A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors.
Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M(1)-M(5) mAChRs). Like other mAChR subtypes, the M(4) mAChR is widely expressed in different regions of the forebrain. Interestingly, M(4) mAChRs are coexpressed with D(1) dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M(4) mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M(4) mAChRs only in D(1) 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 D(1) 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 M(4) 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.
Molecular Signaling Section, and Mammalian Genetics Section, Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Jongrye
J
Jeon
Ditte
D
Dencker
Gitta
G
Wörtwein
David P D
DP
Woldbye
Yinghong
Y
Cui
Albert A
AA
Davis
Allan I
AI
Levey
Günther
G
Schütz
Thomas N
TN
Sager
Arne
A
Mørk
Cuiling
C
Li
Chu-Xia
CX
Deng
Anders
A
Fink-Jensen
Jürgen
J
Wess
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D004298:Dopamine / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000502:physiology*; D009714:Nucleus Accumbens / Q000378:metabolism; D043588:Receptor, Muscarinic M4 / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000096:biosynthesis
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D043588:Receptor, Muscarinic M4; D017447:Receptors, Dopamine D1; D000661:Amphetamine; D000242:Cyclic AMP; D003042:Cocaine; D004298:Dopamine