Melón Laverne C, Nolan Zachary T, Colar Delphine, Moore Eileen M, Boehm Stephen L
Addiction Neuroscience, Department of Psychology, Indiana University/Purdue University-Indianapolis, Indianapolis, IN 46202, USA; Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
Penn State College of Medicine, Hershey, PA 17033, USA.
Horm Behav. 2017 Sep;95:65-75. doi: 10.1016/j.yhbeh.2017.07.015. Epub 2017 Sep 20.
Recent reports support higher than expected rates of binge alcohol consumption among women and girls. Unfortunately, few studies have assessed the mechanisms underlying this pattern of intake in females. Studies in males suggest that alcohol concentrations relevant to the beginning stages of binge intoxication may selectively target tonic GABAergic inhibition mediated by GABA receptor subtypes expressing the δ-subunit protein (δ-GABARs). Indeed, administration of agonists that interact with these δ-GABARs prior to alcohol access can abolish binge drinking behavior in male mice. These δ-GABARs have also been shown to exhibit estrous-dependent plasticity in regions relevant to drug taking behavior, like the hippocampus and periaqueductal gray. The present experiments were designed to determine whether the estrous cycle would alter binge drinking, or our ability to modulate this pattern of alcohol use with THIP, an agonist with high selectivity and efficacy at δ-GABARs. Using the Drinking-in-the-Dark (DID) binge-drinking model, regularly cycling female mice were given 2h of daily access to alcohol (20%v/v). Vaginal cytology or vaginal impedance was assessed after drinking sessions to track estrous status. There was no fluctuation in binge drinking associated with the estrous cycle. Both Intra-posterior-VTA administration of THIP and systemic administration of the drug was also associated with an estrous cycle dependent reduction in drinking behavior. Pre-treatment with finasteride to inhibit synthesis of 5α-reduced neurosteroids did not disrupt THIP's effects. Analysis of δ-subunit mRNA from posterior-VTA enriched tissue samples revealed that expression of this GABA receptor subunit is elevated during diestrus in this region. Taken together, these studies demonstrate that δGABARs in the VTA are an important target for binge drinking in females and confirm that the estrous cycle is an important moderator of the pharmacology of this GABA receptor subtype.
近期报告显示，女性和女童酗酒率高于预期。遗憾的是，很少有研究评估女性这种饮酒模式背后的机制。对男性的研究表明，与暴饮中毒初始阶段相关的酒精浓度可能选择性地作用于由表达δ亚基蛋白的GABA受体亚型介导的强直性GABA能抑制（δ-GABARs）。事实上，在给予酒精之前给予与这些δ-GABARs相互作用的激动剂，可以消除雄性小鼠的暴饮行为。这些δ-GABARs在与药物摄取行为相关的区域，如海马体和导水管周围灰质，也表现出与发情周期相关的可塑性。本实验旨在确定发情周期是否会改变暴饮行为，或者我们使用THIP（一种对δ-GABARs具有高选择性和高效性的激动剂）调节这种饮酒模式的能力。使用黑暗中饮酒（DID）暴饮模型，让规律发情的雌性小鼠每天有2小时的时间接触酒精（20%v/v）。饮酒后通过阴道细胞学或阴道阻抗评估来追踪发情状态。暴饮行为与发情周期没有波动关系。向腹侧被盖区后部注射THIP以及全身性给药也与发情周期依赖性的饮酒行为减少有关。用非那雄胺预处理以抑制5α还原神经甾体的合成，并不影响THIP的作用。对腹侧被盖区后部富集组织样本的δ亚基mRNA分析显示，该区域在动情间期GABA受体亚基的表达升高。综上所述，这些研究表明，腹侧被盖区的δGABARs是女性暴饮行为的重要靶点，并证实发情周期是该GABA受体亚型药理学的重要调节因素。
