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- Title
A Subpopulation of Neuronal M<sub>4</sub> Muscarinic Acetylcholine Receptors Plays a Critical Role in Modulating Dopamine-Dependent Behaviors.
- Authors
Jeon, Jongrye; Dencker, Ditte; Wörtwein, Gitta; Woldbye, David P. D.; Yinghong Cui; Davis, Albert A.; Levey, Allan I.; Schütz, Günther; Sager, Thomas N.; Mørk, Arne; Cuiling Li; Chu-Xia Deng; Fink-Jensen, Anders; Wess, Jürgen
- Abstract
Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M1-M5 mAChRs). Like otherm AChR subtypes, the M4 mAChR is widely expressed in different regions of the forebrain. Interestingly, M4 mAChRs are coexpressed with D1 dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M4 mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M4 mAChRs only in D1 dopamine receptor-expressing cells. The newly generated mutant mice displayed several striking behavioral phenotypes, including enhanced hyperlocomotor activity and increased behavioral sensitization following treatment with psychostimulants. These behavioral changes were accompanied by a lack of muscarinic inhibition of D1 dopamine receptor-mediated cAMP stimulation in the striatum and an increase in dopamine efflux in the nucleus accumbens. These novel findings demonstrate that a distinct subpopulation of neuronal M4 mAChRs plays a critical role in modulating several important dopamine-dependent behaviors. Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance.
- Subjects
ACETYLCHOLINE; MUSCARINIC receptors; CHOLINERGIC receptors; DOPAMINE receptors; SCHIZOPHRENIA; DOPAMINERGIC neurons
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 6, p2396
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3843-09.2010