Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M-4 muscarinic acetylcholine receptor knockout mice

Muscarinic acetylcholine receptors (M-1-M-5) regulate many key functions of the central and peripheral nervous system. Primarily because of the lack o f receptor subtype-selective ligands, the precise physiological roles of th e individual muscarinic receptor subtypes remain to be elucidated; Interest ingly, the M-4 receptor subtype is expressed abundantly in the striatum and various other forebrain regions. To study its potential role in the regula tion of locomotor activity and other central functions, we used gene-target ing technology to create mice that lack functional M-4 receptors. Pharmacol ogic analysis of M-4 receptor-deficient mice indicated that M-4 receptors a re not required for muscarinic receptor-mediated analgesia, tremor, hypothe rmia, and salivation. Strikingly, M-4 receptor-deficient mice showed an inc rease in basal locomotor activity and greatly enhanced locomotor responses (as compared with their wild-type littermates) after activation of D1 dopam ine receptors. These results indicate that M-4 receptors exert inhibitory c ontrol on D1 receptor-mediated locomotor stimulation, probably at the level of striatal projection neurons where the two receptors are coexpressed at high levels. Our findings offer new perspectives for the treatment of Parki nson's disease and other movement disorders that are characterized by an im balance between muscarinic cholinergic and dopaminergic neurotransmission.