Abstract
Despite 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.
Highlights
Despite the vast impact alcohol use disorders (AUDs) have within society [1, 2], current pharmacotherapies remain inadequate
We show that intra-dorsolateral (DL), but not intra-dorsomedial (DM), striatal injection of ML375 reduced ethanol self-administration to a similar extent as the nicotinic ACh receptor ligand varenicline, which has both preclinical and clinical efficacy in reducing the reinforcing effects of ethanol [20,21,22,23] we show for the first time that selectively targeting the M5 muscarinic acetylcholine (ACh) receptor (mAChR) can modulate the reinforcing effects of ethanol in rat models of ethanol seeking
ML380 had no DISCUSSION Our results provide the first evidence that a selective, central nervous system (CNS)-penetrant, M5 mAChR negative allosteric modulator (NAM) attenuates ethanol self-administration and cue-induced reinstatement of ethanol seeking
Summary
Despite the vast impact alcohol use disorders (AUDs) have within society [1, 2], current pharmacotherapies remain inadequate. Used drugs, such as naltrexone and acamprosate, have been linked with low patient compliance due to adverse side effects, leading to high relapse rates [3, 4]. M5 mAChR KO mice demonstrated reduced conditioned place preference to morphine and attenuated morphine withdrawal signs [13]. Taken together, these data support a role of M5 mAChRs in modulating the reinforcing effects of drugs of abuse. To date, the M5 mAChR has not been explicitly studied in models of ethanol use and/or relapse
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