Neurophysiology of addiction: gender and withdrawal

成瘾的神经生理学：性别和戒断

• 批准号: 7675503
• 负责人: Anne Marie Wissman
• 金额: $ 5.01万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675503
• 关键词: Abstinence; Action Potentials; Acute; Address; Affect; Aftercare; Animals; Area; Behavior; Behavioral; Brain; Cells; Chronic; Cocaine; Development; Drug Addiction; Drug Exposure; Electrophysiology (science); Female; Fiber; Gender; Gene Expression; Human; Laboratories; Morphology; Neurons; Nucleus Accumbens; Pharmaceutical Preparations; Physiologic pulse; Physiological; Physiology; Predisposition; Prefrontal Cortex; Protocols documentation; Rattus; Recording of previous events; Role; Saline; Sex Characteristics; Slice; Synapses; Synaptic Transmission; Testing; Time; Withdrawal; addiction; base; drug of abuse; insight; male; neurophysiology; patch clamp; research study; response; voltage clamp

DESCRIPTION (provided by candidate): The nucleus accumbens (NAc) is a brain area integral to the development and expression of addiction-related behaviors. Neurons in the NAc show drug-induced changes in morphology, synaptic and intrinsic physiology, and gene expression. In both human and animal studies, females show greater susceptibility to drug addiction than males. It is unknown to what extent the sex differences in behavioral responses to drugs of abuse are accompanied by differences in the synaptic or intrinsic physiology of NAc neurons. Recent evidence from a number of laboratories suggests that many of the physiological changes in the NAc in response to repeated drug treatment are .modulated or intensified by a period of abstinence. This suggests that chronic drug exposure may serve to prime the brain for rewiring that takes place during the abstinence period. The proposed experiments will address three main questions: 1) Are there underlying sex differences in the synaptic and intrinsic physiology of NAc neurons? 2) Are the morphological changes seen after chronic cocaine and subsequent abstinence reflected by physiological changes in the NAc, and does the physiological response differ between males and females? 3) What is the role of the abstinence period in producing these changes, and do males and females differ in the effect of abstinence? Using whole-cell patch clamp electrophysiology in acute slices of the NAc from male and female rats, I will ask whether chronic treatment with saline or cocaine affects the synaptic and intrinsic physiology of NAc neurons in males and females after 30 days of abstinence, a time at which robust morphological changes are observed in response to chronic cocaine. I will also evaluate the effects of chronic saline or cocaine on NAc physiology without an extended abstinence period in males and females. These studies will provide insight about how chronic drug exposure produces lasting changes in brain physiology. My results will also help us understand the physiological underpinnings of behavioral sex differences in addiction as well as the role of the abstinence period, which could help to provide individually-targeted treatment approaches based on addicts' gender and drug history.

描述（由考生提供）：伏隔核 (NAc) 是成瘾相关行为的发展和表达不可或缺的大脑区域。 NAc 中的神经元表现出药物诱导的形态、突触和内在生理学以及基因表达的变化。在人类和动物研究中，女性比男性更容易吸毒。目前尚不清楚对滥用药物的行为反应的性别差异在多大程度上伴随着 NAc 神经元的突触或内在生理学的差异。许多实验室的最新证据表明，NAc 中因重复药物治疗而发生的许多生理变化会因一段时间的禁欲而受到调节或加强。这表明，长期接触药物可能有助于大脑在禁欲期间进行重新布线。拟议的实验将解决三个主要问题：1）NAc 神经元的突触和内在生理学是否存在潜在的性别差异？ 2) 长期吸食可卡因和随后戒断后所观察到的形态变化是否反映在NAc的生理变化上，男性和女性之间的生理反应是否不同？ 3）禁欲期在产生这些变化中起什么作用？男性和女性的禁欲效果有何不同？在雄性和雌性大鼠的 NAc 急性切片中使用全细胞膜片钳电生理学，我将询问在禁欲 30 天后，用盐水或可卡因进行长期治疗是否会影响雄性和雌性 NAc 神经元的突触和内在生理学。观察到对慢性可卡因的强烈形态变化。我还将评估男性和女性在不延长禁欲期的情况下长期使用盐水或可卡因对 NAc 生理学的影响。这些研究将深入了解长期药物暴露如何产生大脑生理学的持久变化。我的研究结果还将帮助我们了解成瘾行为性别差异的生理基础以及禁欲期的作用，这有助于根据成瘾者的性别和吸毒史提供有针对性的治疗方法。