Estrogen regulation of the prefrontal cortex and drug seeking

项目概要 药物滥用障碍 (SUD) 是社会最紧迫的挑战之一。尽管患病率很高， 缺乏针对 SUD 的有效干预措施。考虑到 SUD 的慢性复发性质， 了解导致复发风险的因素是一个特别重要的研究目标。其中一个因素是 生物性别。一旦建立了 SUD，女性就会经历更大的戒烟困难和复发率， 与男性相比，在复发后恢复使用的时间更长。性别差异 复发脆弱性部分是由性激素（包括雌激素）介导的。我们已经确定了一本小说 雌激素通过前边缘前额皮质的作用急剧促进药物寻求的机制 （PrL-PFC）。雌二醇 (E2) 在雌性大鼠中产生发情前期水平的剂量下，可增强可卡因引发的效果 通过激活 PrL-PFC 中的雌激素受体 β (ERβ) 来恢复女性体内的功能。我们的初步调查结果 表明 E2 的这种作用与 ERβ 依赖性抑制性突触传递减弱有关 PrL-PFC 中的这可能归因于 GABA 释放的减少。该提案将以这些发现为基础 进一步研究E2调节突触传递和药物的PrL-PFC机制 寻找行为（目标 1）并通过表征由 E2 和调节的 PrL-PFC 输出路径 为药物寻找做出贡献（目标 2），重点是对伏隔核 (NAc) 核心的预测和 室旁丘脑（PVT）。女性在压力时期特别容易旧病复发。 与这一观察一致，我们建立了一种临床前方法来检查压力能力 增强对可卡因的寻求，并且已经证明，在雌性大鼠中，压力进一步增加可卡因- 从而导致女性相对于男性寻求毒品的累积风险增加。 我们发现，压力增强的可卡因寻求是由压力激素皮质酮介导的 (CORT)，与 E2 一样，涉及 PrL-PFC 中的 CORT 作用，可能包括减弱的突触 GABA 释放和减少对药物至关重要的 PrL-PFC 输出途径（即 NAc 核心）的限制 寻求。然而，虽然 CORT 增强的药物寻求涉及内源性大麻素/CB1 受体依赖性 PrL-PFC 中胆囊收缩素中间神经元 GABA 释放减少，E2 的作用是 CB1R- 独立且可能涉及快速尖峰小清蛋白中间神经元的 ERβ 调节。我们将测试这个 假设并进一步探讨目标 3 中 CORT 和 E2 之间的交互关系。这种创新的多 PI 提案汇集了突触生理学、系统神经科学和行为分析方面的专业知识。的 目标对于理解激素如何介导生殖和压力“大脑”具有更广泛的影响 “状态”汇聚在前额叶皮层来指导行为。

PROJECT SUMMARY Substance use disorders (SUDs) are among society's most pressing challenges. Despite their high prevalence, effective interventions for SUDs are lacking. Considering the chronically relapsing nature of SUDs, understanding factors that contribute to relapse risk is a particularly important research goal. One such factor is biological sex. Once a SUD is established, women experience greater difficulty abstaining and relapse incidence, and resume use for longer periods of time after relapse has occurred when compared with men. Sex differences in relapse vulnerability are mediated in part by sex hormones, including estrogens. We have identified a novel mechanism through which estrogen acutely promotes drug seeking via actions in the prelimbic prefrontal cortex (PrL-PFC). Estradiol (E2), at a dose that produces proestrus levels in female rats, potentiates cocaine-primed reinstatement in females via estrogen receptor beta (ERβ) activation in the PrL-PFC. Our preliminary findings suggest that this effect of E2 is associated with an ERβ-dependent attenuation of inhibitory synaptic transmission in the PrL-PFC that is likely attributable to reduced GABA release. This proposal will build on these findings by further investigating the PrL-PFC mechanisms through which E2 regulates synaptic transmission and drug- seeking behavior (Aim 1) and by characterizing the PrL-PFC output pathways that are regulated by E2 and contribute to drug seeking (Aim 2) with a focus on projections to the nucleus accumbens (NAc) core and paraventricular thalamus (PVT). Women are particularly susceptible to relapse during periods of stress. Consistent with this observation, we have established a preclinical approach for examining the ability of stress to potentiate cocaine seeking and have demonstrated that, in female rats, stress further increases cocaine- primed reinstatement, thus producing an increased cumulative risk for drug seeking in females relative to males. We have found that stress-potentiated cocaine seeking is mediated by the stress hormone corticosterone (CORT) and that, like E2, involves CORT actions in the PrL-PFC that likely include attenuated synaptic GABA release and reduced constraint of PrL-PFC output pathways (i.e., to the NAc core) that are critical for drug seeking. However, while CORT-potentiated drug seeking involves endocannabinoid/CB1 receptor-dependent reductions in GABA release from cholecystokinin+ interneurons in the PrL-PFC, the actions of E2 are CB1R- independent and likely involve ERβ regulation of fast-spiking parvalbumin+ interneurons. We will test this hypothesis and further explore the interactive relationship between CORT and E2 in Aim 3. This innovative multi- PI proposal pulls together expertise in synaptic physiology, systems neuroscience, and behavior analysis. The aims have broader implications for understanding how hormonally mediated reproductive and stress “brain states” converge in the prefrontal cortex to guide behavior.