Estrogen regulation of the prefrontal cortex and drug seeking

项目总结 物质使用障碍(SODS)是社会最紧迫的挑战之一。尽管它们的流行率很高， 对肥皂症缺乏有效的干预措施。考虑到肥皂泡的长期复发性质， 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 生物性交。一旦建立了SUD，女性戒酒和复发的难度就会更大， 与男性相比，复发后恢复使用的时间更长。性别差异 复发的脆弱性在一定程度上是由性激素(包括雌激素)介导的。我们已经确定了一部小说 雌激素通过作用于前额叶皮质促进药物寻找的机制 (PRL-PFC)。雌二醇(E_2)在雌性大鼠中产生动情前期水平，可增强可卡因刺激 雌性PRL-PFC中雌激素受体β(ER-β)的激活恢复。我们的初步调查结果 提示E2的这种作用与ERβ依赖的抑制性突触传递减弱有关 在PRL-PFC中，这可能是由于GABA释放减少所致。这项提案将以这些调查结果为基础，通过 进一步研究E2调节突触传递和药物释放的PRL-PFC机制。 寻找行为(目标1)和表征受E2和PFC调控的PRL-PFC输出通路 促进药物寻找(目标2)，重点放在伏隔核(NAC)核心和 室旁丘脑(PVT)。女性在压力时期特别容易复发。 与这一观察结果一致，我们已经建立了一种临床前方法来检查应激能力。 为了加强对可卡因的寻求，并已证明，在雌性大鼠中，应激进一步增加可卡因- 因此，与男性相比，女性寻求毒品的累积风险增加。 我们发现，应激增强的可卡因寻找是由应激激素皮质酮介导的。 (CORT)，这和E2一样，涉及PRL-PFC中的CORT活动，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输出通路(即，到NAC核心)的约束 寻找。然而，虽然皮质醇增强的药物寻找涉及内源性大麻素/CB1受体依赖 PRL-PFC内CCK中间神经元GABA释放减少，E_2的作用是CB1R- 独立的，可能涉及ERβ对快速放电的小白蛋白中间神经元的调节。我们将对此进行测试 假设，并在目标3中进一步探索皮质醇和雌二醇之间的相互作用关系。 PI建议汇集了突触生理学、系统神经科学和行为分析方面的专业知识。这个 AIMS对于理解荷尔蒙如何调节生殖和应激“大脑”具有更广泛的意义 状态“汇聚在前额叶皮质来指导行为。

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.