Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release

被引：120

作者：

Foster, Daniel J. ^{[1
,8
]}

Wilson, Jermaine M. ^{[1
,8
]}

Remke, Daniel H. ^{[1
,8
]}

Mahmood, M. Suhaib ^{[1
,8
]}

Uddin, M. Jashim ^{[1
,4
,5
]}

Wess, Jurgen ^{[9
]}

Patel, Sachin ^{[2
,3
,6
]}

Marnett, Lawrence J. ^{[1
,4
,5
]}

Niswender, Colleen M. ^{[1
,8
]}

Jones, Carrie K. ^{[1
,8
]}

Xiang, Zixiu ^{[1
,8
]}

Lindsley, Craig W. ^{[1
,4
,8
]}

Rook, Jerri M. ^{[1
,8
]}

Conn, P. Jeffrey ^{[1
,6
,7
,8
]}

机构：

[1] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Dept Psychiat & Behav Sci, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA

[6] Vanderbilt Univ, Vanderbilt Brain Inst, Nashville, TN 37232 USA

[7] Vanderbilt Univ, Vanderbilt Kennedy Ctr, Nashville, TN 37232 USA

[8] Vanderbilt Univ, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[9] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA

来源：

NEURON | 2016年 / 91卷 / 06期

关键词：

KNOCK-OUT MICE; MUSCARINIC ACETYLCHOLINE; CHOLINERGIC INTERNEURONS; MOLECULAR-MECHANISMS; AGONIST XANOMELINE; SCHIZOPHRENIA; TRANSMISSION; NEURONS; ACTIVATION; EXPRESSION;

D O I：

10.1016/j.neuron.2016.08.017

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Muscarinic receptors represent a promising therapeutic target for schizophrenia, but the mechanisms underlying the antipsychotic efficacy of muscarinic modulators are not well understood. Here, we report that activation of M-4 receptors on striatal spiny projection neurons results in a novel form of dopaminergic regulation resulting in a sustained depression of striatal dopamine release that is observed more than 30 min after removal of the muscarinic receptor agonist. Furthermore, both the M-4-mediated sustained inhibition of dopamine release and the antipsychotic- like efficacy of M-4 activators were found to require intact signaling through CB2 cannabinoid receptors. These findings highlight a novel mechanism by which striatal cholinergic and cannabinoid signaling leads to sustained reductions in dopaminergic transmission and concurrent behavioral effects predictive of antipsychotic efficacy.

引用

页码：1244 / 1252

页数：9

共 28 条

[1] Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease [J].

Bodick, NC ;

Offen, WW ;

Levey, AI ;

Cutler, NR ;

Gauthier, SG ;

Satlin, A ;

Shannon, HE ;

Tollefson, GD ;

Rasmussen, K ;

Bymaster, FP ;

Hurley, DJ ;

Potter, WZ ;

Paul, SM .

ARCHIVES OF NEUROLOGY, 1997, 54 (04) :465-473

[2] Selective Activation of M4 Muscarinic Acetylcholine Receptors Reverses MK-801-Induced Behavioral Impairments and Enhances Associative Learning in Rodents [J].

Bubser, Michael ;

Bridges, Thomas M. ;

Dencker, Ditte ;

Gould, Robert W. ;

Grannan, Michael ;

Noetzel, Meredith J. ;

Lamsal, Atin ;

Niswender, Colleen M. ;

Daniels, J. Scott ;

Poslusney, Michael S. ;

Melancon, Bruce J. ;

Tarr, James C. ;

Byers, Frank W. ;

Wess, Juergen ;

Duggan, Mark E. ;

Dunlop, John ;

Wood, Michael W. ;

Brandon, Nicholas J. ;

Wood, Michael R. ;

Lindsley, Craig W. ;

Conn, P. Jeffrey ;

Jones, Carrie K. .

ACS CHEMICAL NEUROSCIENCE, 2014, 5 (10) :920-942

[3] Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, in vivo phosphoinositide hydrolysis, and pilocarpine-induced seizure activity [J].

Bymaster, FP ;

Carter, PA ;

Yamada, M ;

Gomeza, J ;

Wess, J ;

Hamilton, SE ;

Nathanson, NM ;

McKinzie, DL ;

Felder, CC .

EUROPEAN JOURNAL OF NEUROSCIENCE, 2003, 17 (07) :1403-1410

[4] Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100 [J].

Byun, Nellie E. ;

Grannan, Michael ;

Bubser, Michael ;

Barry, Robert L. ;

Thompson, Analisa ;

Rosanelli, John ;

Gowrishankar, Raajaram ;

Kelm, Nathaniel D. ;

Damon, Stephen ;

Bridges, Thomas M. ;

Melancon, Bruce J. ;

Tarr, James C. ;

Brogan, John T. ;

Avison, Malcolm J. ;

Deutch, Ariel Y. ;

Wess, Juergen ;

Wood, Michael R. ;

Lindsley, Craig W. ;

Gore, John C. ;

Conn, P. Jeffrey ;

Jones, Carrie K. .

NEUROPSYCHOPHARMACOLOGY, 2014, 39 (07) :1578-1593

[5]

Champtiaux N, 2003, J NEUROSCI, V23, P7820

[6] Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia [J].

Chan, W. Y. ;

McKinzie, D. L. ;

Bose, S. ;

Mitchell, S. N. ;

Witkin, J. M. ;

Thompson, R. C. ;

Christopoulos, A. ;

Lazareno, S. ;

Birdsall, N. J. M. ;

Bymaster, F. P. ;

Felder, C. C. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (31) :10978-10983

[7] Heterosynaptic LTD of hippocampal GABAergic synapses: A novel role of endocannabinoids in regulating excitability [J].

Chevaleyre, V ;

Castillo, PE .

NEURON, 2003, 38 (03) :461-472

[8] Involvement of a Subpopulation of Neuronal M4 Muscarinic Acetylcholine Receptors in the Antipsychotic-like Effects of the M1/M4 Preferring Muscarinic Receptor Agonist Xanomeline [J].

Dencker, Ditte ;

Wortwein, Gitta ;

Weikop, Pia ;

Jeon, Jongrye ;

Thomsen, Morgane ;

Sager, Thomas N. ;

Mork, Arne ;

Woldbye, David P. D. ;

Wess, Juergen ;

Fink-Jensen, Anders .

JOURNAL OF NEUROSCIENCE, 2011, 31 (16) :5905-5908

[9] M5 Receptor Activation Produces Opposing Physiological Outcomes in Dopamine Neurons Depending on the Receptor's Location [J].

Foster, Daniel J. ;

Gentry, Patrick R. ;

Lizardi-Ortiz, Jose E. ;

Bridges, Thomas M. ;

Wood, Michael R. ;

Niswender, Colleen M. ;

Sulzer, David ;

Lindsley, Craig W. ;

Xiang, Zixiu ;

Conn, P. Jeffrey .

JOURNAL OF NEUROSCIENCE, 2014, 34 (09) :3253-3262

[10] Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer's disease and schizophrenia [J].

Foster, Daniel J. ;

Choi, Derrick L. ;

Conn, P. Jeffrey ;

Rook, Jerri M. .

NEUROPSYCHIATRIC DISEASE AND TREATMENT, 2014, 10 :183-191

← 1 2 3 →