The Rac1/cofilin signaling pathway is essential for the expression of sensitization induced by chronic restraint stress in nucleus accumbens core.

RIGONI DAIANA; BOEZIO MARIA JULIETA; AVALOS MARIA PAULA; GUZMAN ANDREA SUSANA; SANCHEZ MARIANELA ADELA; BISBAL MARIANO; CANCELA LILIANA M; BOLLATI, FLAVIA A.

Glasgow

Congreso; FENS 2020 Virtual Forum; 2020

Scientific evidences have shown that both repeated drug administration and exposure to stress induce modifications in the density and morphology of dendritic spines which are regulated in part for a small GTPase Rac1. Repeated exposure to cocaine negatively regulates the activity of Rac1 in nucleus accumbens (NA) and is responsible for the expansion of dendritic spines, through a mechanism mediated by Cofilin. Our previous results have shown long-term changes in proteins regulating actin cytoskeleton in the NA during the expression of cross-sensitization between stress and cocaine. We described modifications in levels of Cofilin phosphorylation along with an increase in the PSD size and an enhancement in AMPAR surface expression in NA core. Thus, the main goal of this project is to evaluate the role of Rac/Cofilin signaling pathway facilitating the development of sensitization to cocaine induced by stress. For this purpose, we have generated a lentivirus overexpressing Rac1 protein or an shRNA to suppress Cofilin expression, that were administered intra-NA core 20 days before a challenge with cocaine in chronically pre-stressed rats, when behavioral sensitization was evaluated. Additionally, we have examined changes in the AMPAR surface expression known to contribute to the expression of cocaine sensitization. Our findings reveal that the inhibition of Cofilin or the overexpression of Rac1 are sufficient to prevent stress-induced sensitization to cocaine and impede the GluR1 surface enhancement in NA core in pre-stressed animals. These findings constitute a molecular mechanism influencing actin cytoskeleton remodeling in the NA during cross sensitization between stress and cocaine.