Sex Differences in Aversion-Resistant Ethanol Intake

项目摘要 用于诊断酒精使用障碍的一个核心标准是持续消费 酒精的负面影响。这些后果可能包括负面的 影响工作效率、健康和人际关系。临床前动物模型 已经被开发来研究这种行为和其他在患者中观察到的行为， 成瘾性障碍为了研究不顾负面后果的消费， 已经开发出了抗厌恶酒精摄入。在这个过程中，酒精的获取是 伴随着负面刺激，通常是电击惩罚或奎宁掺假（a 啮齿动物发现的高度厌恶的苦味剂）。奎宁掺假模型已被用于 在过去的几年里，研究了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仅使用雄性小鼠。我们最近 研究表明，雌性小鼠对奎宁掺假的敏感性降低， 它们比雄性小鼠更能抵抗厌恶， 强迫性的酒精摄入这项建议研究了这种性别差异，首先确定 循环性激素在这种行为表型中的作用，然后检查特定的 大脑区域来调节这种效应。使用女性检查成瘾相关行为 受试者至关重要，因为我们对女性的这些过程知之甚少， 成瘾生物学的研究主要使用雄性动物。的成果 这些实验将有助于我们进一步了解有助于 酒精滥用的女性，并将开辟新的途径，药物开发。

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.