Role of synaptogyrin-3 in methamphetamine self-administration and dopamine dysfunction

The National Institute on Drug Abuse awarded Wake Forest University Health Sciences $100,228 on November 7, 2026, under the Drug Use and Addiction Research Programs (CFDA 93.279) to support research investigating the role of synaptogyrin-3 in methamphetamine self-administration and dopamine dysfunction.

The project examines synaptogyrin-3, a synaptic vesicle protein hypothesized to regulate dopamine release and uptake in the brain's reward circuitry. The research tests whether viral overexpression of synaptogyrin-3 in ventral tegmental area dopamine neurons influences methamphetamine self-administration behaviors in animal models. Preliminary data suggest the protein may produce different protective effects against methamphetamine compared to cocaine, prompting investigation of the distinct neurobiological mechanisms underlying methamphetamine use disorder. This work supports the broader goal of identifying pharmacotherapeutic targets to counteract dopamine system deficits associated with chronic methamphetamine use, given the absence of FDA-approved medications for methamphetamine use disorder and rising rates of methamphetamine-related overdose deaths.

Work is performed in Winston-Salem, North Carolina. The period of performance runs from November 7, 2026, through June 26, 2029. The assistance type is a Project Grant.

Abstract

Methamphetamine use disorder (MUD) is characterized as a cluster of symptoms associated with chronic use of methamphetamine (meth) despite negative consequences. The number of overdose deaths related to meth use is on the rise. However, there are no FDA approved MUD therapeutics, making generation of novel pharmacotherapies critical. Meth functions primarily as a dopamine (DA) releaser and produces its reinforcing effects by elevating DA levels in the mesolimbic DA system, which consists of projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAC). Yet, chronic meth use leads to hypodopaminergia (hypoda), a state characterized by reduced DA system function that is theorized to promote negative affective states and perpetuate meth use. Therefore, a therapeutic strategy for MUD is to target proteins that facilitate DA transmission, as this could counteract meth-induced DA deficits. One such protein is the synaptic vesicle protein synaptogyrin-3 (SYNGR3). The exact mechanisms of SYNGR3 activity in DA neurons are unknown, but IT is hypothesized to have a role in (1) DA release by regulating exocytosis and vesicle mobility and (2) DA uptake via interactions with the dopamine transporter (DAT) and vesicular monoamine transporter 2 (vmat-2). Recent studies in our lab found that viral overexpression of SYNGR3 in VTA DA neurons (SYNGR3 OE) decreased cocaine (COC) self-administration (SA) and protected against COC-induced deficits in DA transmission. Given the protective role of SYNGR3 against COC taking, we wanted to probe whether the findings would translate to meth. The initial hypothesis was that SYNGR3 would play a similar protective role; however, preliminary data indicate that SYNGR3 OE rats may show increased meth SA behaviors relative to controls. We postulate that the opposing results are because meth produces its effects in part by inducing DAT-mediated DA efflux, a process that SYNGR3 could enhance by organizing presynaptic release machinery. Further investigation is needed to gain a deeper insight into SYNGR3's role in modulating MUD-related behaviors and the effects of meth on the DA system. The central hypothesis of this study is that meth taking and meth-induced deficits in DA transmission are facilitated by SYNGR3 function in VTA DA neurons. Viral overexpression of SYNGR3 in VTA DA neurons will be used to assess the functional consequences of SYNGR3 activity. This will ultimately aid in the development of a deeper understanding of SYNGR3's role in regulating DA homeostasis, which can be used as a foundation to guide the development of novel therapeutics for MUD in the future.