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 M4 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 M4 receptor in alcohol consumption using M4 knockout (M4(-/-)) and wild-type (M4(+/+)) mice. Experimentally naïve M4(-/-) and M4(+/+) mice were trained to orally self-administer 5%, 8% and 10% alcohol in 60min 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. M4(-/-) mice consumed more alcohol at 5% and 8% compared to their M4(+/+) 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 M4(-/-) mice consuming more alcohol than their M4(+/+) controls were re-established. Moreover, the M4(-/-) mice displayed a reduced capacity to extinguish their alcohol-seeking behavior. Taken together, alcohol consumption is elevated in M4(-/-) mice, indicating that the M4 receptor is involved in mediating the reinforcing effects of alcohol. The M4 receptor should be further explored as a potential target for pharmacological (positive allosteric modulators or future agonists) treatment of alcohol use disorders.