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 (3?,5?)-3-hydroxypregnan-20-one (3?,5?-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.
Alcohol Use Disorders are the most costly public health problem in the world, and effective treatments are needed to help those suffering from this devastating disease. This study will explore whether increasing neuroactive steroids in specific neurons alters alcohol self- administration or escalated drinking after deprivation in a rat model of excessive drinking. Brain steroidogenesis will be increased by viral-vector-mediated gene delivery of the biosynthetic enzyme that produces pregnenolone from cholesterol and ultimately elevates neuroactive steroids known to mitigate symptoms of alcohol dependence. We predict this will reduce alcohol self-administration and relapse drinking or anxiety-like behavior in both male and female rats. This work may lead to an effective therapeutic strategy for alcoholism.
