# Single nucleus gene expression in moderate and compulsive drug self-administration in a rodent model of HIV

> **NIH NIH U01** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $1,342,901

## Abstract

Summary
 The abuse of stimulants such as methamphetamine (METH) exacerbates the deleterious effects of HIV
infection. Here, we will carry out single nucleus RNA-Seq with the goal of identifying cell types and cell states
that are pivotal in the effects of HIV and chronic methamphetamine (METH) self-administration on key brain
regions relevant to the effects of persistent HIV infection and METH use disorder in HIV transgenic (Tg) rats,
which harbor a non-replicating HIV-1 transgene and express chronic low-levels of multiple HIV-1 proteins. The
occasional but limited use of a drug is clinically distinct from escalated drug use, which is characterized by the
emergence of chronic compulsive drug-seeking and taking. Thus, we will use an established, state-of-the-art
paradigm of voluntary intravenous drug self-administration under long access (LgA) conditions that leads to
escalated (compulsive) METH intake in comparison to self-administration under short access (ShA) conditions,
which leads to a moderate and stable pattern of METH intake. The paradigm of escalated drug intake under
LgA conditions is highly relevant to the human substance use disorder (SUD) as it models all 7 of the criteria
for drug addiction in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and 7 of the 11 criteria
in the DSM-V. We showed that HIV Tg rats self-administering METH in this paradigm display increased
compulsivity, neuroinflammation, and neural injury. The project will address the following vexing question about
persistent HIV infection in the CNS: what are the cell types and cell states that drive neuroinflammation,
neurodegeneration, and compulsive METH abuse in the setting of HIV that can reveal the pathogenic
mechanisms behind neuroHIV disease progression, virus expression and persistence? The overarching
hypothesis behind the present project is that the exploration of the gene regulatory network at the single cell
level will elucidate key mechanisms that underlie the effects of HIV and METH abuse and their detrimental
interactions on neuroHIV disease progression, virus expression, and virus persistence and will indicate novel
therapeutic targets for neuroinflammation, neurodegeneration, and compulsivity to take METH. To test this
hypothesis, we will use a validated systems biology strategy for the reconstruction and interrogation of
genome-wide gene regulatory networks to identify the gene network dysregulations associated with the effects
of HIV, compulsive METH use, and their interactions at single cell resolution gene profiling by single nucleus
RNA-Seq. Overall, this collaborative interdisciplinary proposal integrating single cell level transcriptomics,
state-of-the-art behavior methods in HIV Tg and wild-type rats, and computational strategies is expected to
identify novel mechanistic hypotheses that may lead to transformative new therapeutic concepts for substance
use disorder (SUD) in the HIV setting, and will establish key resources for th...

## Key facts

- **NIH application ID:** 10747423
- **Project number:** 5U01DA056004-03
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** PIETRO P SANNA
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,342,901
- **Award type:** 5
- **Project period:** 2022-03-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747423

## Citation

> US National Institutes of Health, RePORTER application 10747423, Single nucleus gene expression in moderate and compulsive drug self-administration in a rodent model of HIV (5U01DA056004-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10747423. Licensed CC0.

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