# Incubated drug-craving and neurochemical interactions

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA BARBARA · 2024 · $336,909

## Abstract

Psychomotor-stimulant Use Disorder (PUD) is a chronic relapsing disorder, characterized by a high propensity
for relapse even during protracted abstinence. In both humans with PUD & animal models, the intensity of cue-
elicited drug craving & drug-seeking behavior increases or “incubates” during protracted withdrawal. The
neurochemical underpinnings of drug craving & its incubation are not well understood. Drug cue-induced
increase in metabolic hyperactivity within the prefrontal cortex (PFC) is correlated with the intensity of drug-
craving in humans. Consistent with this, we have reported a link between the magnitude of drug-seeking in a rat
model of cocaine-taking & a number of abnormalities in glutamate (GLU) transmission within the ventromedial
aspect of the PFC (vmPFC). Notably, incubated cocaine-seeking is associated with a time-dependent increase
in the capacity of drug-predictive cues to increase GLU levels, primarily within the prelimbic (PL) subregion. We
theorize this cue-elicited rise in GLU might underpin cue-elicited increases in metabolic hyperactivity observed
within PFC of PUD patients. Importantly: (1) the increased GLU responsiveness to drug-predictive cues is
selective for rats with a cocaine-taking history; (2) the magnitude of the GLU increase predicts the vigor of
cocaine-seeking behavior; & (3) neuropharmacological inhibition of GLU transmission within the PL eliminates
cocaine-incubated responding. Intriguingly, the incubated cue-responsiveness of vmPFC GLU is inversely
related to cue-elicited changes in vmPFC dopamine (DA). This inverse neurochemical relation has led to the
over-arching hypothesis to be tested in this proposal:
the incubation of cue-elicited drug-seeking behavior
results from dysregulated GLU-DA interactions w ithin the PL subregion of the vmPFC
. Aim 1 of this
proposal employs neuropharmacological approaches to systematically target & dissect the relative contribution
of postsynaptic AMPA & NMDA GLU receptor subtypes to the manifestation of incubated cocaine-seeking &
examine for the generalization of pharmacological effects to a highly prevalent psychomotor-stimulant,
methamphetamine (MA), as well as the non-drug reinforcer, sucrose. It is hypothesized in Aim 1 that the
incubation of COC craving is driven by GLU-mediated activation of ionotropic GLU receptors within
vmPFC. Aim 2 will employ a combination of in vivo microdialysis & neuropharmacological approaches to
examine the role for D1- & D3-type DA receptors & their regulation of GLU, DA & GABA release within the
vmPFC in incubated cocaine-, MA- & sucrose-seeking. It is hypothesized in Aim 2 that
the incubation of cue-
elicited GLU release, cellular hyperactivity & drug-seeking reflect time-dependent anomalies in DA
signaling within PL.
 The proposal presents a series of theoretically innovative experiments designed to address
the biobehavioral underpinnings of incubated craving, which will advance our basic understanding of the
neurobiology of re...

## Key facts

- **NIH application ID:** 10755643
- **Project number:** 5R01DA053328-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA BARBARA
- **Principal Investigator:** Karen Kathleen Szumlinski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $336,909
- **Award type:** 5
- **Project period:** 2021-04-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755643

## Citation

> US National Institutes of Health, RePORTER application 10755643, Incubated drug-craving and neurochemical interactions (5R01DA053328-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10755643. Licensed CC0.

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