Abstract
Cognitive inflexibility covaries with substance use disorder (SUD) risk. To determine if there is a neural relationship between these phenomena, glutamate and dopamine release in the dorsomedial (DMS) and dorsolateral (DLS) striatum were measured as rats performed a discrimination and strategy switching test. Elevations in glutamate release, with reductions in dopamine, at trial initiation (DLS) and prior to choice (DMS and DLS) predicted fast strategy switching and punishment sensitive cocaine seeking. Elevations in DLS and DMS dopamine release at these respective timestamps predicted slow switching and punishment resistance. Orbitofrontal cortex and intralaminar thalamus were significant contributors to DLS and DMS glutamate release, but their relative contributions differed between rats that were fast or slow strategy switchers, and in how they affected behavior. As such, these data describe a neural signature of flexibility and associated circuitry that could be used to predict and treat SUDs in humans.