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

Gunter BW, Gould RW, Bubser M, McGowan KM, Lindsley CW, Jones CK
Addict Biol. 2018 23 (5): 1106-1116

PMID: 29044937 · PMCID: PMC5906200 · DOI:10.1111/adb.12567

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 (M ) 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, M 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 M 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 M 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 M using the M NAM ML375 can attenuate both the reinforcing effects and the relative strength of cocaine and suggest that M NAMs may represent a promising, novel treatment approach for CUD.

© 2017 Society for the Study of Addiction.

MeSH Terms (16)

Animals Behavior, Animal Cocaine Cocaine-Related Disorders Conditioning, Operant Disease Models, Animal Dopamine Uptake Inhibitors Dose-Response Relationship, Drug Male Mice Rats Rats, Sprague-Dawley Receptor, Muscarinic M5 Reinforcement Schedule Reward Self Administration

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