An emerging role for synaptic Zn²⁺ in substance use disorders

Synaptic zinc (Zn²⁺) modulates dopamine and glutamate neurotransmission by binding to the dopamine transporter and glutamate receptors. Among other neurotransmitters, dopamine and glutamate critically regulate physiological processes and behaviors relevant to substance use disorders (SUDs) and addiction. In addition, Zn²⁺ interacts with inhibitory neurotransmitter systems, including GABA and glycine receptors, further influencing the excitatory-inhibitory balance within circuits relevant to addiction. Nevertheless, the specific involvement of synaptic Zn²⁺ in such processes is unknown. We propose that synaptic Zn²⁺ serves as an environmentally derived factor that can influence the vulnerability to and development of SUDs and addiction via its interaction with proteins that regulate dopamine and glutamate neurotransmission in addiction-relevant brain circuits.