Estrogen Facilitation of Female Drug Relapse

 描述(申请人提供)：在药物使用和滥用的所有阶段，妇女表现出高度的反应性，因此更容易受到成瘾药物特性的影响。在妇女对毒品复发表现出更高的易感性方面，情况尤其如此。在女性中，最大的脆弱性在月经周期的卵泡期达到顶峰，此时雌激素水平最高。这些发现在雌性啮齿动物身上重复了一遍，雌二醇会提高药物反应和滥用的多种衡量标准。雌激素调节药物复发易感性的机制是完全未知的。这项建议的两个PI一直在独立研究复发的神经学基础，以及雌激素影响神经元活动的机制。现在，我们共同努力，产生了一个统一的理论，即雌激素受体α(ERα)的雌二醇激活，定位于伏核中棘神经元(NAcSh)的表膜，激活代谢性谷氨酸受体1a(MGluR1a)信号。雌激素激活ERα/mGluR1a信号转而促进mGluR5诱导的复发，这一过程是通过长期抑制下缘皮质传入的NAcSh而介导的。为了验证这一理论，该提案中概述的研究将利用最近开发的雌激素促进药物复发的小鼠模型，利用电生理、光遗传和病毒技术。总的来说，这些研究将为更好地了解和开发治疗女性药物复发的新的治疗方法提供基础。

 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.