# Glutamate and Craving for Cocaine

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $376,746

## Abstract

Project Summary
A treatment for drug addiction remains elusive due to incomplete knowledge of the brain
circuits controlling both the overwhelming motivation to relapse to drug use and the ability to
refrain from using drugs. In part through progress during the 20-yr tenure of this grant, we
know that glutamatergic projections from cortical and allocortical brain regions to the nucleus
accumbens core (NAcore) and GABAergic NAcore projections to the dorsolateral ventral
pallidum (dlVP) are necessary for executing cue-induced cocaine seeking and extinction
training-induced refraining from cocaine seeking. Classically, projections from the striatum
contain two neuronal subtypes, those projecting to the ventral mesencephalon selectively
expressing D1 dopamine receptors (D1-MSNs) and those projecting to the palldum expressing
D2 receptors (D2-MSNs). Through work on this grant, we now know that NAcore D1-MSNs also
innervate the dlVP1, and that activity in this D1-MSN to dlVP subcircuit is necessary for cue-
induced cocaine seeking. Also, we discovered that activity in D2-MSNs is associated with
extinction-induced refraining from cocaine seeking.
 Akin to the NAcore, the dlVP contains two primary cell types, one expressing glutamate
(VPglu) and the other expressing GABA (VPGABA). Also, a subpopulation of VPGABA co-express
enkephalin (VPPenk). We have begun to study the dlVP subcircuits coded by these distinct dlVP
neuronal subtypes in regulating cocaine seeking and refraining from seeking. Cell-type specific
chemogenetic stimulation reveals that VPglu inhibit reinstated cocaine seeking and stimulating
VPPenk induces cocaine seeking. Surprisingly, VPglu and VPGABA cells in dlVP have different
axon terminal fields. These findings indicate distinct roles for the different dlVP neuronal
subtypes, and that divergent roles for subtype selective projections emanating from the dlVP is
likely. We propose to disentangle the circuitry in which the dlVP is embedded using a
combination of behavior, in vivo calcium imaging and slice electrophysiology, and test the
hypothesis that VPglu activity promotes refraining during extinction responding, while VPPenk
codes for cocaine seeking.

## Key facts

- **NIH application ID:** 9967322
- **Project number:** 2R01DA012513-21
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Peter W Kalivas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,746
- **Award type:** 2
- **Project period:** 2000-02-10 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967322

## Citation

> US National Institutes of Health, RePORTER application 9967322, Glutamate and Craving for Cocaine (2R01DA012513-21). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9967322. Licensed CC0.

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