumulating anatomical and electrophysiological evidence indicates that the Muscarinic Acetylcholine Receptor (mAChR) subtype 5 (M₅ ) plays a critical role in the regulation of the mesolimbic dopaminergic reward circuitry, a major site of action for cocaine and other psychostimulants. In addition, M₅ knockout mice exhibit reduced cocaine self-administration behaviors with no differences in sugar pellet-maintained responding relative to wild-type mice. These findings suggest that selective inhibition of M₅ mAChR may provide a novel pharmacological approach for targeting CUD. Recently, we reported the synthesis and characterization of ML375, a selective negative allosteric modulator (NAM) for the rat and human M₅ mAChR with optimized pharmacokinetic properties for systemic dosing in rodents. In the present study, male Sprague-Dawley rats were trained to self-administer intravenous cocaine (0.1-0.75 mg/kg/infusion) under a 10-response fixed ratio or a progressive ratio schedule of reinforcement. Under both schedules of reinforcement, ML375 produced dose-related reductions in cocaine self-administration. ML375 also modestly reduced sugar pellet-maintained responding on the 10-response, fixed ratio schedule but had no effect under a progressive ratio schedule of reinforcement. Further, ML375 did not affect general motor output as assessed by a rotarod test. Collectively, these results provide the first demonstration that selective inhibition of M₅ using the M₅ NAM ML375 can attenuate both the reinforcing effects and the relative strength of cocaine and suggest that M₅ NAMs may represent a promising, novel treatment approach for CUD.