# Cell type transcriptional mechanisms of polysubstance choice

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $471,892

## Abstract

PROJECT SUMMARY
In this new R01 application that is directly responsive to RFA-DA-23-015, our research team proposes to study
the cell type specific molecular mechanisms regulated by fentanyl and methamphetamine polysubstance use
at both the initiation and withdrawal stages of the substance use trajectory. We propose to overcome current
limitations in polysubstance research by utilizing preclinical assays of drug-vs.-food choice procedures in male
and female rats, which more fully capture the severity of polysubstance use seen in humans by modeling the
behavioral misallocation and decision making between concurrently available addictive drugs and alternative
non-drug reinforcers. We will combine these enhanced behavioral models with single nuclei RNA sequencing
(snRNAseq) of the medial prefrontal cortex (PFC) and nucleus accumbens (NAc), key brain regions implicated
in drug reinforcement and drug-taking, to capture and characterize the exact drug-induced molecular
adaptations that occur in specific cell types, including non-neuronal cells. We will directly test the hypothesis
that the synergistic action of combined fentanyl and methamphetamine use produces enhanced drug use
behaviors and brain molecular adaptations that are distinct from what is achieved by either fentanyl or
methamphetamine use alone; that this polysubstance synergy involves unique transcriptional adaptations by
brain region, accumulates as a function of drug experience, and contributes to the behavioral misallocation
towards drug use over more beneficial rewarding activities that is the hallmark of drug addiction. We will test
this overarching hypothesis in two Aims. In Aim 1, we will uncover the impact of fentanyl/methamphetamine
polysubstance use during the withdrawal phase of the substance use trajectory. We will use drug-vs.-food self-
administration choice procedures for saline, fentanyl alone, methamphetamine alone, and
fentanyl/methamphetamine combinations to uncover how an extended history of polysubstance use synergizes
to increase somatic withdrawal effects and drug taking behavior while experiencing withdrawal. We will then
perform snRNAseq in the PFC and NAc to interrogate the brain cell type specific transcriptional adaptations in
these rats. In Aim 2, we will similarly perform drug-vs.-food choice procedures and snRNAseq of these brain
regions to explore the emergence of behavioral and transcriptional adaptations at the of initiation of drug use
experience. We will go on to compare our snRNAseq data from Aims 1 and 2 to understand how the
fentanyl/methamphetamine polysubstance cell type transcriptional profile changes over the substance use
trajectory. This project will reveal how fentanyl and methamphetamine synergize to produce maladaptive drug
choice behaviors and brain cell type specific transcriptional responses at distinct stages of the substance use
trajectory that are common barriers to recovery. Results gained from this project will inform the discovery o...

## Key facts

- **NIH application ID:** 10879042
- **Project number:** 5R01DA058958-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Matthew L Banks
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $471,892
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879042

## Citation

> US National Institutes of Health, RePORTER application 10879042, Cell type transcriptional mechanisms of polysubstance choice (5R01DA058958-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10879042. Licensed CC0.

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