Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, 69978, Tel Aviv, Israel.
Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University, 69978, Tel Aviv, Israel.
Neuropsychopharmacology. 2019 Jan;44(2):415-424. doi: 10.1038/s41386-018-0132-7. Epub 2018 Jun 27.
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.
大脑奖励系统的神经适应性变化是由过度饮酒引起的，导致饮酒加剧和酒精使用障碍表型。活性依赖型神经保护蛋白（ADNP）对大脑发育至关重要，并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的 Adnp 表达，并且 Adnp 以性别依赖的方式适度控制饮酒。具体而言，亚慢性酒精处理（每天 2.5 g/kg，持续 7 天）增加了两性的背侧海马体和雌性小鼠伏隔核中的 Adnp mRNA 水平，在最后一次酒精注射后 24 小时。长期过量饮酒（约 10-15 g/kg/24 h，持续 5 周）会增加雄性小鼠在饮酒后立即海马体中的 Adnp mRNA 水平，但在戒酒后 24 小时内会恢复到基线水平。相比之下，雌性过量饮酒会导致海马体中 Adnp 表达的长期持续减少。我们进一步使用 Adnp 杂合不足小鼠模型测试了 Adnp 在酒精消耗中的调节作用。我们发现，与 Adnp 完整的雌性小鼠相比，Adnp 杂合不足的雌性小鼠表现出更高的酒精消耗和偏好，而雄性小鼠则没有基因型差异。重要的是，ADNP 短肽药物候选物 NAP 的每日鼻腔内给药可使 Adnp 杂合不足的雌性小鼠的酒精消耗正常化。最后，雌性 Adnp 杂合不足的小鼠在戒酒后酒精摄入量急剧增加，表明 Adnp 可预防雌性的复发。目前的数据表明，ADNP 是一种潜在的新型生物标志物和酒精摄入行为的负调节剂。
