Sex-dependent divergence in the effects of GLP-1 agonist exendin-4 on alcohol reinforcement and reinstatement in C57BL/6J mice
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Sex-dependent divergence in the effects of GLP-1 agonist exendin-4 on alcohol reinforcement and reinstatement in C57BL/6J mice. / Díaz-Megido, Claudia; Thomsen, Morgane.
In: Psychopharmacology, Vol. 240, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Sex-dependent divergence in the effects of GLP-1 agonist exendin-4 on alcohol reinforcement and reinstatement in C57BL/6J mice
AU - Díaz-Megido, Claudia
AU - Thomsen, Morgane
N1 - Publisher Copyright: © 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - Rationale: Alcohol use disorder remains a leading cause of preventable deaths, and current treatments have limited efficacy. Glucagon-like peptide 1 (GLP-1) receptor agonists can reduce alcohol drinking in preclinical studies, but mechanisms are still not fully understood, and data in female subjects are scarce. Objectives: To assess whether the GLP-1 receptor agonist exendin-4 could decrease alcohol-seeking behavior in the absence of alcohol consumption or intoxication, to compare the potency and efficacy of exendin-4 in the reduction of alcohol seeking vs. alcohol taking, and to compare effects between male and female mice. Methods: Male and female C57BL/6J mice were trained to self-administer 20% alcohol under an FR 1 schedule of reinforcement. After extinction, systemic exendin-4 (saline, 1.8, and 3.2 μg/kg) was tested in cue-induced reinstatement of alcohol seeking. Effects of exendin-4 on alcohol self-administration were tested in a separate group. Results: Exendin-4 suppressed reinstatement of alcohol seeking to extinction levels, at both doses, in the male mice, but had no effect in the female mice. Both doses of exendin-4 also significantly decreased alcohol self-administration in male mice; females again showed less pronounced effects. Conclusions: In male mice, exendin-4 appeared more effective at suppressing alcohol seeking in the absence of alcohol relative to alcohol self-administration, consistent with modulation of alcohol reward or inhibitory control, rather than satiety or aversive effects of alcohol. We saw marked sex differences with less effect of exendin-4 in female mice, and it will be important to include both sexes in further investigations into GLP-1 receptor agonists.
AB - Rationale: Alcohol use disorder remains a leading cause of preventable deaths, and current treatments have limited efficacy. Glucagon-like peptide 1 (GLP-1) receptor agonists can reduce alcohol drinking in preclinical studies, but mechanisms are still not fully understood, and data in female subjects are scarce. Objectives: To assess whether the GLP-1 receptor agonist exendin-4 could decrease alcohol-seeking behavior in the absence of alcohol consumption or intoxication, to compare the potency and efficacy of exendin-4 in the reduction of alcohol seeking vs. alcohol taking, and to compare effects between male and female mice. Methods: Male and female C57BL/6J mice were trained to self-administer 20% alcohol under an FR 1 schedule of reinforcement. After extinction, systemic exendin-4 (saline, 1.8, and 3.2 μg/kg) was tested in cue-induced reinstatement of alcohol seeking. Effects of exendin-4 on alcohol self-administration were tested in a separate group. Results: Exendin-4 suppressed reinstatement of alcohol seeking to extinction levels, at both doses, in the male mice, but had no effect in the female mice. Both doses of exendin-4 also significantly decreased alcohol self-administration in male mice; females again showed less pronounced effects. Conclusions: In male mice, exendin-4 appeared more effective at suppressing alcohol seeking in the absence of alcohol relative to alcohol self-administration, consistent with modulation of alcohol reward or inhibitory control, rather than satiety or aversive effects of alcohol. We saw marked sex differences with less effect of exendin-4 in female mice, and it will be important to include both sexes in further investigations into GLP-1 receptor agonists.
KW - Alcohol seeking
KW - Alcohol self-administration
KW - Alcohol use disorder
KW - Ethanol
KW - Incretin hormone
KW - Operant behavior
KW - Reinstatement
KW - Sex differences
U2 - 10.1007/s00213-023-06367-x
DO - 10.1007/s00213-023-06367-x
M3 - Journal article
C2 - 37106129
AN - SCOPUS:85153791042
VL - 240
JO - Psychopharmacology
JF - Psychopharmacology
SN - 0033-3158
ER -
ID: 346056521