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Essential role for Rac1 in chronic stress- induced sensitization to cocaine in nucleus accumbens.

Daiana RIgoni

  • cordoba,
  • Argentina
  • Daiana Rigoni ¹
  • , M. Julieta Boezio ¹
  • , M. Paula 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 Nacional de Córdoba, Argentina.
  • 2 Instituto Ferreyra (INIMEC-CONICET-Universidad Nacional de Córdoba), Córdoba, Argentina.

Several laboratories have demonstrated that the RhoGTPase Rac1 mediates structural and behavioral plasticity in response to cocaine exposure in nucleus accumbens (NA). Specifically, repeated exposure to cocaine negatively regulates Rac1 activity in 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 have previously described modifications in levels of Cofilin phosphorylation and enhancement in AMPAR surface expression in NA core. Thus, the main goal of this project is to evaluate the role of Rac1 signaling pathway in the development of cocaine sensitization induced by stress. For this purpose, we have generated a lentivirus overexpressing Rac1 protein or a shRNA to suppress Cofilin expression, that were administered intra-NA core before a challenge with cocaine in pre-stressed rats, when behavioral sensitization was evaluated. Additionally, we have examined changes in the AMPAR surface expression. Our findings reveal that the overexpression of Rac1 is sufficient to prevent stress-induced sensitization to cocaine and impedes the GluR1 surface enhancement in NA core observed in pre-stressed animals. These findings constitute a molecular mechanism influencing actin cytoskeleton remodeling in the NA during cross sensitization between stress and cocaine. -
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