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强迫性使用精神兴奋剂的模式，但矛盾的是，她们对治疗更敏感。雌激素水平的自然波动，如17β-雌二醇（E2），可能是导致滥用风险增加的原因，但对E2在成瘾治疗中的作用知之甚少。治疗是通过消退学习来模拟的，这导致了一种新的抑制记忆的形成，这种记忆抑制了药物的寻找。E2增强了雌性啮齿动物的学习能力，因此可能促进了可卡因寻求的灭绝，因为灭绝需要新的学习能力。然而，对于E2在女性体内对可卡因的抑制作用，我们实际上一无所知。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，雌性大鼠全身注射E2增强了可卡因寻求的表达和消失，E2的缺乏导致持续的消失缺陷

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.