Sex-dependent divergence in the effects of GLP-1 agonist exendin-4 on alcohol reinforcement and reinstatement in C57BL/6J mice.
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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DOI：
10.1007/s00213-023-06367-x
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发表时间：
2023-06
影响因子：
3.4
通讯作者：
Thomsen, Morgane
中科院分区：
文献类型：
--
作者：
Diaz-Megido, Claudia;Thomsen, Morgane
关键词：
酒精使用障碍仍然是可预防死亡的主要原因，目前的治疗效果有限。胰高血糖素样肽1 （GLP-1）受体激动剂在临床前研究中可以减少饮酒量，但其机制尚不完全清楚，女性受试者的数据也很少。评估GLP-1受体激动剂exendin-4是否可以在没有饮酒或中毒的情况下减少寻求酒精的行为，比较exendin-4在减少寻求酒精和饮酒方面的效力和功效，并比较雄性和雌性小鼠的效果。雄性和雌性C57BL/6J小鼠在fr1强化计划下接受自我给予20%酒精的训练。消失后，在线索诱导的酒精寻求恢复中，对全身exendin-4（生理盐水、1.8和3.2 μg/kg）进行测试。在另一组中测试了exendin-4对酒精自我给药的影响。两种剂量的Exendin-4抑制了雄性小鼠的酒精恢复到灭绝水平，但对雌性小鼠没有影响。两种剂量的exendin-4也显著减少雄性小鼠的酒精自我给药；女性再次表现出不那么明显的影响。在雄性小鼠中，相对于酒精自我给药，exendin-4似乎在没有酒精的情况下更有效地抑制酒精寻求，这与酒精奖励或抑制控制的调节一致，而不是酒精的饱腹感或厌恶效应。我们在雌性小鼠中发现了显著的性别差异，exendin-4的影响较小，在GLP-1受体激动剂的进一步研究中，包括两性将是重要的。在线版本包含补充材料，可在10.1007/s00213-023-06367-x获得。
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. 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. 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. 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. 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. The online version contains supplementary material available at 10.1007/s00213-023-06367-x.
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DOI：
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期刊：
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