Neural mechanisms underlying estradiol-enhanced extinction of cocaine seeking

描述（由申请人提供）：女性比男性更容易发展精神兴奋剂使用的强迫模式，但矛盾的是，对治疗更敏感。雌激素水平的自然波动，如17β-雌二醇（E2），可能是增加滥用倾向的原因，但对E2在成瘾治疗中的作用知之甚少。治疗以消退学习为模型，这导致形成一种新的抑制性记忆，抑制药物寻求。E2增强了雌性啮齿动物的学习能力，因此，可能有助于可卡因寻求的灭绝，因为灭绝需要新的学习。然而，几乎没有人知道E2对女性可卡因寻求消失的影响。这种疏忽是药物滥用文献中的一个主要空白，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，雌性大鼠全身给予E2可增强可卡因寻求的表达和消退，缺乏E2会导致持续的消退缺陷 （Twining等人，2013年）。因此，本建议的目的是确定E2促进雌性大鼠可卡因寻求的神经机制。为了实现这一目标，我们将使用微量注射E2来靶向已知参与男性灭绝的大脑区域，包括边缘内侧前额叶皮层、背侧海马和背侧核壳。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，从而调节这些大脑区域的突触可塑性，促进女性的灭绝。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成瘾性疾病女性的个性化治疗提供新的创新方法。在我们强有力的初步数据的指导下，我们的假设将在三个特定目标中进行测试，旨在：1）确定E2诱导的可卡因寻求消退促进的神经解剖学位点，2）定义介导E2诱导的可卡因寻求消退促进的关键神经营养机制，3）确定E2诱导的可卡因寻求消退促进的突触和内在机制。这项研究是创新的，因为它代表了一个实质性的范式转变，从传统的重点收购和表达的药物寻求到强调灭绝。这项研究意义重大，因为了解E2诱导的灭绝增强的神经基础可能会导致新的治疗方法，以提高女性药物成瘾治疗的有效性。这一贡献将使后续开发的治疗，保持最佳水平的E2，以改善治疗结果的可卡因成瘾的妇女。减少妇女中的药物滥用将大大改善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.