A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors

Jongrye Jeon, Ditte Dencker, Gitta Wörtwein, David P.D. Woldbye, Yinghong Cui, Albert A. Davis, Allan I. Levey, Günther Schütz, Thomas N. Sager, Arne Mørk, Cuiling Li, Chu Xia Deng, Anders Fink-Jensen, Jürgen Wess

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M 1-M5 mAChRs). Like other mAChR subtypes, the M4 mAChRis 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.

Original languageEnglish
Pages (from-to)2396-2405
Number of pages10
JournalJournal of Neuroscience
Volume30
Issue number6
DOIs
StatePublished - Feb 10 2010

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