Could variations in nNOS levels drive expression of cocaine sensitization?

GABACH, LAURA A; ARTUR DE LA VILLARMOIS, EMILCE; GHERSI MARISA; CARLINI, VALERIA; PEREZ, MARIELA F

Córdoba

Congreso; III Reunión Internacional de Ciencias Farmacéuticas (RICiFa 2014); 2014

Behavioral sensitization isknown as the increased sensitivity to locomotor stimulating effect after repeatedpsychostimulants administration, and it is believed to be relevant to drug addictionand craving in humans. Repeated cocaine induces behavioral sensitization and modulatessynaptic plasticity in the hippocampus, an important brain region for the associativelearning processes occurring during addiction. Nitric oxide (NO) is a neurotransmitterinvolved in several effects in the central nervous system including synapticplasticity and complex behavioral responses. We have previously demonstrated akey role of neuronal NO synthase (nNOS)/NO/soluble guanylate cyclase (sGC)/cyclic guanosinemonophosphate (cGMP)signaling pathway in the development of cocaine sensitization and in theassociated enhancement of hippocampal synaptic plasticity. In the present work,we attempted to determine constitutive differences in nNOS protein levelsbetween sensitized and non-sensitized groups by western blot, and whether nNOS inhibitionafter sensitization reverses the behavioral effect of cocaine and theassociated hippocampal synaptic plasticity. We administered five daily cocaineinjections (15 mg/kg, i.p) to 35 days old Wistar rats, followed by five daily7-nitroindazole (nNOS inhibitor, 50 mg/kg, i.p) or vehicle injections. We testeddevelopment of cocaine sensitization, by measuring locomotor activity, and thethreshold for long-term potentiation in hippocampus, using electrophysiologicalmultiunitary extracellular recordings, as indicator of synaptic plasticity. Weobserved that only sensitized rats showed significant increases in nNOS proteinlevels compared to non-sensitized group. Furthermore, nNOS inhibition reversed behavioralsensitization and the highest level of hippocampal plasticity. In conclusion,we can speculate that repeated cocaine exposure has differential impact withinsubjects, increasing nNOS protein levels only in sensitized animals. Then, nNOSinhibition can restore NO function in hippocampus and reverse cocainesensitization. Moreover, changes in NO function and nNOS activity in otherbrain areas related to the reward system that contribute to cocainesensitization must be considered.