Muscarinic M5 receptors modulate ethanol seeking in rats

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2018-06, Vol.43 (7), p.1510-1517
• Main Authors: Berizzi, Alice E., Perry, Christina J., Shackleford, David M., Lindsley, Craig W., Jones, Carrie K., Chen, Nicola A., Sexton, Patrick M., Christopoulos, Arthur, Langmead, Christopher J., Lawrence, Andrew J.
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (muscarinic); Alcohol use; Alcoholic beverages; Allosteric properties; Caudate-putamen; Central nervous system; Drinking behavior; Drug abuse; Drug addiction; Drug self-administration; Ethanol; Health risks; Locomotor activity; Microinjection; Neostriatum; Rats; Reinstatement; Rodents; Sucrose; Sugar
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/s41386-017-0007-3

AbstractDespite the cost to both individual and society, alcohol use disorders (AUDs) remain a major health risk within society, and both relapse and heavy drinking are still poorly controlled with current medications. Here we demonstrate for the first time that a centrally active and selective negative allosteric modulator for the rat M5 muscarinic acetylcholine receptor (mAChR), ML375, decreases ethanol self-administration and attenuates cue-induced reinstatement of ethanol seeking in ethanol-preferring (iP) rats. Importantly, ML375 did not affect sucrose self-administration or general locomotor activity indicative of a selective effect on ethanol seeking. Based on the expression profile of M5 mAChRs in the brain and the distinct roles different aspects of the dorsal striatum have on long-term and short-term ethanol use, we studied whether intra-striatal microinjection of ML375 modulated ethanol intake in rats. We show in iP rats with an extensive history of ethanol intake that intra-dorsolateral (DL), but not intra-dorsomedial, striatal injections of ML375 reduced ethanol self-administration to a similar extent as the nicotinic acetylcholine receptor ligand varenicline, which has preclinical and clinical efficacy in reducing the reinforcing effects of ethanol. These data implicate the DL striatum as a locus for the effects of cholinergic-acting drugs on ethanol seeking in rats with a history of long-term ethanol use. Accordingly, we demonstrate in rats that selectively targeting the M5 mAChR can modulate both voluntary ethanol intake and cue-induced ethanol seeking and thereby provide direct evidence that the M5 mAChR is a potential novel target for pharmacotherapies aimed at treating AUDs.