The Rac1/cofilinsignaling pathway is essential for the expression of sensitizationinduced by chronic restraint stress in nucleus accumbens core.
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.
Scientificevidences have shown that both repeated drug administration andexposure to stress induce modifications in the density and morphology ofdendritic spines which are regulated in part for a small GTPase Rac1. Repeatedexposure to cocaine negatively regulates the activity of Rac1 in nucleusaccumbens (NA) and is responsible for the expansion of dendritic spines,through a mechanism mediated by Cofilin. Our previousresults have shown long-term changes in proteins regulating actin cytoskeletonin the NA during the expression of cross-sensitization between stress andcocaine. We described modifications in levelsof Cofilin phosphorylation along with an increase in the PSD size and anenhancement in AMPAR surface expression in NA core. Thus, the maingoal of this project is to evaluate the role of Rac/Cofilin signaling pathwayfacilitating the development of sensitization to cocaine induced by stress. For thispurpose, we have generated a lentivirus overexpressing Rac1 protein or an shRNAto suppress Cofilin expression, that were administered intra-NA core 20 daysbefore a challenge with cocaine in chronically pre-stressed rats, whenbehavioral sensitization was evaluated. Additionally, we have examined changesin the AMPAR surface expression known to contribute to the expression of cocainesensitization. Our findings reveal that the inhibition of Cofilin or the overexpressionof Rac1 are sufficient to prevent stress-induced sensitization to cocaine and impedethe GluR1 surface enhancement in NA core in pre-stressed animals. Thesefindings constitute a molecular mechanism influencing actin cytoskeletonremodeling in the NA during cross sensitization between stress and cocaine.
