Estrogen Underlying Increased Female Vulnerability to Addiction

描述（由申请人提供）：与男性相比，女性滥用药物的风险更高。在成瘾的范围内，女性对成瘾物质的摄入量增加，渴望更大，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大鼠中得到了重申，雌二醇提高了药物反应性和滥用的多种措施。值得注意的是，雌二醇介导对药物成瘾的脆弱性增强的机制是完全未知的。我们提出了一种新的介导雌二醇对伏隔核神经元作用的分子机制。具体来说，我们假设雌二醇刺激伏隔核神经元表面膜上的雌激素受体（ER）激活代谢性谷氨酸受体5 （mGluR5）信号。雌二醇激活ER /mGluR5信号，进而影响伏隔核脊柱结构、伏隔核谷氨酸能神经传递和最终对滥用药物的反应。总的来说，这些研究将为开发针对治疗妇女吸毒成瘾的新治疗方法提供基础。

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.