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Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity
Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Stanford Univ, CA 94305 USA.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0001-7952-8120
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Baylor Coll Med, TX 77030 USA.
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2018 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 11, article id 139Article in journal (Refereed) Published
Abstract [en]

The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a "waiting"-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP) paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs) in the 5-choice-serial-reaction-time-task (5CSRTT) than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG) expression (cFos and FosB) induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2018. Vol. 11, article id 139
Keywords [en]
muscarinic M4 receptor; acetylcholine; dopamine D1 receptor; reward learning; impulsivity; addiction; cocaine
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-147930DOI: 10.3389/fnmol.2018.00139ISI: 000430840200001PubMedID: 29740282OAI: oai:DiVA.org:liu-147930DiVA, id: diva2:1209547
Note

Funding Agencies|European Research Council; Swedish Medical Research Council; Knut and Alice Wallenberg foundation; Swedish Brain foundation; Parkinsonstiftelsen; Region Ostergotland

Available from: 2018-05-23 Created: 2018-05-23 Last updated: 2018-06-19

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