Neural mechanisms underlying estradiol-enhanced extinction of cocaine seeking

雌二醇增强可卡因寻求消除的神经机制

• 批准号: 8756244
• 负责人: DEVIN MUELLER
• 金额: $ 36.98万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8756244
• 关键词: Accounting; Affect; Behavioral; Biochemical; Brain region; Brain-Derived Neurotrophic Factor; Cocaine; Cocaine Dependence; Data; Disease; Dorsal; Drug Addiction; Drug abuse; Effectiveness; Epigenetic Process; Estradiol; Estrogens; Event; Extinction (Psychology); Family; Female; Fibroblast Growth Factor 2; Foundations; Fright; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hippocampus (Brain); Hormonal; Individual Differences; Laboratories; Lead; Learning; Literature; Medial; Mediating; Memory; Mission; Modeling; Molecular; Neurons; Nucleus Accumbens; Outcome; Pattern; Pharmaceutical Preparations; Play; Prefrontal Cortex; Principal Investigator; Protein Biosynthesis; Public Health; Quality of life; Rattus; Relapse; Relative (related person); Research; Research Personnel; Rewards; Rodent; Role; Signal Pathway; Signal Transduction; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Therapeutic; Vision; Woman; Women' s Health; Work; addiction; base; design; drug addiction therapy; experience; improved; innovation; learning extinction; male; men; neuromechanism; neurotrophic factor; pre-clinical; prevent; psychostimulant; relating to nervous system; response; therapy development

DESCRIPTION (provided by applicant): Women are more susceptible than men to developing compulsive patterns of psychostimulant use, but paradoxically, are more responsive to treatment. Natural fluctuations in levels of estrogens, such as 17β- estradiol (E2), may account for the increased abuse liability, but little is known about the role of E2 during treatment of addiction. Treatment is modeled by extinction learning, which results in the formation of a new inhibitory memory that suppresses drug seeking. E2 enhances learning in female rodents, and therefore, may facilitate extinction of cocaine seeking, as extinction requires new learning. However, virtually nothing is known about the effects of E2 on extinction of cocaine seeking in females. This oversight is a major gap in the drug abuse literature, chiefly because E2 has been implicated in the expression of drug seeking without regard to its potential therapeutic benefit. Our long-term goal is to understand how sex hormones impact treatment for addictive disorders. Our preliminary data show that systemic E2 administration in female rats enhances expression and extinction of cocaine seeking, and the absence of E2 results in a persistent extinction deficit (Twining et al., 2013). Thus, the objective of this proposal is to determine the neural mechanisms through which E2 facilitates extinction of cocaine seeking in female rats. To achieve this objective, we will use microinfusions of E2 to target brain regions known to be involved in extinction in males, including the infralimbic medial prefrontal cortex, dorsal hippocampus, and nucleus accumbens shell. Our central hypothesis is that E2 facilitates extinction in females by epigenetically altering the expression of neurotrophins, thereby regulating synaptic plasticity, in these brain regions. The rationale for the proposed research is that identifying the neural mechanisms through which E2 enhances extinction learning will result in new and innovative approaches to individualized treatment for women with addictive disorders. Guided by our strong preliminary data, our hypothesis will be tested in three specific aims designed to: 1) determine the neuroanatomical loci of E2-induced facilitation of extinction of cocaine seeking, 2) define the key neurotrophic mechanisms mediating E2-induced facilitation of extinction of cocaine seeking, and 3) determine synaptic and intrinsic mechanisms underlying E2-induced facilitation of extinction of cocaine seeking. This research is innovative because it represents a substantial paradigm shift from the conventional focus on acquisition and expression of drug seeking to an emphasis on extinction. The proposed research is significant because understanding the neural basis of E2-induced enhancement of extinction could lead to new treatments to increase the effectiveness of therapies for drug addiction in women. This contribution will enable subsequent development of treatments that maintain optimal levels of E2 to improve therapeutic outcomes in cocaine- addicted women. Reducing drug abuse among women will greatly improve the quality of life for millions of women and their families.

描述（由适用提供）：女性比男性更容易发展精神刺激使用的强迫性模式，但自相矛盾的是，对治疗的反应更快。进化水平（例如17β-雌二醇（E2））的自然波动可能占滥用责任的增加，但对E2在成瘾治疗中的作用知之甚少。治疗是通过扩展学习来建模的，这导致形成了一种新的抑制性记忆，从而抑制了寻求药物。 E2增强了女性啮齿动物的学习，因此，由于扩展需要新的学习，因此可以促进可卡因寻求的扩展。但是，对于E2对女性寻求可卡因寻求的影响几乎一无所知。这种疏忽是药物滥用文献中的一个主要差距，这主要是因为在寻求药物的表达中暗示了E2，而无需考虑其潜在的治疗益处。我们的长期目标是了解性恐怖如何影响累加障碍的治疗方法。我们的初步数据表明，雌性大鼠的全身性E2给药增强了可卡因寻求的表达和扩展，并且缺乏E2导致持续的扩展不足赤字 （Twining等，2013）。这是该提议的目的是确定E2雌性大鼠可卡因寻求可卡因的神经机制。为了实现这一目标，我们将使用E2的微吸收来靶向已知参与男性延伸的大脑区域，包括脱发介质前额叶前皮层，背部海马和副壳壳。我们的中心假设是，通过表观遗传改变神经营养蛋白的表达，女性的E2设施扩展，从而调节了这些大脑区域的突触可塑性。拟议研究的理由是，确定E2增强扩展学习的神经力学将为具有添加剂疾病的女性提供个性化治疗的新方法。在我们强大的初步数据的指导下，我们的假设将以三个特定的目的进行测试：1）确定可卡因寻求可卡因扩展的E2诱导的设施的神经解剖位置，2）定义关键的神经营养机制，定义了介导E2诱导的E2诱导的Entiment ococains and Sentins and Syntins and Syntins的神经营养机制。可卡因寻求扩展的设施。这项研究具有创新性，因为它代表了从常规的对寻求药物的获取和表达的关注，重点是扩展的范式。拟议的研究很重要，因为了解E2诱导的扩展增强的神经元基础可能会导致新的治疗方法，以提高女性添加药物疗法的有效性。这项贡献将使随后的治疗方法得以维持最佳水平的E2水平，以改善可卡因成瘾妇女的治疗结果。减少女性滥用药物将大大改善数百万妇女及其家人的生活质量。