Actin dynamics in dendritic spines can be associated with the neurobiological mechanisms supporting the comorbidity between stress exposure and cocaine increase rewards. The actin cytoskeleton remodeling in the nucleus accumbens (NA) has been implicated in the expression of stress-induced cross-sensitization with cocaine. The present study evaluates the involvement of cofilin, a direct regulator of actin dynamics, in the impact of stress on vulnerability to cocaine addiction. We assess whether the neurobiological mechanisms that modulate repeated-cocaine administration also occur in a chronic restraint stress-induced cocaine self-administration model. We also determine if chronic stress induces alterations in dendritic spines through dysregulation of cofilin activity in the NA core. Here, we show that the inhibition of cofilin expression in the NA core using viral short-hairpin RNA is sufficient to prevent the cocaine sensitization induced by chronic stress. The reduced cofilin levels also impede a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor surface expression enhancement and promote the reduction of head diameter in animals pre-exposed to stress after a cocaine challenge in the NA core. Moreover, downregulation of cofilin expression prevents facilitation of the acquisition of cocaine self-administration (SA) in male rats pre-exposed to chronic stress without modifying performance in sucrose SA. These findings reveal a novel, crucial role for cofilin in the neurobiological mechanisms underpinning the comorbidity between stress exposure and addiction-related disorders.

树突棘中的肌动蛋白动力学可能与支持压力暴露和可卡因增加奖励之间共病的神经生物学机制有关。伏隔核（NA）中的肌动蛋白细胞骨架重塑与应激诱导的可卡因交叉致敏的表达有关。本研究评估了肌丝蛋白丝切蛋白（肌动蛋白动力学的直接调节剂）在压力对可卡因成瘾脆弱性的影响中的作用。我们评估调节重复可卡因给药的神经生物学机制是否也发生在慢性束缚应激诱导的可卡因自我给药模型中。我们还确定慢性压力是否会通过 NA 核心丝切蛋白活性的失调来诱导树突棘的改变。在这里，我们证明使用病毒短发夹 RNA 抑制 NA 核心中的丝动蛋白表达足以防止慢性应激诱导的可卡因致敏。降低的丝动蛋白水平还阻碍α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体表面表达的增强，并促进在NA中可卡因攻击后预先暴露于应激的动物的头部直径的减小核。此外，在预先暴露于慢性应激的雄性大鼠中，cofilin表达下调可防止促进可卡因自我给药（SA）的获得，而不改变蔗糖SA的表现。这些发现揭示了丝切蛋白在支撑压力暴露和成瘾相关疾病之间共病的神经生物学机制中的新的关键作用。