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

被引:314
作者
Miyakawa, T
Yamada, M
Duttaroy, A
Wess, J
机构
[1] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37205 USA
[2] Vanderbilt Univ, Med Ctr, Ctr Mol Neurosci, Nashville, TN 37205 USA
[3] NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA
关键词
acetylcholine; muscarinic receptor; M-1; receptor; hyperactivity; learning; gene targeting; knock-out; behavioral phenotyping;
D O I
10.1523/JNEUROSCI.21-14-05239.2001
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 M-1 muscarinic receptor (M1R), which is abundantly expressed in the forebrain, we subjected M-1 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 lest 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 M-1 muscarinic receptors play an important role in the regulation of locomotor activity but appear to be less critical for cognitive processes, as generally assumed.
引用
收藏
页码:5239 / 5250
页数:12
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