Gene Delivery of Neuroactive Steroids to Modulate Ethanol Reinforcement/Consumption

项目摘要 动物和人类研究表明，神经活性类固醇的升高可能解决许多行为 与酒精使用障碍相关的病理学。这个项目的目标是评估假设 腹侧被盖区类固醇激素生成增加将减少可操作性乙醇的自我给药 男性和女性饮酒偏好在被剥夺后自愿饮酒的增加(P 老鼠。内源性神经活性类固醇激素将通过病毒载体介导的基因传递而增加 生物合成酶P450scc，可将胆固醇转化为孕烯醇酮。我们最近的研究表明 载体介导的P450scc到VTA的传递减少了乙醇的自我给药并增加了局部 表达(3α，5α)-3-羟孕酮-20-酮(3α，5α-THP，别孕酮)(Cook等人，2014年)。我们现在 建议通过检查对雄性和雌性P大鼠的影响来扩展这些研究，探索对 剥夺诱导饮酒，并将载体靶向VTA内的酪氨酸羟化酶(TH)神经元。我们会 检查媒介和行为的特异性，以及影响的持久性。AIM 1将调查是否 向VTA转导P450scc基因促进类固醇合成改变A)可操纵性乙醇自身给药 在非依赖的雄性和雌性P大鼠或B)酒精依赖的雄性和 雌性P级大鼠。目标2将研究VTA中神经元特异性类固醇激素生成的升高是否改变A) 非依赖雄性和雌性大鼠的可操作性乙醇自我给药或B)剥夺诱导的饮酒 在酒精依赖的雄性和雌性P大鼠中。这些研究将加深我们对VTA的作用的理解 酒精强化、焦虑样行为和饮酒增加中的神经活性类固醇 剥夺。

Project Summary Animal and human studies suggest that elevation of neuroactive steroids may address many of the behavioral pathologies associated with alcohol use disorders. The goal of this project is to evaluate the hypotheses that elevated steroidogenesis in the ventral tegmental area will reduce operant ethanol self-administration and the escalation of voluntary drinking following deprivation in male and female alcohol preferring (P) rats. Endogenous neuroactive steroids will be elevated by viral vector-mediated gene delivery of the biosynthetic enzyme P450scc that converts cholesterol to pregnenolone. Our recent studies demonstrate that vector-mediated delivery of P450scc to the VTA reduces ethanol self-administration and increases local expression of (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone) (Cook et al., 2014). We now propose to extend these studies by examining effects in both male and female P rats, probing effects on deprivation-induced drinking and targeting the vector to tyrosine hydroxylase (TH) neurons in the VTA. We will examine vector and behavioral specificity as well as the persistence of effects. Aim 1 will investigate if elevation of steroidogenesis by gene delivery of P450scc to VTA alters A) operant ethanol self-administration in non–dependent male and female P rats or B) deprivation-induced drinking in ethanol dependent male and female P rats. Aim 2 will examine whether TH neuron-specific elevation of steroidogenesis in VTA alters A) operant ethanol self-administration in non–dependent male and female rats or B) deprivation-induced drinking in ethanol dependent male and female P rats. These studies will increase our understanding of the role of VTA neuroactive steroids in ethanol reinforcement, anxiety-like behavior and escalated drinking following ethanol deprivation.