Chronic Loss of Muscarinic M5 Receptor Function Manifests Disparate Impairments in Exploratory Behavior in Male and Female Mice despite Common Dopamine Regulation

John A. Razidlo, Skylar Fausner, Anna E. Ingebretson, Liuchang C. Wang, Christopher L. Petersen, Salahudeen Mirza, Isabella N. Swank, Veronica A. Alvarez, Julia Lemos

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

There are five cloned muscarinic acetylcholine receptors (M1–M5). Of these, the muscarinic type 5 receptor (M5) is the only one localized to dopamine neurons in the ventral tegmental area and substantia nigra. Unlike M1–M4, the M5 receptor has relatively restricted expression in the brain, making it an attractive therapeutic target. Here, we performed an in-depth characterization of M5-dependent potentiation of dopamine transmission in the nucleus accumbens and accompanying exploratory behaviors in male and female mice. We show that M5 receptors potentiate dopamine transmission by acting directly on the terminals within the nucleus accumbens. Using the muscarinic agonist oxotremorine, we revealed a unique concentration–response curve and a sensitivity to repeated forced swim stress or restraint stress exposure. We found that constitutive deletion of M5 receptors reduced exploration of the center of an open field while at the same time impairing normal habituation only in male mice. In addition, M5 deletion reduced exploration of salient stimuli, especially under conditions of high novelty, yet had no effect on hedonia assayed using the sucrose preference test or on stress-coping strategy assayed using the forced swim test. We conclude that M5 receptors are critical for both engaging with the environment and updating behavioral output in response to environment cues, specifically in male mice. A cardinal feature of mood and anxiety disorders is withdrawal from the environment. These data indicate that boosting M5 receptor activity may be a useful therapeutic target for ameliorating these symptoms of depression and anxiety.

Original languageEnglish (US)
Pages (from-to)6917-6930
Number of pages14
JournalJournal of Neuroscience
Volume42
Issue number36
DOIs
StatePublished - Sep 7 2022

Bibliographical note

Funding Information:
This work was supported by National Institute of Mental Health Grants MH109627 (J.C.L.), and MH122749 (J.C.L.), Department of Neuroscience and Medical Discovery Team on Addiction Start-Up Funds (J.C.L.), and National Institute on Alcohol Abuse and Alcoholism Grant AA000421 (V.A.A.). We thank Dr. Jürgen Wess at the National Institute of Diabetes and Digestive and Kidney Diseases for providing the M5 KO mouse line, Ms. Rachel Dick for help with cryosectioning used for RNAscope techniques, Dr. Anna Lee for the use of the MATLAB-based RNAscope analysis pipeline, Dr. Sade Spencer and the Spencer lab for performing pilot Western blot experiments, and Drs. Erin Calipari, Mark Thomas, Michael Bruchas, and Larry Zweifel, and Ms. Elizabeth Souter for input and comments on this work. The authors declare no competing financial interests. Correspondence should be addressed to Julia C. Lemos at [email protected]. https://doi.org/10.1523/JNEUROSCI.1424-21.2022 Copyright © 2022 the authors

Funding Information:
This work was supported by National Institute of Mental Health Grants MH109627 (J.C.L.), and MH122749 (J.C.L.), Department of Neuroscience and Medical Discovery Team on Addiction Start-Up Funds (J.C.L.), and National Institute on Alcohol Abuse and Alcoholism Grant AA000421 (V.A.A.). We thank Dr. Jürgen Wess at the National Institute of Diabetes and Digestive and Kidney Diseases for providing the M5 KO mouse line, Ms. Rachel Dick for help with cryosectioning used for RNAscope techniques, Dr. Anna Lee for the use of the MATLAB-based RNAscope analysis pipeline, Dr. Sade Spencer and the Spencer lab for performing pilot Western blot experiments, and Drs. Erin Calipari, Mark Thomas, Michael Bruchas, and Larry Zweifel, and Ms. Elizabeth Souter for input and comments on this work.

Publisher Copyright:
Copyright © 2022 the authors.

Keywords

  • M5 receptor
  • acetylcholine
  • dopamine
  • nucleus accumbens

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