Enhanced self-administration of alcohol in muscarinic acetylcholine M4 receptor knockout mice

Modulation of cholinergic neurotransmission via nicotinic acetylcholine receptors is known to alter alcohol-drinking behavior. It is not known if muscarinic acetylcholine receptor subtypes have similar effects. The muscarinic M-4 receptor is highly expressed in the brain reinforcement system and involved in regulation of cholinergic and dopaminergic transmission. Here we investigate, for the first time, the role of the M-4 receptor in alcohol consumption using M-4 knockout (M-4(-/-)) and wild-type (M-4(+/+)) mice. Experimentally naive M-4(-/-) and M-4(+/+) mice were trained to orally self-administer 5%, 8% and 10% alcohol in 60 min sessions, 6 days/week, after having undergone a standard sucrose fading training procedure on a fixed ratio schedule. The mice were further subjected to an extinction period followed by a 1 day reinstatement trial. M-4(-/-) mice consumed more alcohol at 5% and 8% compared to their M-4(+/+) littermates. The highest alcohol concentration used (10%) did not immediately result in divergent drinking patterns, but after 4 weeks of 10% alcohol self-administration, baseline levels as well as a pattern of M-4(/) mice consuming more alcohol than their M-4(+/+) controls were re-established. Moreover, the M-4(-/-) mice displayed a reduced capacity to extinguish their alcohol-seeking behavior. Taken together, alcohol consumption is elevated in M-4 mice, indicating that the M-4 receptor is involved in mediating the reinforcing effects of alcohol. The M-4 receptor should be further explored as a potential target for pharmacological (positive allosteric modulators or future agonists) treatment of alcohol use disorders. (C) 2014 Elsevier B.V. All rights reserved,