# Predicting addictive vulnerability to alcohol: Initial sensitivity, tolerance, allostasis and self-administration

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2020 · $184,656

## Abstract

Individuals who generate especially vigorous (but usually hidden) regulatory responses to an initial drug
challenge can appear to be initially insensitive to the drug based on summative outcome measures. Such
individuals are vulnerable to acquiring hyperactive response(s) over repeated drug exposures, putting them at
increased risk to escalate drug use and develop drug addiction. The allostatic model of addiction posits that
drug-induced allostatic changes cause the growth of hyper-responsive and/or otherwise dysregulated
responses that promote the development of addiction; i.e., an allostatic state motivates escalating drug use,
creating a vicious cycle characterized by loss of control and compulsive drug-taking. While only a modest
percentage of drug-exposed individuals become addicted, the aggregate costs to society are immense. Thus,
understanding the causal mechanisms responsible for individual differences in addictive vulnerability has high
priority. We have found that individual variation in initial drug sensitivity predicts future drug tolerance, drug
self-administration, and the transition to allostatic dysregulation. The R21 phase proposes to develop a novel
live-in ethanol-vapor exposure chamber for rats that also can be used for ethanol vapor self-administration.
Specific Aim 1 (SA1) builds the apparatus and tests its reliability to deliver a specified ethanol vapor
concentration and clear it from the chamber. SA2 will measure the relationship between inhaled ethanol vapor
concentration and blood ethanol levels and validate the functionality of the apparatus by assessing individual
differences in initial sensitivity, acquisition of self-administration, and degree of chronic tolerance
development. SA3 validates the use of alcohol vapor in a live-in thermal gradient apparatus. In the R33 phase,
SA4 tests the hypothesis that individual differences in initial sensitivity to alcohol reliably predict persistent
differences in alcohol vapor self-administration. SA5 tests the hypothesis that individual differences in initial
sensitivity to alcohol predict the development of allostatic dysregulation over repeated alcohol exposures in a
thermal gradient. SA6 tests the hypothesis that a non-drug challenge can substitute for an initial alcohol
challenge in identifying reliable inter-individual response variation that predicts the development of allostatic
dysregulation. The translational impact of our research will be enhanced if an individual's likelihood of
developing allostasis could be assessed without requiring an initial drug challenge. The proposed studies will
provide robust and unbiased results through the use of rigorous experimental designs and methods that
include continuous measurements of variables such as behavioral and metabolic-rate responses during
naturalistic or alcohol-induced regulatory challenges. This innovative research is based on a strong conceptual
framework and is of theoretical and practical importance for advancing ...

## Key facts

- **NIH application ID:** 10019315
- **Project number:** 5R21AA027574-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Douglas S Ramsay
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $184,656
- **Award type:** 5
- **Project period:** 2019-09-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019315

## Citation

> US National Institutes of Health, RePORTER application 10019315, Predicting addictive vulnerability to alcohol: Initial sensitivity, tolerance, allostasis and self-administration (5R21AA027574-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10019315. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*