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; Jongrye Jeon; Ditte Dencker Nielsen; 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

doi:10.1523/JNEUROSCI.3843-09.2010

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

Eyepath Lab

104 Citations (Scopus)

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 language	English
Journal	Journal of Neuroscience
Volume	30
Issue number	6
Pages (from-to)	2396-405
Number of pages	10
ISSN	0270-6474
DOIs	https://doi.org/10.1523/JNEUROSCI.3843-09.2010 https://doi.org/10.1523/JNEUROSCI.3843-09.2010
Publication status	Published - 10 Feb 2010

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Jeon, J., Dencker, D., Wörtwein, G., Woldbye, D. P. D., Cui, Y., Davis, A. A., Levey, A. I., Schütz, G., Sager, T. N., Mørk, A., Li, C., Deng, C-X., Fink-Jensen, A., Wess, J., Jeon, J., Nielsen, D. D., Wörtwein, G., Woldbye, D. P. D., Cui, Y., ... Wess, J. (2010). A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors. Journal of Neuroscience, 30(6), 2396-405. https://doi.org/10.1523/JNEUROSCI.3843-09.2010, https://doi.org/10.1523/JNEUROSCI.3843-09.2010

Jeon, J, Dencker, D, Wörtwein, G , Woldbye, DPD, Cui, Y, Davis, AA, Levey, AI, Schütz, G, Sager, TN, Mørk, A, Li, C, Deng, C-X, Fink-Jensen, A, Wess, J, Jeon, J, Nielsen, DD, Wörtwein, G, Woldbye, DPD, Cui, Y, Davis, AA, Levey, AI, Schütz, G, Sager, TN, Mørk, A, Li, C, Deng, C-X, Fink-Jensen, A & Wess, J 2010, 'A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors', Journal of Neuroscience, vol. 30, no. 6, pp. 2396-405. https://doi.org/10.1523/JNEUROSCI.3843-09.2010, https://doi.org/10.1523/JNEUROSCI.3843-09.2010

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

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.",

author = "Jongrye Jeon and Ditte Dencker and Gitta W{\"o}rtwein and Woldbye, {David P D} and Yinghong Cui and Davis, {Albert A} and Levey, {Allan I} and G{\"u}nther Sch{\"u}tz and Sager, {Thomas N} and Arne M{\o}rk and Cuiling Li and Chu-Xia Deng and Anders Fink-Jensen and J{\"u}rgen Wess and Jongrye Jeon and Nielsen, {Ditte Dencker} and Gitta W{\"o}rtwein and Woldbye, {David P D} and Yinghong Cui and Davis, {Albert A} and Levey, {Allan I} and G{\"u}nther Sch{\"u}tz and Sager, {Thomas N} and Arne M{\o}rk and Cuiling Li and Chu-Xia Deng and Anders Fink-Jensen and J{\"u}rgen Wess",

note = "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",

year = "2010",

month = feb,

day = "10",

doi = "10.1523/JNEUROSCI.3843-09.2010",

language = "English",

volume = "30",

pages = "2396--405",

journal = "The Journal of neuroscience : the official journal of the Society for Neuroscience",

issn = "0270-6474",

publisher = "Society for Neuroscience",

number = "6",

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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-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.

AB - 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.

U2 - 10.1523/JNEUROSCI.3843-09.2010

DO - 10.1523/JNEUROSCI.3843-09.2010

M3 - Journal article

C2 - 20147565

SN - 0270-6474

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

IS - 6

ER -

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

Abstract

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