Estrogen Underlying Increased Female Vulnerability to Addiction

描述(申请人提供)：与男性相比，女性滥用药物的风险更大。在所有的成瘾症状中，女性表现出更多的成瘾物质的摄入，更大的渴望，导致成瘾和复发的可能性增加。这些反应在月经周期的卵泡期达到顶峰，此时雌激素水平最高。这些发现在雌性实验鼠身上进行了总结，雌二醇会提高药物反应和滥用的多项指标。值得注意的是，雌二醇介导人对药物成瘾易感性的机制完全未知。我们提出了一种新的分子机制来介导雌激素对伏核神经元的作用。具体地说，我们假设雌激素刺激伏核神经元表膜上的雌激素受体(ER)激活代谢性谷氨酸受体5(MGluR5)信号。雌激素激活ER？/mGluR5信号，进而影响伏隔核棘结构、伏核谷氨酸能神经传递，最终影响药物滥用反应。总而言之，这些研究将为开发针对女性药物成瘾的新的治疗方法提供基础。

DESCRIPTION (provided by applicant): In comparison to men, women are at an increased risk to abuse drugs. Across the spectrum of addiction, women show heightened intake of addictive substances, with greater craving, leading to an increased likelihood of addiction and relapse. These responses peak during the follicular phase of the menstrual cycle when estrogen levels are at their highest. These findings have been recapitulated in the female laboratory rat, where estradiol heightens multiple measures of drug responsiveness and abuse. Remarkably, the mechanisms by which estradiol mediates enhanced vulnerability to drug addiction are completely unknown. We propose a novel molecular mechanism mediating the actions of estradiol on nucleus accumbens neurons. Specifically we hypothesize that estradiol stimulation of estrogen receptor ¿ (ER¿) localized to the surface membrane of nucleus accumbens neurons activates metabotropic glutamate receptor 5 (mGluR5) signaling. Activation of ER¿/mGluR5 signaling by estradiol, in turn, affects nucleus accumbens spine structure, nucleus accumbens glutamatergic neurotransmission and ultimately responsiveness to drugs of abuse. Collectively, these studies will provide a foundation for developing novel therapeutic approaches targeted to treating drug addiction in women.