Estrogen Facilitation of Female Drug Relapse

雌激素促进女性吸毒复吸

• 批准号: 9534036
• 负责人: Paul G Mermelstein
• 金额: $ 41.11万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9534036
• 关键词: Affect; Behavior; Behavioral; Cardiovascular Physiology; Cocaine; Data; Drug Addiction; Drug Receptors; Drug abuse; Drug usage; Electrophysiology (science); Endocrine; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Estrus; Exhibits; Exposure to; Female; Foundations; Goals; Healthcare; Hormonal; Hour; Individual; Intake; Long-Term Depression; Measures; Mediating; Medical; Membrane; Metabotropic Glutamate Receptors; Methods; Modeling; Mus; Nervous System Physiology; Nervous system structure; Neurologic; Neurons; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacology; Play; Predisposition; Process; Property; Receptor Signaling; Relapse; Research; Rodent; Role; Sex Characteristics; Signal Transduction; Surface; Synaptic plasticity; Technology; Testing; Therapeutic; Viral; Woman; addiction; clinically relevant; drug relapse; estrogen disruption; experimental study; genetic manipulation; mouse model; novel; novel therapeutic intervention; optogenetics; preference; proliferative phase Menstrual cycle; public health relevance; receptor function; relating to nervous system; response; reward circuitry; theories

 DESCRIPTION (provided by applicant): Across all stages of drug use and abuse, women exhibit heightened responsiveness and hence greater vulnerability to the properties of addictive drugs. This is especially true regarding the increased susceptibility women exhibit towards drug relapse. In women, maximal vulnerability peaks during the follicular phase of the menstrual cycle when estrogen levels are at their highest. These findings have been recapitulated in female rodents, where estradiol heightens multiple measures of drug responsiveness and abuse. The mechanisms by which estradiol mediates enhanced vulnerability to drug relapse are completely unknown. The two PIs of this proposal have been independently studying the neurological underpinnings of relapse, and the mechanisms by which estrogens affect neuronal activity. Now working together, we have generated a unifying theory, whereby estradiol activation of estrogen receptor α (ERα), localized to the surface membrane of medium spiny neurons of the nucleus accumbens shell (NAcSh), activates metabotropic glutamate receptor 1a (mGluR1a) signaling. Activation of ERα/mGluR1a signaling by estradiol is hypothesized to in turn promote mGluR5-induced relapse, a process mediated through the long-term depression of NAcSh afferents from the infralimbic cortex. To test this theory, the studies outlined in this proposal will utilize a recently developed mouse model of estradiol facilitation of drug relapse, taking advantage of electrophysiological, optogenetic and viral technologies. Collectively, these studies will provide a foundation to better understand and develop novel therapeutic approaches to treat drug relapse in women.

 描述（由申请人提供）：在药物使用和滥用的所有阶段，妇女表现出更高的反应性，因此更容易受到成瘾药物的影响。这是特别真实的增加易感性的妇女表现出对药物复吸。在女性中，最大的脆弱性在月经周期的卵泡期达到峰值，此时雌激素水平最高。这些发现在雌性啮齿动物中得到了重现，其中雌二醇提高了药物反应性和滥用的多个指标。雌二醇介导药物复吸脆弱性增强的机制完全未知。这项提议的两名PI一直在独立研究复发的神经基础，以及雌激素影响神经元活动的机制。现在，我们一起工作，产生了一个统一的理论，即雌激素受体α（ERα）的激活，定位于细胞核壳（NAcSh）的中型多刺神经元的表面膜，激活代谢型谷氨酸受体1a（mGluR 1a）信号。雌激素激活ERα/mGluR 1a信号传导可能反过来促进mGluR 5诱导的复发，这是一个通过长期抑制来自边缘下皮层的NAcSh传入介导的过程。为了验证这一理论，本提案中概述的研究将利用最近开发的雌二醇促进药物复发的小鼠模型，利用电生理学，光遗传学和病毒技术。总的来说，这些研究将为更好地理解和开发治疗女性药物复发的新治疗方法提供基础。