Dopaminergic modulation of NMDA receptor signaling in the Nucleus Accumbens

Project Summary Alterations in both dopamine (DA) and glutamate signaling in the Nucleus Accumbens (NAc) are thought to play a key role in substance use disorders and addiction. DA regulates NAc circuit activity by modulating glutamatergic transmission and receptor activity, however, the precise mechanisms remain unclear. Synaptic plasticity and regulation of intracellular excitability is primarily attributed to the functions of glutamatergic NMDA recept ors (NMDARs). How dopamine receptors regulate NMDAR activity and how this differs between synaptic connections in accumbal circuitry remain important questions. This proposal will utilize ex vivo slice electrophysiology in combination with optogenetics and iontophoresis in transgenic mouse lines to investigate the synapse specificity and intracellular signaling mechanisms underlying DA receptor regulation of NMDAR current in both D1 and D2 type dopamine receptors. Understanding the synergistic role of D1 and D2 receptor signaling in regulating glutamate transmission and receptor activity in the NAc is a critical step in the investigation of both motivation and the dysfunctions that arise in this system after exposure to drugs of abuse.