Actindynamics in dendritic spines can be associated with the neurobiologicalmechanisms supporting the comorbidity between stress exposure and cocaineincrease rewards. The actin cytoskeleton remodeling in the nucleus accumbens(NA) has been implicated in the expression of stress-inducedcross-sensitization with cocaine. The main of the present study is evaluate theinvolvement of cofilin, a direct regulator of actin dynamics, in the impact ofstress on vulnerability to cocaine addiction. Here, we show that the inhibitionof cofilin expression in the NA core using viral short-hairpin RNA issufficient to prevent the cocaine sensitization induced by chronic stress. Moreover,the reduced cofilin levels also impede a-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid (AMPA) receptor surface expression enhancement and promote thereduction of head diameter of spines in animals pre-exposed to stress after acocaine challenge in the NA core. We report that cofilin downregulation preventsfacilitation of the acquisition of cocaine self-administration (SA) in malerats pre-exposed to chronic stress. These findings highlight the role ofcofilin in the neurobiological mechanisms supporting the comorbidity betweenstress exposure and addiction-related disorders.