Synaptogyrin-3 plays a critical role in addiction-related dopamine dysfunction and behavioral maladaptations
Abstract
Cocaine use disorder is marked by deficits in dopamine signaling; however, the molecular mechanisms driving these deficits remain unclear. The synaptic vesicle protein Synaptogyrin-3 (Syngr3) has recently garnered attention for its association with disorders involving dopamine dysfunction and impaired cognition. Here, we found low Syngr3 expression in the ventral tegmental area (VTA) of men who died of cocaine overdose and in male rats that had chronically self-administered cocaine. Syngr3 was confirmed to be in dopamine neurons, and its expression was correlated with dopamine markers in both humans and rats. Syngr3 levels showed a robust inverse correlation with motivation to self-administer cocaine in the rat model. Moreover, viral overexpression of Syngr3 in VTA dopamine neurons improved cognitive flexibility and substantially reduced cocaine reinforcement and drug-taking behavior. Finally, Syngr3 overexpression prevented cocaine-induced dopamine deficits. These findings establish Syngr3 as a key dopamine regulator and potential therapeutic target for cocaine use disorder.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Emily G. Peck
Department of Translational Neuroscience, Wake Forest University School of Medicine
Soren D. Emerson
Department of Pharmacology, Vanderbilt University
Alyson M. Curry
Department of Translational Neuroscience, Wake Forest University School of Medicine
Kimberly M. Holter
Department of Translational Neuroscience, Wake Forest University School of Medicine
Paige M. Estave
Department of Translational Neuroscience, Wake Forest University School of Medicine
Jonathon P. Sens
Department of Translational Neuroscience, Wake Forest University School of Medicine
Olivia A. Colarusso
Department of Translational Neuroscience, Wake Forest University School of Medicine
Sean P. Farris
Department of Anesthesiology, University of Pittsburgh
Drew D. Kiraly
Department of Translational Neuroscience, Wake Forest University School of Medicine
Robert W. Gould
Department of Translational Neuroscience, Wake Forest University School of Medicine
Brian A. McCool
Department of Translational Neuroscience, Wake Forest University School of Medicine
Erin S. Calipari
Department of Pharmacology, Vanderbilt University
Katherine M. Holleran
Department of Translational Neuroscience, Wake Forest University School of Medicine
Sara R. Jones
Department of Translational Neuroscience, Wake Forest University School of Medicine