Dopamine D2 receptors bypass canonical signaling to directly tune NMDA receptor function and aversive learning

Abstract

Dopamine D2 receptors (D2Rs) modulate reward learning and aversive behaviors, with dysfunction linked to addiction and psychiatric disorders. D2Rs regulate behavior through modulation of striatal glutamatergic transmission, yet how D2Rs control postsynaptic glutamate signaling remains poorly understood. Using molecular tools to selectively disrupt heteromeric interactions while preserving canonical signaling, we show that physical coupling between D2Rs and GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in nucleus accumbens medium spiny neurons enables D2Rs to suppress NMDA receptor function independent of canonical G protein and arrestin signaling. This modulation was input specific, occurred at thalamic but not cortical synapses converging on the same neurons, constrained long-term potentiation, and, within the medial ventral nucleus accumbens, facilitated aversive learning. These findings reveal that D2Rs can bypass second messenger systems to tune glutamatergic transmission through receptor-receptor interactions, providing a mechanism by which dopamine selectively gates specific glutamatergic inputs to control striatal plasticity and behavioral adaptation.