Psychomotor-stimulant Use Disorder (PUD) is a chronic relapsing disorder, characterized by a high propensity for relapse even during protracted abstinence. In both humans with PUD & animal models, the intensity of cue- elicited drug craving & drug-seeking behavior increases or “incubates” during protracted withdrawal. The neurochemical underpinnings of drug craving & its incubation are not well understood. Drug cue-induced increase in metabolic hyperactivity within the prefrontal cortex (PFC) is correlated with the intensity of drug- craving in humans. Consistent with this, we have reported a link between the magnitude of drug-seeking in a rat model of cocaine-taking & a number of abnormalities in glutamate (GLU) transmission within the ventromedial aspect of the PFC (vmPFC). Notably, incubated cocaine-seeking is associated with a time-dependent increase in the capacity of drug-predictive cues to increase GLU levels, primarily within the prelimbic (PL) subregion. We theorize this cue-elicited rise in GLU might underpin cue-elicited increases in metabolic hyperactivity observed within PFC of PUD patients. Importantly: (1) the increased GLU responsiveness to drug-predictive cues is selective for rats with a cocaine-taking history; (2) the magnitude of the GLU increase predicts the vigor of cocaine-seeking behavior; & (3) neuropharmacological inhibition of GLU transmission within the PL eliminates cocaine-incubated responding. Intriguingly, the incubated cue-responsiveness of vmPFC GLU is inversely related to cue-elicited changes in vmPFC dopamine (DA). This inverse neurochemical relation has led to the over-arching hypothesis to be tested in this proposal: the incubation of cue-elicited drug-seeking behavior results from dysregulated GLU-DA interactions w ithin the PL subregion of the vmPFC . Aim 1 of this proposal employs neuropharmacological approaches to systematically target & dissect the relative contribution of postsynaptic AMPA & NMDA GLU receptor subtypes to the manifestation of incubated cocaine-seeking & examine for the generalization of pharmacological effects to a highly prevalent psychomotor-stimulant, methamphetamine (MA), as well as the non-drug reinforcer, sucrose. It is hypothesized in Aim 1 that the incubation of COC craving is driven by GLU-mediated activation of ionotropic GLU receptors within vmPFC. Aim 2 will employ a combination of in vivo microdialysis & neuropharmacological approaches to examine the role for D1- & D3-type DA receptors & their regulation of GLU, DA & GABA release within the vmPFC in incubated cocaine-, MA- & sucrose-seeking. It is hypothesized in Aim 2 that the incubation of cue- elicited GLU release, cellular hyperactivity & drug-seeking reflect time-dependent anomalies in DA signaling within PL. The proposal presents a series of theoretically innovative experiments designed to address the biobehavioral underpinnings of incubated craving, which will advance our basic understanding of the neurobiology of relapse.

Narrative The U.S. is in the midst of a psychostimulant epidemic. Drug-craving is a diagnostic criterion of Psychostimulant Use Disorder for which there exists no clinically effective intervention. This project examines disrupted glutamate- dopamine interactions within prefrontal cortex as a core neuropathology driving drug-craving.