Genetic inhibition of Nuclear Factor kappa B (NF-kB) in Nucleus Accumbens core prevents chronic stress - induced facilitation of cocaine self-administration.

Porto

Congreso; ISN-ESN 2023 Meeting; 2023

International Society of Neurochemistry (ISN) - European Society of Neurochemistry (ESN)

Stress is a well-known risk factor in the development of addiction and relapse vulnerability. Studies from our lab, showed that stress can elicit a sensitized response to the psychomotor and stimulant effects of cocaine, as well as a facilitation of cocaine self-administration behavior. Consistently, stress induced alterations in glutamate mechanisms in the nucleus accumbens core (NAcc) have been linked with behavioral findings. Several lines of evidence reported a close linkage between glutamate and the activation of the Nuclear Factor-Kappa B (NF-kB). This transcription factor induces the expression of gene targets tightly linked to glia maintenance of glutamate homeostasis. Considering these evidences, we propose a central role of Nf-kB signaling in stress -enhanced vulnerability to cocaine self-administration. Thus we designed lentiviral vectors DnIKK, that expresses the dominant negative of the IKK activity to nullify the transcription factor activity. Sprague-Dawley rats were exposed to restraint stress 2 hs daily for a week. One week after the last stress session, all animals were treated intra-NAcc whit lentivirus DnIKK. On day 21, animals were assigned to behavioral studies and immunofluorescence to determine NF-kB activity in accumbal glial cells. Ours results demonstrated that the genetic inhibition of NF-kB, was sufficient to prevent stress-induced cross sensitization to cocaine and the facilitation of cocaine self-administration. Morever, by immunofluorescence we observed a marked NF-kB expression in astrocytes, the glial cell population responsible for maintaining proper glutamate homeostasis. These result suggest a central role of NF-kB on the long-term neurobiological mechanism induced in the NAcc by stress, promoting the expression of cross-sensitization to cocaine and facilitation of cocaine self-administration behavior. These findings reveal a novel, crucial role of the NF-kB in the neurobiological mechanisms underpinning the comorbidity between stress exposure and addiction-related disorders. This work was supported by Argentine grants from FONCyT, CONICET and SECyT.