# Astrocyte-mediated glutamate transport in dorsal striatum associated with habitual cocaine seeking

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $171,563

## Abstract

Drug addiction is a significant societal issue, with more than 20 million individuals being diagnosed with a
substance use disorder (SUD) in the past year. While current treatments show some success, more than 50%
of patients treated for SUD relapse within one year. Corticostriatal circuitry and plastic changes therein are
involved in the transition from drug abuse to addiction. In particular, the dorsal lateral striatum (DLS) has
emerged as a key brain region regulating habitual control over behavior, including that underlying addiction to
stimulants. Astrocytes play fundamental roles in brain neuroplasticity through several mechanisms, including
regulation of extracellular glutamate levels. Presently, nothing is known about functional changes in astrocytic
networks in DLS of animals exhibiting habitual vs. goal-directed control over drug-seeking behavior.! The
proposed experiments will therefore directly determine the function of astrocytes in DLS of rats exhibiting
habitual vs. goal-directed control over cocaine seeking, and relative to yoked-saline controls. In Aim 1 we will
test the hypothesis that transition to habitual control over cocaine-seeking behavior is concomitant
with a decrease in astrocytic glutamate transport via decreased GLT-1 expression and function in DLS.
Recent data provide the first indication that expression of GLT1, the primary glutamate transporter in
astrocytes, is significantly decreased in dorsal striatum following extended cocaine self-administration in rats.
However, whether the function of glutamate transporters in astrocytes of the dorsal striatum changes in concert
with the development of habitual control over cocaine seeking is completely unknown. Therefore, we will use
patch clamp electrophysiology to record slow transporter currents in astrocytes (Aim 1a) and AAV-mediated
expression of the iGluSnFR protein and 2-photon microscopy to measure the levels and dwell time of
glutamate in the extrasynaptic space (Aim 1b) in DLS in brain slices prepared from rats trained to self-
administer cocaine and exhibiting habitual vs. goal-directed control over cocaine seeking, as well as from
yoked-saline controls. In Aim 2, we will test the hypothesis that these changes in glutamate transport
result in significantly altered extrasynaptic and synaptic NMDA receptor-mediated transmission in
spiny efferent neurons in DLS. We will use whole-cell patch clamp to assess changes in extrasynaptic
NMDA receptor-mediated currents by examining the amplitude of tonic NMDA receptor-mediated currents, as
well as the amplitudes and decay kinetics of evoked NMDA receptor-mediated EPSCs in striatal efferent
neurons in DLS. AMPA/NMDA ratios will also be determined. Completion of these aims will provide the first
insights into whether the transition to habitual control over cocaine-seeking behavior occurs concomitant with
changes in astrocyte function and structural connectivity in DLS and the effects of cocaine self-administration
history on...

## Key facts

- **NIH application ID:** 9850240
- **Project number:** 5R21DA046600-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** KRISTEN A KEEFE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $171,563
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850240

## Citation

> US National Institutes of Health, RePORTER application 9850240, Astrocyte-mediated glutamate transport in dorsal striatum associated with habitual cocaine seeking (5R21DA046600-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9850240. Licensed CC0.

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