Mental Health Research Institute, 155 Oak Street, Parkville, Victoria 3052, Australia.
Pharmacol Biochem Behav. 2010 Dec;97(2):293-300. doi: 10.1016/j.pbb.2010.08.013. Epub 2010 Sep 9.
Oxidative stress has been implicated in several psychiatric illnesses, including schizophrenia. Glutathione is the brain's primary antioxidant and decreased levels of brain glutathione are reported in schizophrenia. Prepulse inhibition (PPI) is a measure of sensory gating, and PPI is reduced in schizophrenia. This study aimed to investigate the effects of brain glutathione depletion on PPI regulation. Rats and mice were treated with the glutathione-depleting agent, 2-cyclohexene-1-one (CHX), and tested for baseline PPI and its disruption by treatment with amphetamine and MK-801. Treatment with CHX caused significant depletion of GSH in frontal cortex and striatum of rats and mice. Baseline PPI and startle were not altered. However, the disruption of PPI after treatment with amphetamine was absent in CHX-treated rats. In contrast, the effect of MK-801 was not altered by CHX-treatment, nor was there any effect of CHX treatment in mice. These data show an interaction of glutathione depletion with the effects of amphetamine treatment on PPI in rats. This effect could reflect loss of plasticity in PPI regulation caused by the additive effects of CHX-induced glutathione depletion and additional oxidative stress caused by amphetamine-induced dopamine release. The significance of these results for schizophrenia is discussed.
氧化应激与包括精神分裂症在内的几种精神疾病有关。谷胱甘肽是大脑的主要抗氧化剂，有报道称精神分裂症患者大脑中的谷胱甘肽水平降低。前脉冲抑制（PPI）是一种感觉门控的测量方法，精神分裂症患者的 PPI 会降低。本研究旨在探讨大脑谷胱甘肽耗竭对 PPI 调节的影响。用谷胱甘肽耗竭剂 2-环己烯-1-酮（CHX）处理大鼠和小鼠，检测其基础 PPI 及其对安非他命和 MK-801 处理的破坏作用。CHX 处理导致大鼠和小鼠前额叶皮层和纹状体中的 GSH 明显耗竭。基础 PPI 和惊跳反应没有改变。然而，CHX 处理的大鼠在安非他命处理后 PPI 的破坏作用消失了。相比之下，CHX 处理并不改变 MK-801 的作用，CHX 处理对小鼠也没有任何影响。这些数据显示，谷胱甘肽耗竭与安非他命处理对大鼠 PPI 的影响存在相互作用。这种作用可能反映了由 CHX 诱导的谷胱甘肽耗竭和安非他命诱导的多巴胺释放引起的额外氧化应激的累加效应导致 PPI 调节的可塑性丧失。讨论了这些结果对精神分裂症的意义。
