Estrogen regulation of the prefrontal cortex and drug seeking

项目摘要 物质使用障碍（SUD）是社会最紧迫的挑战之一。尽管其发病率很高， 缺乏有效的干预措施。考虑到SUD长期复发的性质， 了解导致复发风险的因素是一个特别重要的研究目标。一个这样的因素是 生理性别一旦确定SUD，女性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 在复发时，脆弱性部分是由性激素，包括雌激素介导的。我们发现了一本小说 雌激素通过前边缘前额叶皮层的作用强烈促进药物寻求的机制 （PrL-PFC）。在雌性大鼠中产生发情前期水平的剂量下，E2增强可卡因引发的 通过激活PrL-PFC中的雌激素受体β（ERβ）， 提示E2这种作用与ERβ依赖性抑制性突触传递衰减有关 在PrL-PFC中，这可能归因于GABA释放减少。本提案将以这些调查结果为基础， 进一步研究E2调节突触传递和药物的PrL-PFC机制， 寻求行为（目标1），并通过表征由E2调节的PrL-PFC输出途径， 有助于药物寻求（目标2），重点是投射到丘脑核（NAc）核心， 室旁丘脑（PVT）。妇女在压力时期特别容易复发。 与这一观察结果相一致，我们已经建立了一个临床前的方法来检查压力的能力， 加强可卡因寻求，并已证明，在雌性大鼠中，压力进一步增加可卡因- 因此，与男性相比，女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应激激素皮质酮介导的 （CORT），并且像E2一样，涉及PrL-PFC中的CORT作用，可能包括衰减的突触GABA 释放和减少PrL-PFC输出途径的限制（即，对药物至关重要的 寻找然而，尽管CORT增强的药物寻求涉及内源性大麻素/CB 1受体依赖性 减少GABA释放胆囊收缩素+中间神经元在PrL-PFC，E2的行动是CB 1 R- 独立且可能涉及ERβ对快速尖峰小清蛋白+中间神经元的调节。我们将测试这个 假设，并进一步探讨目标3中CORT与E2之间的相互作用关系。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 这些目标对于理解生殖和压力是如何通过大脑介导的具有更广泛的意义 状态”在前额叶皮层集中以指导行为。

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.