# Dissecting Ventral Pallidal Subcircuit Contributions to Drug Seeking in Addiction

> **NIH NIH DP5** · UNIVERSITY OF COLORADO DENVER · 2020 · $388,750

## Abstract

ABSTRACT
Drug addiction is a pervasive health problem in our society. We still lack specific therapeutic interventions to
break the recurrent pattern of relapse to drug seeking that characterizes the disorder; a result of poor
understanding of the neural circuits and cellular adaptations responsible for relapse. The use of illicit drugs is
rising steadily in the Unites States, with the number of deaths related to drug overdose dramatically accelerating
over the last 5 years. Relapse and drug craving are critically driven by neuronal activity in the interconnected
nuclei of the ventral basal ganglia, which have a well described role in motivated behavior and reward learning.
Within this network the ventral pallidum (VP) is a critical regulator of relapse to all known drugs of abuse. To
date, much addiction research has focused on the nucleus accumbens, a primary input structure to the VP, but
the VP itself has been largely disregarded as an inhibitory downstream relay of addiction-related information.
However, VP neurons respond temporally quicker to rewarding emotional stimuli than upstream nucleus
accumbens neurons. Furthermore, while VP neurons are generally thought to be largely GABAergic, the VP also
contains a subpopulation (~30%) of glutamatergic neurons that project to the same downstream areas as
inhibitory GABAergic VP neurons. These findings challenge the accepted idea that the VP is an inhibitory relay
structure and suggest advanced processing of emotional information in the VP independent of nucleus
accumbens inputs, with implications that transform our understanding of basal ganglia function. By using my
recently developed mouse model for drug relapse, I identified an inhibitory role for glutamatergic VP neurons
during relapse, demonstrating that these neurons act oppositely to GABAergic VP neurons. Based on these
observations I predict that drug abuse reduces the capacity of glutamatergic VP neurons to inhibit drug seeking,
and that behavioral engagement during drug seeking is carried by activity in GABAergic VP neurons. This
proposal employs cutting edge technological advances in the cell type specific dissection of neural circuit function
and connectivity such as optogenetics, chemogenetics, in vivo cell-type specific monitoring of calcium activity in
freely behaving mice, and slice electrophysiology recordings from genetically labeled glutamatergic and
GABAergic VP neurons to investigate cell type and pathway specific VP circuit adaptations following drug self
administration and relapse. These studies will place the VP as a central component of basal ganglia circuits
controlling addiction, and reveal the distinct functions of VP glutamatergic versus GABAergic neurons in
regulating drug seeking, which could lay the groundwork for novel VP targeted strategies to treat addiction.

## Key facts

- **NIH application ID:** 10014520
- **Project number:** 7DP5OD026407-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jasper Heinsbroek
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,750
- **Award type:** 7
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10014520

## Citation

> US National Institutes of Health, RePORTER application 10014520, Dissecting Ventral Pallidal Subcircuit Contributions to Drug Seeking in Addiction (7DP5OD026407-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10014520. Licensed CC0.

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