Pronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice

Members of the muscarinic acetylcholine receptor family (M1-M5) are known t o be involved in a great number of important central and peripheral physiol ogical and pathophysiological processes. Because of the overlapping express ion patterns of the M1-M5 muscarinic receptor subtypes and the lack of liga nds endowed with sufficient subtype selectivity, the precise physiological functions of the individual receptor subtypes remain to be elucidated. To e xplore the physiological roles of the M2 muscarinic receptor, we have gener ated mice lacking functional M2 receptors bg using targeted mutagenesis in mouse embryonic stem cells. The resulting mutant mice were analyzed in seve ral behavioral and pharmacologic tests. These studies showed that the M2 mu scarinic receptor subtype, besides its well documented involvement in the r egulation of heart rate, plays a key role in mediating muscarinic receptor- dependent movement and temperature control as well as antinoeiceptive respo nses, three of the most prominent central muscarinic effects, These results offer a rational basis for the development of novel muscarinic drugs.