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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00139

Muscarinic M4 receptors on cholinergic and dopamine D1 receptor-expressing neurons have opposing functionality for positive reinforcement and influence impulsivity

Anna M. Klawonn1,  Daniel Björk Wilhelms2,  Sarah H. Lindström1,  Anand K. Singh3, Maarit Jaarola1, Jürgen Wess4,  Michael Fritz1* and  David Engblom1
  • 1Department for Experimental Medicine, Linköping University, Sweden
  • 2Linköping University, Sweden
  • 3Baylor College of Medicine, United States
  • 4National Institute of Diabetes and Digestive and Kidney Diseases, United States

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 paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses in the 5-choice-serial-reaction-time-task 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 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.

Keywords: Muscarinic M4 receptor, Acetylcholine, dopamine D1 receptor, Reward Learning, impulsivity, Addiction, Cocaine

Received: 01 Feb 2018; Accepted: 05 Apr 2018.

Edited by:

Gregg E. Homanics, University of Pittsburgh, United States

Reviewed by:

Peter Vanhoutte, Centre national de la recherche scientifique (CNRS), France
Carlos C. Crestani, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista Júlio de Mesquita Filho, Brazil  

Copyright: © 2018 Klawonn, Björk Wilhelms, Lindström, Singh, Jaarola, Wess, Fritz and Engblom. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Michael Fritz, Linköping University, Department for Experimental Medicine, Linköping, Sweden,