Estrogen regulation of the prefrontal cortex and drug seeking

雌激素对前额皮质的调节和药物寻求

• 批准号: 10197870
• 负责人: Matthew Carl Hearing
• 金额: $ 34.78万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10197870
• 关键词: Acute; Address; Attenuated; Behavior; Brain; CNR1 gene; Cholecystokinin; Chronic; Cocaine; Corticosterone; Diagnosis; Dose; Endocannabinoids; Estradiol; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Female; Fiber; Goals; Gonadal Steroid Hormones; High Prevalence; Hormonal; Hormones; Incidence; Interneurons; Intervention; Mediating; Mus; Nature; Neurobiology; Neurons; Neurosciences; Nucleus Accumbens; Optics; Output; Parvalbumins; Pathway interactions; Pharmaceutical Preparations; Photometry; Physiology; Population; Predisposition; Prefrontal Cortex; Proestrus; Rattus; Regulation; Relapse; Research; Risk; Role; Sex Differences; Societies; Stress; Substance Use Disorder; Synapses; Synaptic Transmission; System; Testing; Thalamic structure; Time; Treatment outcome; Variant; Woman; attenuation; base; biological sex; drug seeking behavior; effective intervention; experience; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; improved; in vivo; innovation; male; men; neural circuit; novel; pre-clinical; receptor; relapse risk; reproductive; stressor; transmission process

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.

项目摘要 药物使用障碍（SUD）是社会最紧迫的挑战之一。尽管患病率很高， 缺乏有效的SUD干预措施。考虑到泡沫的长期复发性质， 了解导致继电器风险的因素是一个特别重要的研究目标。一个因素是 生物性别。一旦建立了SUD，妇女就会遇到更大的困难和接力事件， 与男性相比，退休后发生更长的时间。性别差异 救济脆弱性部分是由包括进化在内的性恐怖症所介导的。我们已经确定了一本小说 雌激素急性通过前额叶皮层中的作用促进药物寻求药物的机制 （PRL-PFC）。雌二醇（E2），剂量产生雌性大鼠的肌含水平，可卡因剂 通过PRL-PFC中的雌激素受体β（ERβ）激活在女性中恢复原状。我们的初步发现 表明E2的这种影响与抑制性突触传播的ERβ依赖性衰减有关 在PRL-PFC中可能归因于降低的GABA释放。该建议将以这些发现为基础 进一步研究了E2调节突触传播和药物的PRL-PFC机制 寻求行为（目标1），并通过表征由E2和 为寻求药物（AIM 2）做出贡献，重点是伏隔核（NAC）核心和 脊髓丘脑丘脑（Pvt）。妇女在压力期间特别容易发生复发。 与此观察一致，我们建立了一种临床前方法来检查压力的能力 潜在的可卡因寻求并证明，在雌性大鼠中，压力进一步增加了可卡因 启动恢复原状，因此相对于男性，女性寻求药物的累积风险增加。 我们发现，应力受力体可卡因寻求是由压力马可皮质酮介导的 （cort），就像E2一样，涉及PRL-PFC中的Cort动作，可能包括衰减的突触GABA 对药物至关重要 寻求。但是，虽然cort受侵蚀药的寻求涉及内源性大麻素/CB1接收器依赖性 在PRL-PFC中，胆囊基蛋白+中间神经元的GABA释放减少，E2的作用是CB1R- 独立且可能涉及快速刺激性白蛋白+中间神经元的ERβ调节。我们将测试这个 假设并进一步探讨了AIM 3中Cort与E2之间的互动关系。 PI建议将突触生理学，系统神经科学和行为分析方面的专业知识汇总在一起。 目的对了解荷尔蒙介导的生殖和压力如何“大脑 状态”在前额叶皮层中收敛以指导行为。