Inactivation of the cholinergic M4 receptor results in a disinhibited endophenotype predicting alcohol use
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Inactivation of the cholinergic M4 receptor results in a disinhibited endophenotype predicting alcohol use. / Molander, Anna; Thorbek, Ditte Dencker; Lysne, Christian; Weikop, Pia; Fink-Jensen, Anders; Wörtwein, Gitta.
In: Behavioural Brain Research, Vol. 430, 113921, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Inactivation of the cholinergic M4 receptor results in a disinhibited endophenotype predicting alcohol use
AU - Molander, Anna
AU - Thorbek, Ditte Dencker
AU - Lysne, Christian
AU - Weikop, Pia
AU - Fink-Jensen, Anders
AU - Wörtwein, Gitta
N1 - Publisher Copyright: © 2022 The Authors
PY - 2022
Y1 - 2022
N2 - The muscarinic cholinergic M4 receptor subtype (M4 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 M4 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 M4 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 M4 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.
AB - The muscarinic cholinergic M4 receptor subtype (M4 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 M4 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 M4 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 M4 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.
KW - Alcohol preference
KW - Alcohol use disorder
KW - Anxiety-like behaviour
KW - M knockout (M) mice
KW - Novelty seeking
KW - Spatial learning
U2 - 10.1016/j.bbr.2022.113921
DO - 10.1016/j.bbr.2022.113921
M3 - Journal article
C2 - 35533894
AN - SCOPUS:85130570514
VL - 430
JO - Behavioural Brain Research
JF - Behavioural Brain Research
SN - 0166-4328
M1 - 113921
ER -
ID: 312824122