Pyrrolidine dithiocarbamate-mediated inhibition of nuclear factor-κB reverses stress-induced cross-sensitization to cocaine and associated gene expression changes in the nucleus accumbens core.

Stress is a major risk factor for substance use disorders, promoting vulnerability to cocaine-related behaviors through neuroimmune-glutamatergic dysregulation in the nucleus accumbens core (NAcore). Previous evidence from our laboratory has identified nuclear factor kappa B (NF-κB) as a key transcriptional regulator that sustains stress-induced glial activation, proinflammatory signaling, and downregulation of the glutamate transporter (GLT-1) in this region. Although lentiviral inhibition of NF-κB within the NAcore prevents these alterations, it remains unclear whether this pathway can be effectively targeted pharmacologically to restore the disrupted inflammatory-glutamatergic balance associated with cocaine sensitization. Here, we investigated whether local pharmacological inhibition of NF-κB using pyrrolidine dithiocarbamate (PDTC) reverses stress-induced cocaine cross-sensitization and associated molecular adaptations. Rats were exposed to chronic restraint stress (2 h/day for 7 days). Fourteen days after the first stress exposure, guide cannulae were implanted into the NAcore. On day 21, stressed and non-stressed animals received intra-NAcore microinjections of PDTC (5-20 μM) or vehicle prior to a saline or cocaine challenge (15 mg/kg, i.p.), and locomotor activity was assessed. NF-κB signaling (p65 nuclear translocation, cytosolic p65 levels and IKK phosphorylation), protein levels of GLT-1 and TNF-α, and related gene expression of GLT-1, TNF-α, IL-6, and IL-10 were quantified. PDTC dose-dependently abolished behavioral sensitization, suppressed p65 nuclear translocation and IKK phosphorylation, reversed TNF-α upregulation, and increased GLT-1 expression, while not preventing IL-10 induction. These findings provide pharmacological evidence supporting a central role for NF-κB activation within the NAcore in stress-induced cocaine sensitization and associated neuroimmune-glutamatergic adaptations. Targeting this pathway with PDTC or related NF-κB inhibitors may represent a promising strategy to reduce stress-related vulnerability to substance use disorders.