# Rapid identification of cocaine sensitivity genes using a novel reduced complexity cross

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $227,394

## Abstract

ABSTRACT
Substance use disorders (SUD) result in increased risk of morbidity and mortality and impose substantial
personal and financial burdens on affected individuals and society as a whole. There is considerable evidence
that genetics increases the risk for SUDs, but identifying specific gene variants has been hampered by disease
heterogeneity, genetic complexity and the inability to control or account for environmental exposures in human
populations. Some of these issues can be overcome with addiction genetic studies in rodent models. However,
standard methods of mapping in rodent populations often result in identification of large genomic regions that
require considerable effort to narrow and thus delay or prevent identification of the causal gene variant. Recent
technology and bioinformatic resources have made it possible to conduct genetic mapping studies using crosses
between inbred mouse substrains (called Reduced Complexity Crosses or RCCs). Inbred mouse substrains
diverge when inbred strain breeding colonies are transferred between collaborators or commercial entities.
Polymorphisms segregate between these subpopulations at regions of the genome for which the parental strain
has not yet become fixed, or from genetic drift, resulting in sets of strains that are genetically very closely related.
Therefore, while standard inbred strains differ from each other at hundreds of thousands of loci, inbred substrains
differ at thousands of loci – only a fraction of which will be functional. These characteristics expedite identification
of causal genes in substrains for which phenotypic differences exist. This approach has been used to identify a
cocaine-sensitivity gene but has been limited to C57BL/6 substrains. Dozens of inbred substrains exist and
opportunities for identifying genes that influence addiction-related behaviors are being missed. We have
identified a striking phenotypic difference in cocaine locomotor sensitivity between the C3H substrains, C3H/HeJ
and C3H/HeNTac. In this R21 application, we propose to use a RCC to identify the causal allele(s) for the
phenotypic differences in these substrains. We will also examine substrain-specific pharmacokinetic and dose
response phenotypes and examine the rewarding and reinforcing effects of cocaine using the drug self-
administration paradigm. These studies will establish a drug response profile for each C3H substrain and allow
us to begin exploring mechanisms by which the causal allele alters behavior.

## Key facts

- **NIH application ID:** 10072857
- **Project number:** 1R21DA052171-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Lisa M Tarantino
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $227,394
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072857

## Citation

> US National Institutes of Health, RePORTER application 10072857, Rapid identification of cocaine sensitivity genes using a novel reduced complexity cross (1R21DA052171-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072857. Licensed CC0.

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