Department of Psychology, Developmental Neuropsychobiology Laboratory, Northeastern University, Boston, MA 02115, USA.
Department of Psychology, Developmental Neuropsychobiology Laboratory, Northeastern University, Boston, MA 02115, USA.
Brain Behav Immun. 2019 May;78:41-51. doi: 10.1016/j.bbi.2019.01.006. Epub 2019 Jan 14.
Exposure to early life adversity can predispose adolescents to the formation of substance abuse disorders. In rodents, early stressors such as repeated maternal separation (MS) impact AMPAR activity in the prefrontal cortex (PFC) and nucleus accumbens (NAc), regions involved in drug-cue association after cocaine-induced conditioned place preference (CPP). Notably, previous reports suggest that the pro-inflammatory cytokine tumor necrosis factor (TNF) regulates AMPAR subunit composition; increased TNF levels are reported to reduce GluA2-positive AMPARs. Since MS can elevate adolescent TNF levels, the stressor may therefore alter AMPAR subunit composition via neuroimmune signaling, thereby affecting cocaine-induced CPP. We tested the specific role of soluble TNF in MS-induced GluA2 loss and cocaine-induced CPP with biologic disruption of TNF signaling. TNF gene and protein expression were elevated in both PFC and NAc of MS males, but not females. GluA2 expression was reduced in both regions in only male MS rats, and systemic treatment with either ibudilast - a phosphodiesterase inhibitor, or XPro1595 - a blood-brain barrier-permeable blocker of soluble TNF - reversed such loss. MS males also formed greater preference for a cocaine-paired environment, the expression of which returned to control levels after XPro1595 administration. These data suggest a sex-specific mechanistic link between TNF signaling and changes in GluA2 expression and drug-cue conditioning, thereby providing further evidence for a role of MS and neuro-immune activity in cortical and striatal AMPAR changes. Moreover, manipulation of the TNF signaling pathway represents a novel approach for influencing response to reinforcing effects of drug use.
早期生活逆境的暴露会使青少年更容易形成物质滥用障碍。在啮齿动物中，反复的母体分离（MS）等早期应激源会影响前额叶皮层（PFC）和伏隔核（NAc）中的 AMPAR 活性，这些区域涉及可卡因诱导的条件性位置偏好（CPP）后药物线索的关联。值得注意的是，先前的报告表明，促炎细胞因子肿瘤坏死因子（TNF）调节 AMPAR 亚基组成；据报道，TNF 水平升高会减少 GluA2 阳性 AMPAR。由于 MS 会增加青少年 TNF 水平，因此应激源可能通过神经免疫信号改变 AMPAR 亚基组成，从而影响可卡因诱导的 CPP。我们通过生物破坏 TNF 信号转导来测试可溶性 TNF 在 MS 诱导的 GluA2 丢失和可卡因诱导的 CPP 中的特定作用。MS 雄性大鼠的 PFC 和 NAc 中 TNF 基因和蛋白表达均升高，但雌性大鼠则没有。仅在雄性 MS 大鼠的两个区域中，GluA2 的表达减少，而全身给予磷酸二酯酶抑制剂伊布地尔或血脑屏障可渗透的可溶性 TNF 阻断剂 XPro1595 则可逆转这种丢失。MS 雄性大鼠也对可卡因配对环境表现出更大的偏好，而 XPro1595 给药后，其表达恢复到对照水平。这些数据表明，TNF 信号转导与 GluA2 表达和药物线索条件变化之间存在性别特异性的机制联系，从而为 MS 和神经免疫活动在皮质和纹状体 AMPAR 变化中的作用提供了进一步的证据。此外，操纵 TNF 信号通路代表了一种影响对药物使用的强化作用反应的新方法。
