“Cross sensitization between chronic restraint stress and cocaine: Role of Nuclear factor kappa B (NF-kB) in Nucleus Accumbens core

SANCHEZ MA; MONGI-BRAGATO B; AVALOS MP; GUZMAN AS; RIGONI D; VEDELAGO G; BISBAL M; BOLLATI F; CANCELA LM

Belen

Congreso; 3 rd FALAN CONGRESS.; 2022

FALAN - Federación de Sociedades Latinoamericana y el Caribe de Neurociencias

Stressful experience induced crosssensitization to cocaine is associated with a significant impairment ofglutamate mechanisms in the Nucleus Accumbens core (Nacore). The hallmark ofdisrupted glutamate homeostasis following restraint stress is the increasedbasal concentrations of extracellular glutamate attributed to glutamatetransporter (GLT-1) downregulation within this brain area. Recent evidence fromour lab, demonstrated that microglia, the immunocompetent cells in the brain,play a key role in the proactive influence of stress on impaired glutamatehomeostasis in the NAcore. It has been reported a close linkage betweenglutamate and the activation of the Nuclear Factor-Kappa B (NF-kB). Thistranscription factor induces the expression of gene targets tightly linked toglia maintenance of glutamate homeostasis, such as GLT-1, and controls theexpression of numerous genes involved in inflammation and immune response.Considering these evidences, we hypothesized that the stress-induced disruptionof glutamate homeostasis underlying cross-sensitization to cocaine, depends onNF-kB signaling. So, we evaluate the role of NF-kB in NAcore on the long-termexpression of restraint stress-induced behavioral cross-sensitization to cocaine.To test this, we used lentiviral vectors DnIKK, that expresses the dominantnegative of the IKK activity, and the potent pharmacological inhibitor of NF-kBnuclear translocation, PDTC, to nullify the transcription factor activity.Chronically pre-stressed animals were administered intra-NAcore with DnIKK 7days, or PDTC 20 minutes before a cocaine challenge administration,respectively. On day 21, behavioral sensitization and the expression of NF-kBand IKKα/β were evaluated. We also determined the GLT1, TNFa, IL6 mRNA levelsby qPCR and Western blot. Our results demonstrate that stress induced a markedactivation of the canonical NF-kB pathway in the NAcore, determined byincreased p65 nuclear levels and of phosphorylation of the cytoplasmic IKKα/β. Consistently, the pharmacological or genetic inhibition of NF-kB activation,was sufficient to prevent stress-induced sensitization to cocaine. Moreover, byDnIKK or PDTC administration, stress-induced GLT-1 downregulation and TNF-alphaelevation in the NAcore were prevented. Thus, this evidence suggests that NF-kBsignaling activation would be crucial in the neuroinflammation-dependentimbalance of glutamate mechanisms induced by stress. Furthemore, our resultsindicate a central role for NF-kB in the long-term neurobiological mechanismswithin the Nacore underpinning stress-induced vulnerability to cocaineaddiction. All animal experiments were approved by the Animal Care and UseCommittee of the Facultad de Ciencias Quimicas (CICUAL), Universidad Nacionalde Córdoba (RES HCD 1220/18), which is consistent with the National Institutesof Health Guide for the Care and Use of Laboratory Animals.This work was supported by Argentinegrants from FONCyT BID PICT 2013-958 and PICT 2016-674 (to F.B.), FONCyT BID PICT2015-1622, and SECyT Res. 212/16, 411/18,472/18 and 411/18 (to F.B.)