Pharmacology and Therapeutics - Research Publications

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Author: Chen, Nicola × Author: Christopoulos, Arthur × Author: Sexton, Patrick × End date: 2020 × Start date: 2010 ×

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    Muscarinic M5 receptors modulate ethanol seeking in rats
    Berizzi, AE ; Perry, CJ ; Shackleford, DM ; Lindsley, CW ; Jones, CK ; Chen, NA ; Sexton, PM ; Christopoulos, A ; Langmead, CJ ; Lawrence, AJ (NATURE PUBLISHING GROUP, 2018-06)
    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.