Generation and pharmacological analysis of M 2 and M 4 muscarinic receptor knockout mice

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Muscarinic acetylcholine receptors (M 1–M 5) play important roles in the modulation of many key functions of the central and peripheral nervous system. To explore the physiological roles of the two G i-coupled muscarinic receptors, we disrupted the M 2 and M 4 receptor genes in mice by using a gene targeting strategy. Pharmacological and behavioral analysis of the resulting mutant mice showed that the M 2 receptor subtype is critically involved in mediating three of the most striking central muscarinic effects, tremor, hypothermia, and analgesia. These studies also indicated that M 4 receptors are not critically involved in these central muscarinic responses. However, M 4 receptor-deficient mice showed an increase in basal locomotor activity and greatly enhanced locomotor responses following drug-induced activation of D1 dopamine receptors. This observation is consistent with the concept that M 4 receptors exert inhibitory control over D1 receptor-mediated locomotor stimulation, probably at the level of striatal projection neurons where the two receptors are known to be coexpressed. These findings emphasize the usefulness of gene targeting approaches to shed light on the physiological and pathophysiological roles of the individual muscarinic receptor subtypes.