Inhibition of NF-κB by Pyrrolidine Dithiocarbamate Prevents Stress-Induced Cross-Sensitization to Cocaine and Neuroimmune–Glutamatergic Alterations in the Nucleus Accumbens Core

Stress is a major risk factor for substance use disorders, increasing vulnerability to cocaine-related behaviors through persistent neuroimmune and glutamatergic dysregulation in the nucleus accumbens core (NAcore). Nuclear factor kappa B (NF-κB) is a central transcriptional regulator of stress-induced glial activation, proinflammatory signaling, and glutamate transporter (GLT-1) downregulation. We investigated whether local NF-κB inhibition by pyrrolidine dithiocarbamate (PDTC) in the NAcore reverses stress-induced cocaine cross-sensitization and associated molecular alterations. Rats underwent chronic restraint stress (2 h/day, 7 days). Fourteen days later, bilateral cannulae were implanted into the NAcore. On day 21, stressed and non-stressed rats received intra-NAcore PDTC (5–20 μM) or vehicle before saline or cocaine challenge (15 mg/kg, i.p.). Locomotor activity assessed cross-sensitization. NF-κB signaling and mRNA expression of TNF-α, GLT-1, and IL-10 were analyzed. PDTC dose-dependently abolished behavioral sensitization, suppressed p65 nuclear translocation and IKK phosphorylation, reversed TNF-α upregulation, and restored GLT-1 expression, but did not prevent IL-10 induction. These findings provide pharmacological evidence for a central role of NF-κB activation in the NAcore in stress-induced cocaine sensitization and associated immune–glutamatergic adaptations. Inhibiting this pathway may reduce stress-related vulnerability to substance use disorders.