Hyperactivity and intact hippocampus-dependent learning in mice lacking the M₁ muscarinic acetylcholine receptor

Members of the muscarinic acetylcholine receptor family are thought to play key roles in the regulation of a large number of important functions of the CNS. However, the precise roles of the individual muscarinic receptor subtypes in modulating these processes are not well understood at present, primarily because of the lack of ligands with sufficient receptor subtype selectivity. To investigate the behavioral significance of the M₁ muscarinic receptor (M₁R), which is abundantly expressed in the forebrain, we subjected M₁ receptor-deficient mice (M₁R^-/- mice) to a battery of behavioral tests. M₁R^-/- mice showed no significant impairments in neurological reflexes, motor coordination, pain sensitivity, and prepulse inhibition. Strikingly, however, M₁R^-/- mice consistently exhibited a pronounced increase in locomotor activity in various tests, including open field, elevated plus maze, and light/dark transition tests. Moreover, M₁R^-/- mice showed reduced immobilization in the Porsolt forced swim test and reduced levels of freezing after inescapable footshocks, suggesting that M₁R^-/- mice are hyperactive under stressful conditions as well. An increased number of social contacts was observed in a social interaction test. Surprisingly, M₁R^-/- mice displayed no significant cognitive impairments in the Morris water maze and in contextual fear conditioning. M₁R^-/- mice showed slight performance deficits in auditory-cued fear conditioning and in an eight-arm radial maze, most likely because of the hyperactivity phenotype displayed by the M₁R^-/- mice. Our results indicate that M₁ muscarinic receptors play an important role in the regulation of locomotor activity but appear to be less critical for cognitive processes, as generally assumed.