Ellis Alexandra S, Fosnocht Anne Q, Lucerne Kelsey E, Briand Lisa A
Department of Psychology, Temple University, United States; Neuroscience Program, Temple University, United States.
Department of Psychology, Temple University, United States.
Behav Brain Res. 2017 Aug 30;333:83-89. doi: 10.1016/j.bbr.2017.06.046. Epub 2017 Jun 28.
Cocaine addiction is characterized by persistent craving and addicts frequently relapse even after long periods of abstinence. Exposure to stress can precipitate relapse in humans and rodents. Stress and drug use can lead to common alterations in synaptic plasticity and these commonalities may contribute to the ability of stress to elicit relapse. These common changes in synaptic plasticity are mediated, in part, by alterations in the trafficking and stabilization of AMPA receptors. Exposure to both cocaine and stress can lead to alterations in protein kinase C-mediated phosphorylation of GluA2 AMPA subunits and thus alter the trafficking of GluA2-containing AMPARs. However, it is not clear what role AMPAR trafficking plays in the interactions between stress and cocaine. The current study utilized a mouse with a point mutation within the GluA2 subunit c-terminus resulting in a disruption of PKC-mediated GluA2 phosphorylation to examine stress responsivity. Although no differences were seen in the response to a forced swim stress in naïve mice, GluA2 K882A knock-in mice exhibited an increased stress response following cocaine self-administration. Furthermore, we demonstrated that disrupting GluA2 phosphorylation increases vulnerability to stress-induced reinstatement of both cocaine seeking and cocaine-conditioned reward. Finally, GluA2 K882A knock-in mice exhibit an increased vulnerability to social defeat as indicated by increased social avoidance. Taken together these results indicate that disrupting GluA2 phosphorylation leads to increased responsivity to acute stress following cocaine exposure and increased vulnerability to chronic stress. These results highlight the GluA2 phosphorylation site as a novel target for the stress-related disorders.
可卡因成瘾的特征是持续的渴望，即使经过长时间的戒断，成瘾者仍频繁复发。暴露于应激状态可促使人类和啮齿动物复发。应激和药物使用可导致突触可塑性的共同改变，这些共性可能有助于应激引发复发的能力。这些突触可塑性的共同变化部分是由AMPA受体的运输和稳定性改变介导的。暴露于可卡因和应激均可导致蛋白激酶C介导的GluA2 AMPA亚基磷酸化改变，从而改变含GluA2的AMPARs的运输。然而，尚不清楚AMPAR运输在应激与可卡因之间的相互作用中起什么作用。当前的研究利用了一种在GluA2亚基c末端存在点突变导致PKC介导的GluA2磷酸化破坏的小鼠来检查应激反应性。尽管在未接触过可卡因的小鼠中，对强迫游泳应激的反应未观察到差异，但GluA2 K882A基因敲入小鼠在可卡因自我给药后表现出增强的应激反应。此外，我们证明破坏GluA2磷酸化会增加对压力诱导的可卡因寻求行为恢复和可卡因条件性奖赏恢复的易感性。最后，GluA2 K882A基因敲入小鼠表现出对社会挫败的易感性增加，表现为社交回避增加。综上所述，这些结果表明破坏GluA2磷酸化会导致可卡因暴露后对急性应激的反应性增加以及对慢性应激的易感性增加。这些结果突出了GluA2磷酸化位点作为应激相关疾病的新靶点。
