Neural mechanisms underlying estradiol-enhanced extinction of cocaine seeking

描述(由申请人提供)：女性比男性更容易形成精神刺激剂的强迫使用模式，但矛盾的是，女性对治疗更敏感。雌激素水平的自然波动，如17β-雌二醇(17-雌二醇，E_2)，可能是导致滥用倾向增加的原因，但对E_2在成瘾治疗中的作用知之甚少。治疗是通过灭绝学习来模拟的，这导致了一种新的抑制性记忆的形成，从而抑制了药物寻找。E2增强雌性啮齿动物的学习能力，因此，可能会促进寻求可卡因的灭绝，因为灭绝需要新的学习。然而，关于雌二醇对女性寻求可卡因的消退的影响，人们几乎一无所知。这一疏漏是药物滥用文献中的一个重大空白，主要是因为E2与寻求药物的表达有关，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障碍的治疗。我们的初步数据显示，雌性大鼠全身注射E2可增强可卡因寻求的表达和消失，而缺乏E2会导致持续的消失赤字 (Twning等人，2013年)。因此，这项建议的目的是确定雌激素促进雌性大鼠戒断寻找可卡因的神经机制。为了实现这一目标，我们将使用微量注射E2来靶向已知与男性灭绝有关的大脑区域，包括边缘下内侧前额叶皮质、背侧海马体和伏隔核外壳。我们的中心假设是，E2通过表观遗传学改变神经营养因子的表达，从而调节这些脑区的突触可塑性，从而促进女性的灭绝。这项拟议研究的基本原理是，确定E2增强消亡学习的神经机制将导致对患有成瘾障碍的女性进行个性化治疗的新的创新方法。在我们强大的初步数据的指导下，我们的假设将在三个特定的目标下进行检验，旨在：1)确定E2诱导的可卡因寻求消退的神经解剖学基因座；2)确定介导E2诱导的可卡因寻求消退的关键神经营养机制；3)确定E2诱导的可卡因寻求消退的突触和内在机制。这项研究具有创新性，因为它代表了一种实质性的范式转变，从传统的关注药物的获得和表达转向强调灭绝。这项拟议的研究意义重大，因为了解E2诱导的促进消退的神经基础可以导致新的治疗方法，以提高女性药物成瘾治疗的有效性。这一贡献将使随后能够开发保持最佳E2水平的治疗方法，以改善可卡因成瘾妇女的治疗结果。减少妇女吸毒将极大地提高数百万妇女及其家庭的生活质量。

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.