# Pathway-specific Intervention in Prelimbic Cortical Circuitry Decreases Cocaine-seeking

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $339,750

## Abstract

Specific Aims
A major challenge for individuals suffering from substance use disorders (SUDs) is the lack of effective
treatments that reduce relapse vulnerability. Drug predictive cues in the environment are powerful triggers for
relapse and understanding how these persistent associations are formed and maintained is a critical focus of
preclinical SUD research. In this proposal, we have built on our discovery that immediately after the end of
cocaine self administration (SA), an infusion of brain-derived neurotrophic factor (BDNF) into the prelimbic (PL)
prefrontal cortex prevents the cocaine SA-induced dephosphorylation of key glutamatergic-related plasticity-
related proteins (PRPs), including GluN2A, GluN2B, ERK MAP kinase, and CREB32,96. This early intervention
with BDNF also prevents prolonged cocaine-induced deficits in PL-NA core glutamatergic transmission that
promote subsequent cocaine seeking9. In contrast, by the end of the first week of abstinence, protein kinase A
(PKA)-dependent augmentation of GluA1 and CREB phosphorylation emerges. At that time, intra-PL BDNF
has no effect on relapse8 but intra-PL infusion of a PKA inhibitor, Rp-cAMPs, reverses the
hyperphosphorylation and decreases relapse70,92. More recently, we have shown that the biphasic changes in
GluA1 and pCREB within the first week of abstinence are associated with similar biphasic changes in the head
diameters (dH) of dendritic spines of PL–NA core neurons89. These data have spurred the overall hypothesis
that interventions to decrease drug seeking must be tailored to the dynamic changes in neuroadaptations that
emerge during different phases of the addiction cycle.
 In chemogenetic studies to investigate the contribution of specific pathways originating in PL cortex to drug
seeking, we discovered that PL-NA core and PL-posterior paraventricular thalamic nucleus (pPVT) pathways
oppose each others’ effects during early withdrawal. Selective cre-dependent DREADD inhibition of PL-NA
core neurons infected with a retrogradely transported cre-AAV immediately after cocaine SA has no effect by
itself, but reverses the suppressive effect of intra-PL BDNF on subsequent drug seeking31. In contrast,
selective inhibition of the PL-pPVT pathway immediately after cocaine SA decreases subsequent cocaine-
seeking, an effect that is prevented by intra-PL BDNF31. Interestingly, we also found that selective inhibition of
the PL-pPVT pathway reduces anxiety-related behavior in rats withdrawing from cocaine and inactivation of
pPVT decreases conditioned aversion to cocaine, suggesting that cocaine’s engagement of anxiety- and
aversion-related circuitry that contributes to drug seeking includes pPVT.
 Taken together, our new findings suggest the novel hypothesis that cocaine SA produces differential
regulation of PL-NA core and PL-pPVT pathways and that these two distinct circuits conspire to support future
drug seeking. In this proposal, we will use pathway-specific, combinatorial chemogene...

## Key facts

- **NIH application ID:** 10453594
- **Project number:** 5R01DA049711-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Jacqueline F. McGinty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $339,750
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453594

## Citation

> US National Institutes of Health, RePORTER application 10453594, Pathway-specific Intervention in Prelimbic Cortical Circuitry Decreases Cocaine-seeking (5R01DA049711-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10453594. Licensed CC0.

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