Generation and pharmacological analysis of M-2 and M-4 muscarinic receptorknockout mice

Muscarinic acetylcholine receptors (M-1-M-5) play important roles in the mo dulation of many key functions of the central and peripheral nervous system . To explore the physiological roles of the two G(i)-coupled muscarinic rec eptors, we disrupted the M-2 and M-4 receptor genes in mice by using a gene targeting strategy, pharmacological and behavioral analysis of the resulti ng 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 receptor s are not critically involved in these central muscarinic responses. Howeve r, M-4 receptor-deficient mice showed an increase in basal locomotor activi ty and greatly enhanced locomotor responses following drug-induced activati on of D1 dopamine receptors, This observation is consistent with the concep t that M-4 receptors exert inhibitory control over D1 receptor-mediated loc omotor stimulation, probably at the level of striatal projection neurons wh ere the two receptors are known to be coexpressed. These findings emphasize the usefulness of gene targeting approaches to shed light on the physiolog ical and pathophysiological roles of the individual muscarinic receptor sub types. (C) 2001 Elsevier Science Inc. All rights reserved.