# Gene Delivery of Neuroactive Steroids to Modulate Ethanol Reinforcement/Consumption

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $400,240

## Abstract

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.

## Key facts

- **NIH application ID:** 9894698
- **Project number:** 5R01AA024095-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Joyce Besheer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,240
- **Award type:** 5
- **Project period:** 2017-05-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894698

## Citation

> US National Institutes of Health, RePORTER application 9894698, Gene Delivery of Neuroactive Steroids to Modulate Ethanol Reinforcement/Consumption (5R01AA024095-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9894698. Licensed CC0.

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