# Project 2: Acute Cocaine Sensitivity and Chronic Sensitization

> **NIH NIH P50** · JACKSON LABORATORY · 2024 · $224,774

## Abstract

PROJECT SUMMARY SENSITIZATION (PROJECT 2)
Most people who use cocaine do not go on to develop a cocaine use disorder (CUD) suggesting that individual
differences drive susceptibility to addiction. The progression from initial drug use to drug dependence is driven,
in part, by genetic differences but there remain significant gaps in our knowledge of the genetic and biological
etiologies underlying CUD. Individual differences in behavioral and neurobiological changes that occur in
response to repeated drug exposure have been associated with CUD risk. In rodents, repeated psychostimulant
exposure progressively augments locomotor activation – a phenomenon referred to as behavioral or
psychomotor sensitization. Repeated exposure to drugs of abuse that yields psychomotor sensitization also
alters the reward circuitry and results in hypersensitivity to the incentive motivational effects of drugs and drug-
associated stimuli (incentive sensitization). Although psychomotor sensitization is often used as an indirect
measure of underlying neuroadaptations, direct comparisons between individual variation in psychomotor
sensitization and incentive sensitization have not been reported. The overall objective of Project 2 is to identify
neurogenetic mechanisms contributing to individual differences in cocaine sensitization that may be relevant to
patterns of drug use. Using our high-throughput screening regimen for behavioral sensitization developed over
the current funding period, and implemented in the Behavioral Phenotyping Core, we found significant
phenotypic variation in behavioral sensitization across 50 Collaborative Cross (CC) strains. We also identified
CC strains with extreme phenotypes in cocaine-induced locomotor sensitivity and demonstrated that these
strains exhibit divergent phenotypes in cocaine self-administration (Project 3). In this renewal, our research goals
will be achieved with the following three aims: 1) To establish the relationship between behavioral and incentive
sensitization in CC strains. In collaboration with the Behavioral Phenotyping Core, we will measure incentive
sensitization in the same 50 CC strains. These studies will enable us to understand how strain variation in
behavioral sensitization relates to differences in the motivational salience of cocaine. 2) To evaluate potential
mechanisms for behavioral phenotypes observed in the CC. In collaboration with the Integrated Genetics and
Genomics Core, we will characterize CC strains with extreme phenotypes to identify biological mechanisms that
contribute to behavioral differences. 3) To validate candidate genes by studying behavioral sensitization and
other CSNA behaviors in genetically engineered mouse models. In collaboration with the Mouse Resources and
Validation Core, we will engineer overexpression and knockout models of Eed to test the role of this candidate
gene in behavioral sensitization. We will also continue mapping efforts using our Diversity Outbred (DO)
phenoty...

## Key facts

- **NIH application ID:** 10879009
- **Project number:** 5P50DA039841-08
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Lisa M Tarantino
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $224,774
- **Award type:** 5
- **Project period:** 2016-08-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879009

## Citation

> US National Institutes of Health, RePORTER application 10879009, Project 2: Acute Cocaine Sensitivity and Chronic Sensitization (5P50DA039841-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10879009. Licensed CC0.

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