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

Belem

Congreso; 3rd FALAN Congress; 2022

Stress is a well-known risk factor in the development of psychostimulant addiction and relapse vulnerability. Stressfull experience induced cross sensitization to cocaine is associated to a significant impairment of glutamate mechanisms in the Nucleus Accumbens core (Nacore). The hallmark of disrupted glutamate homeostasis following restraint stress is the increased basal concentrations of extracellular glutamate attributed to glutamate transporter (GLT-1) downregulation within this brain area. Recent evidence from our lab, demonstrated that microglia, the immune cells in the brain, play a key role in the proactive influence of stress on impaired glutamate homeostasis in the NAcore. It has been reported a close linkage between glutamate and the activation of a ubiquitous transcription factor, the Nuclear Factor-Kappa B (NF-kB). The NF-kB, induce the expression of gene targets tightly linked to glia maintenance of glutamate homeostasis, such us (GLT-1), and controls the expression of numerous genes involved in inflammation and immune response. Considering these evidences, we hypothesized that the stress-induced homeostatic disruption of glutamate underlying cross-sensitization to cocaine depends on NF-kB signaling. So, the aim of the present research is the study the role of accumbal NFκB pathway in the expression of cocaine sensitization induced by chronic restraint stress. To test this, we used lentiviral vectors DnIKK, that expresses the dominant negative of the IKK activity, and the potent pharmacological inhibitor of NF-kB nuclear translocation, PDTC, to nullify the transcription factor activity. The animals were stressed 2 hours a day for 7 days, then they were treated with DNIKK or PDTC to evaluate behavioral tests and molecular changes on day 21. Locomotor activity and biochemical changes (expression of GLT1, TNFa, IL6 mRNA levels, cytoplasmic IKKα/β enzyme phosphorylation levels and nuclear p65 subunit levels) was measured in response to a saline or cocaine injection in pre-stressed and non-stressed rats after a pre-treatment with DnIKK or PDTC into the NAc core. Our results demonstrate that stress induced a marked activation of the NF-kB pathway, determined by increases in the levels of phosphorylation of the cytoplasmic IKKα/β enzyme, and in the levels of the nuclear p65 subunit in the NAcore. It was observed decrease in the expression levels of GLT1 and an increase in the expression levels of TNF-a mRNA. PDTC treatment administered intra-NAcore three weeks after the last chronic stress session increased GLT-1 levels in this brain area. This suggests that the activation of the signaling of NFkB would be crucial in the deregulation of glutamate homeostasis induced by stress. Another of our results demonstrate the inhibition of NF-kB activation, either genetic or pharmacological, was sufficient to prevent stress-induced sensitization to cocaine. These findings indicate a central role for NF-kB in the long-term neurobiological mechanisms within the Nacore underpinning stress-induced vulnerability to cocaine addiction