Essential role for Rac1 in chronic stress- induced sensitization tococaine in nucleus accumbens.
Daiana Rigoni 1, M. Julieta Boezio 1, María P.Avalos 1, Andrea S. Guzmán 1, Marianela A. Sánchez 1,Mariano Bisbal 2, Liliana M. Cancela 1, Flavia Bollati 1
(1)IFEC- CONICET.Departamento de Farmacología, Fac. De Ciencias Químicas, Universidad Nacionalde Córdoba, Argentina.
(2)Instituto Ferreyra(INIMEC-CONICET-Universidad Nacional de Córdoba), Córdoba, Argentina.
Several laboratories have demonstratedthat the RhoGTPase Rac1 mediates structural and behavioral plasticity inresponse to cocaine exposure in nucleus accumbens (NA). Specifically, repeatedexposure to cocaine negatively regulates Rac1 activity in NA and is responsiblefor the expansion of dendritic spines, through a mechanism mediated by Cofilin.Our previous results have shown long-term changes in proteins regulatingactin cytoskeleton in the NA during the expression of cross-sensitizationbetween stress and cocaine. We havepreviously described modifications in levels of Cofilin phosphorylation andenhancement in AMPAR surface expression in NA core. Thus, the maingoal of this project is to evaluate the role of Rac1 signaling pathway in thedevelopment of cocaine sensitization induced by stress. For thispurpose, we have generated a lentivirus overexpressing Rac1 protein or a shRNA tosuppress Cofilin expression, that were administered intra-NA core before achallenge with cocaine in pre-stressed rats, when behavioral sensitization wasevaluated. Additionally, we have examined changes in the AMPAR surfaceexpression. Our findings reveal that the overexpression of Rac1 is sufficientto prevent stress-induced sensitization to cocaine and impedes the GluR1surface enhancement in NA core observed in pre-stressed animals. These findingsconstitute a molecular mechanism influencing actin cytoskeleton remodeling inthe NA during cross sensitization between stress and cocaine.
