# Ventral pallidum molecular mediators in cocaine addiction

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $434,284

## Abstract

Drug abuse is a debilitating chronic disease characterized by compulsive drug seeking and use despite
negative personal consequences. Repeated exposure to drugs of abuse is accompanied by persistent
alterations in molecular processes. This includes alterations in transcription factors that regulate synaptic and
structural plasticity molecules, which underlie the persistent behavioral responses to repeated drug exposure.
Psychostimulant induced molecular alterations have been well characterized in critical reward brain regions,
such as the nucleus accumbens (NAc). The two NAc medium spiny-projection neuron (MSN) subtypes display
classically distinct projection outputs but recent studies demonstrate converging output from these neurons to
the ventral pallidum (VP) in the actions of cocaine. Surprisingly, there is no information into psychostimulant
induced molecular adaptations in VP, despite it being a main target of both NAc MSN subtypes and its critical
role in behavioral responses to drugs of abuse. Our studies will investigate the underlying molecular processes
occurring in VP after cocaine self-administration and determine how the two NAc MSN subtypes contribute to
cocaine induced molecular alterations in the VP. We will focus on the transcription factor nuclear receptor
subfamily 4 group A member 1 (Nr4a1) and the Nr4a1 transcriptional target, polo like kinase 2 (Plk2), which we
identified to be upregulated in VP after cocaine self-administration using RNA-seq. Our studies will first identify
which VP neuron subtype displays upregulation of these molecules after cocaine-self administration. We will
then use genetic tools to overexpress or knockdown Nr4a1 and Plk2 in specific VP neuron subtypes during
cocaine self-administration and relapse behavior. We will additionally determine if Nr4a1 transcriptionally
regulates Plk2 in VP in these conditions. Next we will explore how VP neuron subtype structural and synaptic
plasticity is regulated through Nr4a1 and Plk2. Finally, we will determine if the upstream NAc MSN subtypes
can regulate these transcriptional and cellular adaptations in VP during cocaine self-administration. Our studies
will for the first time provide information into the molecular adaptations that mediate cellular adaptations in VP
neuron subtypes, which ultimately underlies drug self-administration or relapse behavior. Our studies can
provide a foundation for molecular analysis in VP in addiction that in the future can be applied to other drugs of
abuse. Finally, our studies have the ability to identify molecular targets for therapeutic intervention in addiction.

## Key facts

- **NIH application ID:** 10306374
- **Project number:** 5R01DA047843-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Mary Kay Lobo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $434,284
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10306374

## Citation

> US National Institutes of Health, RePORTER application 10306374, Ventral pallidum molecular mediators in cocaine addiction (5R01DA047843-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10306374. Licensed CC0.

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