# Genomic mechanisms of decision-making and opioid use trajectories in the rat

> **NIH NIH U01** · YALE UNIVERSITY · 2022 · $634,855

## Abstract

PROJECT SUMMARY / ABSTRACT
The transition from opioid use to abuse and, eventually, to dependence may be governed by distinct genetic
mechanisms that alter the molecular pathways that mediate opioid use disorder (OUD). The identity of these
genetic/genomic mechanisms is unknown, in part, because the majority of OUD studies have been done in
substance-dependent individuals where the dissociation between susceptibility and consequence is ambiguous
and genetic/environmental factors are equivocal. One potential strategy for investigating the genetic mechanisms
underlying differences in opiate-use trajectories that we have been pursuing in rats is to examine the
neurobiology of complex behavioral phenotypes that are associated with different phases of drug use. Our work
has identified a decision-making phenotype (e.g., ¨+ parameter) that predicts opiate-taking behaviors in rats,
which differs from the decision-making phenotype that is affected by opiate use (e.g., ¨0 parameter). We have
found that these distinct phenotypes are controlled by different orbitofrontal circuits that involve the amygdala
and nucleus accumbens, and our preliminary proteomic data indicates that these phenotypes are mediated by
divergent signaling pathways. We posit, therefore, that these computationally-derived phenotypes could serve
as a powerful tool for dissociating the genomic/genetic mechanisms of opioid use susceptibility from those that
are consequential to drug use. Here, we propose to use state-of-the-art genomic approaches to identify genes
that mediate susceptibility to opiate-taking behaviors and those that mediate drug-induced behavioral changes.
In Aim 1, we will investigate the genomic mechanisms underlying susceptibility to oxycodone use. Decision
making will be assessed in rats (N=300) to identify individuals who either have low or high ¨+ parameter
(N=60/group) that predicts susceptibility to opiate-taking behaviors. RNA sequencing will be performed on tissue
from the orbitofrontal cortex, nucleus accumbens and amygdala to identify genes whose expression differs
between rats with a low or high ¨+ parameter. We will then perform ATAC sequencing to identify the open
chromatin regions associated with the genes that differ between rats with a low or high ¨+ parameter. In Aim 2,
we will investigate the genomic mechanisms underlying the decision-making consequences of oxycodone self-
administration. Decision making will be assessed in rats (N=300) before and after they self-administer oxycodone
to identify individuals who either have low or high ¨0 parameter (N=60/group) following drug exposure. Tissue
collected from the orbitofrontal cortex, nucleus accumbens and amygdala will be sequenced using next-
generation RNA sequence to identify genes whose expression differs between rats with a low or high ¨0
parameter. We will then perform ATAC sequencing to identify the open chromatin regions associated with the
differentially expressed genes. Our results – integrating...

## Key facts

- **NIH application ID:** 10454299
- **Project number:** 5U01DA051977-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** RALPH J DILEONE
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $634,855
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454299

## Citation

> US National Institutes of Health, RePORTER application 10454299, Genomic mechanisms of decision-making and opioid use trajectories in the rat (5U01DA051977-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10454299. Licensed CC0.

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