# Synaptic vesicle glycoprotein 2C (SV2C) and psychostimulant actions

> **NIH NIH U18** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $242,269

## Abstract

Project Summary/Abstract
New approaches to treat methamphetamine addiction are desperately needed. Enhanced synaptic transmission
of dopamine is a key feature of methamphetamine action. We have identified a novel mediator of dopamine
release that we propose will reduce the reinforcing properties of methamphetamine. An isoform (A, B, or C) of
the synaptic vesicle glycoprotein 2 (SV2) is found on every synaptic vesicle in the nervous system, suggesting
an important yet unknown role for SV2 in neurotransmission. While SV2A and B are ubiquitously distributed
throughout the brain, SV2C expression is highly restricted to dopaminergic regions such as the basal ganglia.
Of particular note, SV2C expression is highest in the ventral pallidum, a region of emerging importance in
addiction research that is thought to mediate the translation of limbic motivation into motor output. Data
generated in our laboratory show that genetic deletion of SV2C results in a 50% decrease in stimulated dopamine
release, a 20% decrease in vesicular dopamine storage capacity, and enhance leakage of dopamine from the
vesicle. Furthermore, mice lacking SV2C show a loss of METH conditioned place preference compared to wild-
type animals. Given the observed effect of SV2C loss on dopamine transmission and its restricted expression
pattern we hypothesize that SV2C, through its ability to retain dopamine within synaptic vesicles, regulates the
psychostimulant effects of methamphetamine, and therefore is a druggable target for psychostimulant substance
use disorder. The experiments proposed here will establish a novel in vitro assay to measure SV2C activity (Aim
1) and identify compounds that regulate SV2C activity (Aim 2). Our technical resources and expertise in
measuring numerous aspects of dopamine neurotransmission uniquely position our lab to accomplish this timely
project.

## Key facts

- **NIH application ID:** 10107087
- **Project number:** 1U18DA052498-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** GARY W MILLER
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $242,269
- **Award type:** 1
- **Project period:** 2020-09-30 → 2021-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107087

## Citation

> US National Institutes of Health, RePORTER application 10107087, Synaptic vesicle glycoprotein 2C (SV2C) and psychostimulant actions (1U18DA052498-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10107087. Licensed CC0.

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