Neuroadaptations in the brain reward system caused by excessive alcohol intake, lead to drinking escalation and alcohol use disorder phenotypes. Activity-dependent neuroprotective protein (ADNP) is crucial for brain development, and is implicated in neural plasticity in adulthood. Here, we discovered that alcohol exposure regulates Adnp expression in the mesolimbic system, and that Adnp keeps alcohol drinking in moderation, in a sex-dependent manner. Specifically, Sub-chronic alcohol treatment (2.5 g/kg/day for 7 days) increased Adnp mRNA levels in the dorsal hippocampus in both sexes, and in the nucleus accumbens of female mice, 24 h after the last alcohol injection. Long-term voluntary consumption of excessive alcohol quantities (~10-15 g/kg/24 h, 5 weeks) increased Adnp mRNA in the hippocampus of male mice immediately after an alcohol-drinking session, but the level returned to baseline after 24 h of withdrawal. In contrast, excessive alcohol consumption in females led to long-lasting reduction in hippocampal Adnp expression. We further tested the regulatory role of Adnp in alcohol consumption, using the Adnp haploinsufficient mouse model. We found that Adnp haploinsufficient female mice showed higher alcohol consumption and preference, compared to Adnp intact females, whereas no genotype difference was observed in males. Importantly, daily intranasal administration of the ADNP-snippet drug candidate NAP normalized alcohol consumption in Adnp haploinsufficient females. Finally, female Adnp haploinsufficient mice showed a sharp increase in alcohol intake after abstinence, suggesting that Adnp protects against relapse in females. The current data suggest that ADNP is a potential novel biomarker and negative regulator of alcohol-drinking behaviors.

中文翻译：

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活动依赖性神经保护蛋白 (ADNP) 是一种酒精反应基因，是雌性小鼠饮酒的负调节因子。

过量饮酒引起的大脑奖励系统中的神经适应导致饮酒升级和酒精使用障碍表型。活动依赖性神经保护蛋白 (ADNP) 对大脑发育至关重要，并且与成年期的神经可塑性有关。在这里，我们发现酒精暴露调节中脑边缘系统中 Adnp 的表达，并且 Adnp 以一种依赖于性别的方式保持适度饮酒。具体来说，在最后一次酒精注射后 24 小时，亚慢性酒精治疗（2.5 g/kg/天，持续 7 天）增加了两性海马背侧和雌性小鼠伏隔核中的 Adnp mRNA 水平。长期自愿摄入过量酒精（~10-15 g/kg/24 h，5 周）在饮酒后立即增加雄性小鼠海马中的 Adnp mRNA，但在戒酒 24 小时后水平恢复到基线水平。相比之下，女性过度饮酒会导致海马 Adnp 表达长期下降。我们使用 Adnp 单倍体不足小鼠模型进一步测试了 Adnp 在饮酒中的调节作用。我们发现，与 Adnp 完整的雌性小鼠相比，Adnp 单倍体不足的雌性小鼠表现出更高的酒精消耗和偏好，而在雄性小鼠中未观察到基因型差异。重要的是，ADNP-snippet 候选药物 NAP 的每日鼻内给药使 Adnp 单倍体不足女性的饮酒量正常化。最后，雌性 Adnp 单倍体不足的小鼠在禁欲后酒精摄入量急剧增加，表明 Adnp 可以防止女性复发。目前的数据表明，ADNP 是一种潜在的新型生物标志物和饮酒行为的负调节剂。