# Aberrant Synaptic Plasticity in Cocaine Use Disorder: A 11C UCB J PET Study

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $743,762

## Abstract

Abstract
In seminal preclinical studies nearly 20 years ago, Robinson & Kolb [1, 2] demonstrated enduring
changes in synaptic (dendritic spine) density in medial prefrontal cortex (mPFC) of rodents following
behaviorally sensitizing regimens of cocaine. Their findings suggested a potentially important
pathophysiological mechanism – aberrant structural synaptic plasticity – whereby cocaine might produce
the chronic, recalcitrant behaviors (e.g., craving, compulsive use, and relapse) so seemingly ‘hard-wired’
in those suffering from the disorder.
Our group has developed a novel radiotracer, 11C-UCB-J, for imaging synaptic density (i.e., synaptic
vesicle glycoprotein type 2A or SV2A availability) in the living human brain using positron emission
tomography (PET) [3, 4]. . Pilot data collected under the Cutting Edge Basic Research Award
(CEBRA)/R21 mechanism are compelling, we believe, and provide the first translation support for: 1)
altered (i.e., lower) synaptic density in the mPFC of individuals with CUD that is both 2) positively
correlated with the frequency (days per month) of recent cocaine use, and 3) negatively correlated with
duration of cocaine abstinence (days since last use). Together, these data suggest a dynamic model of
synaptic plasticity in which SV2A availability is “normalized” by recurrent cocaine use, only to return to
abnormal (i.e., low) levels during periods of sustained drug abstinence.
The current R01 application proposes to replicate and extend these promising preliminary findings
and more definitively test the former model through two experimental aims: Aim 1) a larger cohort of
40 CUD and 40 matched HC subjects using a single-scan, between group design, and Aim 2) the same
40 CUD subjects using a longitudinal, two-scan (baseline/pre-abstinence vs. 3 weeks of in-hospital
abstinence) within-subject design.
If confirmed, the current study would have a potentially major impact, providing powerful clinical-
translational support for the aberrant synaptic plasticity hypothesis of CUD, advancing our
neurobiological understanding of the role of drug-induced changes in synaptic function in CUD, and
ultimately, encouraging the development of more effective treatments for CUD (e.g., those based
on synaptotrophic mechanisms).

## Key facts

- **NIH application ID:** 10428611
- **Project number:** 5R01DA052454-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** GUSTAVO Adolfo ANGARITA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $743,762
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428611

## Citation

> US National Institutes of Health, RePORTER application 10428611, Aberrant Synaptic Plasticity in Cocaine Use Disorder: A 11C UCB J PET Study (5R01DA052454-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10428611. Licensed CC0.

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