Gene Delivery of Neuroactive Steroids to Modulate Ethanol Reinforcement/Consumption

神经活性类固醇的基因传递以调节乙醇强化/消耗

基本信息

批准号：
9237639
负责人：
JOYCE BESHEER
金额：
$ 39.87万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9237639
关键词：
Address Adult Alcohol consumption Alcohol dependence Alcoholism Alcohols Allopregnanolone Animals Behavioral Body Weight Brain Cholesterol Consumption Corticosterone Disease Enzymes Ethanol Ethanol Metabolism Ethanol dependence Female Gene Delivery Goals Heavy Drinking Human Injection of therapeutic agent Lead Locomotion Measures Mediating Methods Modeling Motor Activity Neurons Pathology Plasma Pregnanolone Pregnenolone Protocols documentation Public Health Rattus Recombinant adeno-associated virus (rAAV)Relapse Role Self Administration Self-Administered Specificity Steroid biosynthesis Sucrose Symptoms Testing Training Treatment Efficacy Tyrosine 3-Monooxygenase Ventral Tegmental Area Viral Vector Water consumption Work alcohol preferring rats alcohol reinforcement alcohol use disorder anxiety-like behavior cooking cost deprivation drinking drinking behavior effective therapy experimental study food consumption male neuron loss neurosteroids novel pregnane-20-one prevent reinforcer sex tetrahydrodeoxycorticosterone vector vector control

项目摘要

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.

项目概要动物和人类研究表明，提高神经活性类固醇可能会解决许多行为问题该项目的目标是评估与酒精使用障碍相关的病理学。腹侧被盖区类固醇生成的增加将减少操作性乙醇的自我给药以及偏好饮酒的男性和女性在剥夺后自愿饮酒的升级（P）大鼠体内的内源性神经活性类固醇将通过病毒载体介导的基因传递而升高。我们最近的研究表明，生物合成酶 P450scc 可将胆固醇转化为孕烯醇酮。载体介导的 P450scc 至 VTA 的递送减少了乙醇的自我施用并增加了局部 (3α,5α)-3-羟基孕烷-20-酮（3α,5α-THP，allopregnanolone）的表达（Cook 等人，2014）。建议通过检查雄性和雌性 P 大鼠的影响来扩展这些研究，探讨对剥夺诱导饮酒并将载体靶向 VTA 中的酪氨酸羟化酶 (TH) 神经元。检查向量和行为特异性以及效果的持久性，目标 1 将调查是否。通过将 P450scc 基因传递至 VTA 来提高类固醇生成改变 A) 操作性乙醇自我给药在非依赖的雄性和雌性 P 大鼠中或 B) 在乙醇依赖的雄性和雌性大鼠中剥夺诱导饮酒目标 2 将检查 VTA 中 TH 神经元特异性升高是否会改变雌性 P 大鼠 A) 对非依赖性雄性和雌性大鼠进行操作性乙醇自我给药或 B) 剥夺诱导饮酒这些研究将增加我们对 VTA 作用的理解。神经活性类固醇在乙醇强化、焦虑样行为和乙醇后饮酒增加中的作用剥夺。