California State University East Bay, Hayward, CA, USA.
Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
Sci Rep. 2021 Jan 8;11(1):231. doi: 10.1038/s41598-020-79935-2.
Alcohol use disorder exhausts substantial social and economic costs, with recent dramatic increases in female problem drinking. Thus, it is critically important to understand signaling differences underlying alcohol consumption across the sexes. Orexin-1 receptors (Ox1Rs) can strongly promote motivated behavior, and we previously identified Ox1Rs within nucleus accumbens shell (shell) as crucial for driving binge intake in higher-drinking male mice. Here, shell Ox1R inhibition did not alter female mouse alcohol drinking, unlike in males. Also, lower dose systemic Ox1R inhibition reduced compulsion-like alcohol intake in both sexes, indicating that female Ox1Rs can drive some aspects of pathological consumption, and higher doses of systemic Ox1R inhibition (which might have more off-target effects) reduced binge drinking in both sexes. In contrast to shell Ox1Rs, inhibiting shell calcium-permeable AMPA receptors (CP-AMPARs) strongly reduced alcohol drinking in both sexes, which was specific to alcohol since this did not reduce saccharin intake in either sex. Our results together suggest that the shell critically regulates binge drinking in both sexes, with shell CP-AMPARs supporting intake in both sexes, while shell Ox1Rs drove drinking only in males. Our findings provide important new information about sex-specific and -general mechanisms that promote binge alcohol intake and possible targeted therapeutic interventions.
酒精使用障碍消耗了大量的社会和经济成本，最近女性酗酒问题急剧增加。因此，了解性别之间饮酒行为的信号差异至关重要。食欲素-1 受体（Ox1Rs）可以强烈促进动机行为，我们之前发现伏隔核壳（壳）内的 Ox1Rs 对于驱动高饮酒雄性小鼠的 binge 摄入至关重要。在这里，壳内 Ox1R 抑制并没有改变雌性小鼠的酒精摄入，与雄性小鼠不同。此外，较低剂量的全身 Ox1R 抑制减少了两性的强迫性酒精摄入，表明雌性 Ox1Rs 可以驱动某些病理性消费方面，而更高剂量的全身 Ox1R 抑制（可能有更多的脱靶效应）减少了两性的 binge 饮酒。与壳内 Ox1Rs 相反，抑制壳内钙通透性 AMPA 受体（CP-AMPARs）强烈减少了两性的酒精摄入，这是特异性的酒精摄入，因为这并没有减少两性的蔗糖摄入。我们的研究结果共同表明，壳在两性的 binge 饮酒中起着关键作用，壳内 CP-AMPARs 支持两性的摄入，而壳内 Ox1Rs 仅在雄性中驱动饮酒。我们的发现提供了关于促进 binge 酒精摄入的性别特异性和一般性机制的重要新信息，以及可能的靶向治疗干预措施。
