Inactivation of the cholinergic M 4 receptor results in a disinhibited endophenotype predicting alcohol use.

Autor: Molander A; Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Mental Health Services, Capital Region of Copenhagen and University Hospital of Copenhagen, Denmark., Thorbek DD; Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Mental Health Services, Capital Region of Copenhagen and University Hospital of Copenhagen, Denmark., Lysne C; Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Mental Health Services, Capital Region of Copenhagen and University Hospital of Copenhagen, Denmark., Weikop P; Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Mental Health Services, Capital Region of Copenhagen and University Hospital of Copenhagen, Denmark., Fink-Jensen A; Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Mental Health Services, Capital Region of Copenhagen and University Hospital of Copenhagen, Denmark., Wörtwein G; Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Mental Health Services, Capital Region of Copenhagen and University Hospital of Copenhagen, Denmark; Section of Environmental Health, Department of Public Health, University of Copenhagen, Øster Farimagsgade 5, DK-1014 Copenhagen, Denmark. Electronic address: gwoe0002@regionh.dk.
Jazyk: angličtina
Zdroj: Behavioural brain research [Behav Brain Res] 2022 Jul 26; Vol. 430, pp. 113921. Date of Electronic Publication: 2022 May 06.
DOI: 10.1016/j.bbr.2022.113921
Abstrakt: The muscarinic cholinergic M 4 receptor subtype (M 4 mAChR) is densely expressed in brain areas known to be involved in the reinforcing effects of drugs of abuse and we were the first to show that mice lacking M 4 mAChRs exhibit elevated operant responding for alcohol and reduced capacity to extinguish this alcohol-seeking behaviour. Here we explore possible underlying determinants of this phenotype. We subjected M 4 mAChR knockout mice and their littermate wildtype controls to tests of spontaneous activity, learning and memory, novelty seeking, as well as anxiety and examined the relationship of a newly discovered "disinhibited" endophenotype of these mice with voluntary alcohol consumption and relapse. We found a positive correlation between "disinhibited" behaviour on the plus maze and alcohol preference as well as relapse to alcohol drinking after a period of abstinence. Taken together, these data point to M 4 mAChRs as a potential target for improved treatment strategies for alcohol use disorder. This receptor should be further investigated for its involvement in modulating behavioural inhibition in relation to loss of control over consumption of alcohol.
(Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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