A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors
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A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors. / Jeon, Jongrye; Dencker, Ditte; Wörtwein, Gitta; Woldbye, David P D; Cui, Yinghong; Davis, Albert A; Levey, Allan I; Schütz, Günther; Sager, Thomas N; Mørk, Arne; Li, Cuiling; Deng, Chu-Xia; Fink-Jensen, Anders; Wess, Jürgen; Jeon, Jongrye; Nielsen, Ditte Dencker; Wörtwein, Gitta; Woldbye, David P D; Cui, Yinghong; Davis, Albert A; Levey, Allan I; Schütz, Günther; Sager, Thomas N; Mørk, Arne; Li, Cuiling; Deng, Chu-Xia; Fink-Jensen, Anders; Wess, Jürgen.
In: Journal of Neuroscience, Vol. 30, No. 6, 10.02.2010, p. 2396-405.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors
AU - Jeon, Jongrye
AU - Dencker, Ditte
AU - Wörtwein, Gitta
AU - Woldbye, David P D
AU - Cui, Yinghong
AU - Davis, Albert A
AU - Levey, Allan I
AU - Schütz, Günther
AU - Sager, Thomas N
AU - Mørk, Arne
AU - Li, Cuiling
AU - Deng, Chu-Xia
AU - Fink-Jensen, Anders
AU - Wess, Jürgen
AU - Jeon, Jongrye
AU - Nielsen, Ditte Dencker
AU - Wörtwein, Gitta
AU - Woldbye, David P D
AU - Cui, Yinghong
AU - Davis, Albert A
AU - Levey, Allan I
AU - Schütz, Günther
AU - Sager, Thomas N
AU - Mørk, Arne
AU - Li, Cuiling
AU - Deng, Chu-Xia
AU - Fink-Jensen, Anders
AU - Wess, Jürgen
N1 - Keywords: Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Central Nervous System Stimulants; Cocaine; Corpus Striatum; Cyclic AMP; Dopamine; Mice; Mice, Mutant Strains; Motor Activity; Neurons; Nucleus Accumbens; Receptor, Muscarinic M4; Receptors, Dopamine D1
PY - 2010/2/10
Y1 - 2010/2/10
N2 - 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.
AB - 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.
U2 - 10.1523/JNEUROSCI.3843-09.2010
DO - 10.1523/JNEUROSCI.3843-09.2010
M3 - Journal article
C2 - 20147565
VL - 30
SP - 2396
EP - 2405
JO - The Journal of neuroscience : the official journal of the Society for Neuroscience
JF - The Journal of neuroscience : the official journal of the Society for Neuroscience
SN - 0270-6474
IS - 6
ER -
ID: 19096703