Activation of Nuclear Factor-kappa B in the nucleus accumbens core is necessary for chronic stress-induced glutamate and neuro-immune alterations that facilitate cocaine self-administration

• Published in: Brain, behavior, and immunity Vol. 128; pp. 1 - 15
• Main Authors: Mongi-Bragato, Bethania, Sánchez, Marianela Adela, Avalos, María Paula, Boezio, María Julieta, Guzman, Andrea Susana, Rigoni, Diana, Perassi, Eduardo Marcelo, Mas, Carlos Ruben, Bisbal, Mariano, Bollati, Flavia Andrea, Cancela, Liliana Marina
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2025
• Subjects: 1, Nucleus Accumbens; Animals; Astrocytes; Cocaine; Cocaine - administration & dosage; Cocaine - pharmacology; Cocaine-Related Disorders - immunology; Cocaine-Related Disorders - metabolism; Excitatory Amino Acid Transporter 2 - metabolism; Glutamate transporter; Glutamic Acid - metabolism; Male; Microglia - metabolism; NF-kappa B - metabolism; Nuclear Factor kappa B; Nucleus Accumbens - immunology; Nucleus Accumbens - metabolism; Rats; Rats, Sprague-Dawley; Self Administration; Signal Transduction; Stress; Stress, Psychological - immunology; Stress, Psychological - metabolism; Tumor Necrosis Factor-alpha - metabolism; Cocaine; 1, Nucleus Accumbens; Astrocytes; Nuclear Factor kappa B; Glutamate transporter; Stress
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2025.03.028

•Activation of NF-κB is observed in the NAcore of stressed rats.•Inhibiting NF-κB prevents stress-induced facilitation of cocaine self-administration.•NF-κB inhibition restores stress-reduced GLT-1 levels and suppresses TNF-α in the NAcore.•NF-κB links neuroimmune and glutamate changes to stress-induced addiction vulnerability. Stressful events are associated with impaired glutamate signaling and neuroimmune adaptations that may increase the vulnerability of individuals to cocaine addiction. We previously demonstrated that chronic stress induced reactive microglia and increased TNF-α expression in the nucleus accumbens core (NAcore), both alterations strongly linked with impaired glutamate homeostasis and the facilitation of cocaine self-administration. The nuclear factor kappa-B (NF-κB) is a critical regulator of many immune- and addiction-related genes, such as the gene coding for glutamate transporter (GLT-1), and it is considered a master regulator of inflammation, reported to be a key driver of microglia activation in psychiatric diseases. However, no studies have examined the role of NF-κB signaling within the NAcore in the neuroimmune and glutamate mechanism, underpinning stress-induced vulnerability to cocaine self-administration. Here we investigate whether viral dominant negative inhibition of I kappa B kinase (IKKdn), a signaling molecule responsible for NF-κB activation, would prevent stress-induced facilitation to cocaine self-administration and associated changes in accumbal GLT-1 and TNF-α expression. We also explore N-myc proto-oncogene protein (N-myc) levels as a link between NF-κB and stress-induced GLT-1 downregulation. For seven days (days 1–7), adult male rats were restrained for 2 h/day. Animals were administered an intra-NAcore with IKKdn or empty lentiviruses on day 14 after the first restraint stress session. Marked activation of NF-κB was detected in the NAcore of stressed subjects, along with increased NF-κB expression in astrocytes. Consistently, viral NF-κB inhibition prevented stress-induced facilitation of cocaine self-administration. Moreover, NF-κB blockade results in the restoration of stress-induced reduction in GLT-1 levels and was effective in suppressing stress-induced TNF-α within the NAcore. These findings suggest that accumbal NF-κB signaling exerts a central control over stress-altered downstream neuroimmune and glutamate function underlying vulnerability to cocaine use disorders.