Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice
- David J. Gerber*,
- Tatyana D. Sotnikova†,
- Raul R. Gainetdinov†,
- Shu Ying Huang*,
- Marc G. Caron†, and
- Susumu Tonegawa*,‡
- *Howard Hughes Medical Institute, RIKEN–Massachusetts Institute of Technology Neuroscience Research Center, Center for Learning and Memory, Departments of Biology and Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; and †Howard Hughes Medical Institute, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710
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Contributed by Susumu Tonegawa
Abstract
Acetylcholine serves an important modulatory role in the central nervous system. Pharmacological evidence has suggested that cholinergic activity can modulate central dopaminergic transmission; however, the nature of this interaction and the receptors involved remain undefined. In this study we have generated mice lacking the M1 muscarinic acetylcholine receptor and examined the effects of M1 deletion on dopaminergic transmission and locomotor behavior. We report that M1 deficiency leads to elevated dopaminergic transmission in the striatum and significantly increased locomotor activity. M1-deficient mice also have an increased response to the stimulatory effects of amphetamine. Our results provide direct evidence for regulation of dopaminergic transmission by the M1 receptor and are consistent with the idea that M1 dysfunction could be a contributing factor in psychiatric disorders in which altered dopaminergic transmission has been implicated.
Footnotes
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↵ ‡ To whom reprint requests should be addressed at: Center for Learning and Memory, Massachusetts Institute of Technology, Building E25-353, 77 Massachusetts Avenue, Cambridge, MA 02139. E-mail: tonegawa{at}mit.edu.
- Abbreviations:
- DOPAC,
- 3,4-dihydroxyphenylacetic acid;
- HVA,
- homovanillic acid
- Copyright © 2001, The National Academy of Sciences
