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: 9221693
• 负责人: DEVIN MUELLER
• 金额: $ 8.72万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 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/9221693
• 关键词: Neural; mechanisms; underlying; estradiol; enhanced

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（由申请人提供）：女性比男性更容易出现精神兴奋剂使用的强迫模式，但矛盾的是，女性对治疗的反应更敏感，雌激素水平的自然波动，例如 17β-雌二醇 (E2)，可能是造成这种情况的原因。滥用倾向增加，但人们对 E2 在成瘾治疗过程中的作用知之甚少。治疗是通过消退学习来建模的，这会导致抑制 E2 寻求药物的新抑制性记忆的形成。增强雌性啮齿类动物的学习能力，因此可能会促进可卡因寻求的灭绝，因为灭绝需要新的学习。然而，实际上对于 E2 对雌性啮齿类动物的可卡因寻求灭绝的影响一无所知，这一疏忽是该药物的一个主要空白。滥用文献，主要是因为 E2 与药物寻求的表达有关，而不考虑其潜在的治疗益处。我们的长期目标是了解性激素如何影响成瘾性疾病的治疗。我们的初步数据表明，女性全身使用 E2。大鼠增强可卡因的表达和消除寻找，而 E2 的缺乏会导致持续的灭绝赤字 （Twining 等，2013）因此，该提案的目的是确定 E2 促进雌性大鼠消除可卡因寻求的神经机制。为了实现这一目标，我们将使用 E2 的微量输注来靶向已知的大脑区域。参与雄性的灭绝，包括边缘下内侧前额叶皮层、背侧海马和伏核壳，我们的中心假设是 E2 通过表观遗传促进雌性的灭绝。改变神经营养素的表达，从而调节这些大脑区域的突触可塑性。这项研究的基本原理是，确定 E2 增强消退学习的神经机制将为患有成瘾性疾病的女性提供新的个体化治疗方法。在我们强有力的初步数据的指导下，我们的假设将在三个具体目标上进行检验，这些目标旨在：1）确定 E2 诱导促进可卡因寻求灭绝的神经解剖位点，2）定义介导可卡因寻求的关键神经营养机制E2 诱导的可卡因寻求灭绝的促进，以及 3) 确定 E2 诱导的可卡因寻求的灭绝促进的突触和内在机制 这项研究具有创新性，因为它代表了传统关注药物获取和表达的重大范式转变。寻求强调消退的研究具有重要意义，因为了解 E2 诱导的消退增强的神经基础可能会导致新的治疗方法，以提高女性毒瘾治疗的有效性。维持 E2 的最佳水平以改善减少可卡因成瘾妇女的治疗效果将大大改善数百万妇女及其家人的生活质量。