# Cocaine Modulation of Synapses onto Dopamine Neurons

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $186,563

## Abstract

Abstract
Identification of the mechanism(s) responsible for drug reinforcement is a key step in understanding the
mechanism of reinforcement learning, but has so far proven elusive. The dopamine neurons of the ventral
tegmental area and substantia nigra pars compacta, located within the ventral mesencephalon, are a central
locus for drug reinforcement. Even a single exposure to cocaine is sufficient to alter synaptic transmission to
dopamine neurons, with attention focused on postsynaptic mechanisms of plasticity mediated by AMPA
receptors (AMPARs). Most AMPARs are impermeable to Ca2+ (CI-AMPAR) whereas receptors that lack the
GluR2 subunit are permeable to Ca2+ (CP-AMPAR). A biophysical characteristic known as rectification is
commonly used to differentiate CP-AMPARs from the more common CI-AMPARs . It is commonly accepted
that cocaine exposure alters rectification of AMPAR synaptic currents on dopamine neurons without affecting
measures of release probability, pointing to postsynaptic mechanisms of synaptic plasticity. However, our new
data challenges the assumptions that rectification is sufficient to infer AMPAR subunit composition and that
release probability is sufficient to assess presynaptic efficacy. Rather, our data shows that changes in the
readily-releasable pool of vesicles can robustly alter presynaptic efficacy without a change in the release
probability and that presynaptic mechanisms can affect rectification properties of AMPAR synaptic currents.
Based on our data, we hypothesize that presynaptic mechanisms contribute to synaptic changes in
dopamine neurons following cocaine exposure. We will first test AMPAR properties in dopamine neurons
from naïve and cocaine-treated mice under conditions that isolate postsynaptic mechanisms. We will then
follow up to test whether presynaptic changes contribute to synaptic plasticity induced by cocaine exposure.
Presynaptic efficacy and AMPAR subunit composition have important functional consequences ranging from
regulating the ability of postsynaptic cells to precisely follow high-frequency synaptic activity and mediating
Ca2+ influx that can trigger plasticity or pathology like addiction. Successful completion of the proposed studies
has potential to reveal novel mechanisms underlying synaptic plasticity at synapses onto dopamine neurons
following exposure to drugs of abuse.

## Key facts

- **NIH application ID:** 10197089
- **Project number:** 5R21DA051693-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Jacques Wadiche
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $186,563
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197089

## Citation

> US National Institutes of Health, RePORTER application 10197089, Cocaine Modulation of Synapses onto Dopamine Neurons (5R21DA051693-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10197089. Licensed CC0.

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