# Genomic Analysis of Avoidance Learning in Addiction

> **NIH NIH U01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $685,115

## Abstract

Abstract:
Addictions are among the most heritable of human neuropsychiatric disorders, but human genetic
studies have been hampered by the extreme complexity of human genetics, as well as the sheer
behavioral complexity of the addictive process, with multiple stages at which humans can exhibit
addiction vulnerability – e.g. initial drug exposure, escalation, relapse, etc. We address these
shortcomings by studying heterogeneous stock (HS) rats, which have extremely well characterized
genetic profiles, and using behavioral models that examine multiple well-defined time periods in the
progression of addictive behaviors. Our preliminary findings show that even though addiction is often
viewed as aberrant reward learning, much individual variation in addiction propensity is actually due
to differences in avoidance learning. For example, in addition to its well-known rewarding properties,
cocaine has aversive effects that show greater individual variability than its rewarding effects, and are
stronger predictors of cocaine-seeking. Furthermore, we found that rats differ greatly in “punishment
resistance”, i.e. propensity to seek rewards despite adverse outcomes, which is one of the defining
characteristics of addiction. Both cocaine avoidance and punishment resistance are highly heritable in
HS rats (h2 = 0.58 and 0.48, respectively), and both are critically regulated by the rostromedial
tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons that plays key
roles in avoidance learning. Building on these findings, we seek to identify the genetic differences
underlying these two distinct addiction vulnerability phenotypes using a genome-wide association
screen (GWAS) to identify candidate genes in HS rats, followed by eQTL analysis on gene
expression in the RMTg and afferent circuits that drive these behaviors. This project will identify
candidate addiction-related genes using a highly innovative combination of powerful behavioral tests,
extensive neural circuitry knowledge, and the Palmer lab's groundbreaking sequencing and analytical
approaches.

## Key facts

- **NIH application ID:** 10098021
- **Project number:** 5U01DA044468-04
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** THOMAS C JHOU
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $685,115
- **Award type:** 5
- **Project period:** 2018-04-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098021

## Citation

> US National Institutes of Health, RePORTER application 10098021, Genomic Analysis of Avoidance Learning in Addiction (5U01DA044468-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10098021. Licensed CC0.

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