# Defining Disruptions to Dopaminergic Control of Striatal Activity after Chronic Cocaine Use

> **NIH NIH F32** · VANDERBILT UNIVERSITY · 2024 · $77,284

## Abstract

PROJECT SUMMARY
While cocaine use disorder (CUD) is often studied in the context of dysregulated drug taking, less often studied
is how chronic drug use alters the processing of non-drug stimuli within the brain. One prominent example is
the fact that individuals suffering from CUD have deficits in responding to aversive stimuli. It is hypothesized
that these deficits influence a range of behaviors and render these individuals insensitive to negative
consequences associated with specific actions. Importantly, these deficits in stimulus processing are
associated with worse treatment outcomes in individuals suffering from CUD. Thus, understanding how drug
use alters the neural encoding of non-drug, aversive stimuli is critical to better treating individuals with CUD.
 At the center of drug-induced neural dysfunction is the mesolimbic dopamine system. Importantly, the
ability of aversive stimuli to evoke dopamine release is the nucleus accumbens core (NAcc) is necessary for
both conditioned and unconditioned aversive stimulus responses. Importantly, a hallmark of prolonged cocaine
use in both human and animal models is deficits in both basal and aversive stimulus-evoked dopamine
release. Thus, the goal of this proposal is to understand how dopamine release regulates the cellular
responses of genetically-defined cell types in the NAc and define how this relationship is disrupted by
cocaine use.
 The first aim seeks to define the temporal parameters under which dopamine release modulates the
activity of D1 or D2-containing MSN populations in the NAc, at baseline and in response to an aversive
stimulus. Dopamine is a modulatory neurotransmitter that does not induce action potential firing on its own, but
rather acts to modulate the activity patterns of medium spiny neurons (MSNs) that are characterized by their
expression of D1 and D2 type dopamine receptors. While nearly all of our understanding of this relationship
has been defined in acute slice preparations, here we will employ single-cell calcium imaging with
simultaneous optogenetic manipulation of dopamine terminals in behaving animals to establish the precise
temporal conditions during which dopamine modulates MSN activity at baseline and in response to a range of
aversive stimuli (aim 1). Next, I will establish how cocaine self-administration disrupts the capacity for
dopamine to modulate MSN activity during aversive stimulus processing (aim 2). The present proposal will
provide training in integrating traditional addiction models (self-administration) with cutting-edge
microdendoscopic tools, which I intend to employ towards defining how drug-induced dysfunction in the brain
gives rise to phenotypes associated with CUD.

## Key facts

- **NIH application ID:** 10902596
- **Project number:** 1F32DA060662-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Michael Z. Leonard
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $77,284
- **Award type:** 1
- **Project period:** 2024-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902596

## Citation

> US National Institutes of Health, RePORTER application 10902596, Defining Disruptions to Dopaminergic Control of Striatal Activity after Chronic Cocaine Use (1F32DA060662-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10902596. Licensed CC0.

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