Sex Differences in Aversion-Resistant Ethanol Intake

项目总结 诊断酒精使用障碍的一个核心标准是持续饮酒 面对酒精带来的负面后果。这些后果可能包括负面影响 对工作效率、健康和人际关系的影响。临床前动物模型 已经被开发用来研究这种行为和其他观察到的 令人上瘾的障碍。为了研究不考虑负面后果的消费， 抗厌恶的酒精摄入量已经被开发出来。在此过程中，酒精访问是 伴随着负面刺激，通常是脚电击惩罚或奎宁掺假(a 啮齿动物非常厌恶的苦味)。奎宁掺杂模型已被用于 近几年来研究厌恶抵抗的药理学和神经回路 酒精摄入量。然而，这些研究中的绝大多数只使用了雄性小鼠。我们最近 研究表明，雌性老鼠对奎宁掺假的敏感度降低，这表明 它们比雄性老鼠更耐厌恶，可能有更高的 强迫性酒精摄入。这项提案考察了这种性别差异，首先确定了 循环性激素在这种行为表型中的作用，然后检查特定的 负责调节这一效应的大脑区域。女性吸毒成瘾相关行为的调查 受试者至关重要，因为我们对女性的这些过程知之甚少，因为 事实上，成瘾生物学的研究主要使用了雄性动物。其结果是 这些实验将有助于我们进一步了解 在女性中滥用酒精，将为药物开发开辟新途径。

PROJECT SUMMARY A core criterion used to diagnose alcohol use disorders is the continued consumption of alcohol in the face of negative consequences. These consequences may include negative impact on work productivity, health, and interpersonal relationships. Preclinical animal models have been developed to study this and other behaviors that are observed in patients with addictive disorders. To study consumption despite negative consequences, the model of aversion-resistant alcohol intake has been developed. In this procedure, alcohol access is paired with a negative stimulus, usually either footshock punishment or quinine adulteration (a bitter tastant that rodents find highly aversive). The quinine adulteration model has been used in the last several years to examine the pharmacology and neurocircuitry of aversion resistant alcohol intake. However, the vast majority of these studies used male mice only. Our recent studies suggest that female mice show decreased sensitivity to quinine adulteration, suggesting that they are more aversion-resistant than male mice and may have a higher propensity for compulsive-like alcohol intake. This proposal examines this sex difference, first determining the role of circulating sex hormones in this behavioral phenotype and then examining the specific brain regions that mediate this effect. Examination of addiction-related behaviors using female subjects is of critical importance as we know far less about these processes in females due to the fact that studies in addiction biology have primarily used male animals. The outcomes of these experiments will help to further our understanding of the mechanisms that contribute to alcohol abuse in females and will open new avenues for medications development.