Protein Kinase C delta Gene Depletion Protects Against Methamphetamine-Induced Impairments in Recognition Memory and ERK1/2 Signaling via Upregulation of Glutathione Peroxidase-1 Gene

초록

Accumulating evidence has suggested that repeated treatment with methamphetamine (MA) resulted in cognitive impairments. Importantly, we show that selective upregulation of protein kinase C delta (PKC delta) in the prefrontal cortex (PFC) of wild-type mice persisted for 28 days post withdrawal of MA. On day 28, the MA-induced increase in phospho-PKC delta expression and decrease in phospho-ERK1/2 expression were significantly attenuated by both the Src inhibitor PP2 and the dopamine D1 receptor antagonist SCH 23390. However, neither protein kinase A inhibitor H89 nor calmodulin-dependent protein kinase II inhibitor KN93 attenuated MA-induced alterations in phospho-PKC delta expression and phospho-ERK1/2 expression. Since PKC delta knockout (KO) significantly increased the expression of glutathione peroxidase (GPx)-1, we also utilized GPx-1 KO and GPx-1-overexpressing transgenic (GPx-1 TG) mice. Repeated MA treatment induced cognitive impairment, as assessed by the novel object recognition test. Moreover, the extent of cognitive impairment correlated with the extent of increased phospho-PKC delta expression and decreased GPx1 expression. In the absence of MA, exposure to novel objects increased phospho-ERK1/2 and GPx-1 expression in the PFC; however, these expression levels were decreased in the presence of MA. PKC delta KO and GPx-1 TG mice each exhibited significantly attenuated MA-induced decreases in phospho-ERK1/2 and GPx-1 expression. Consistently, PKC delta inhibition induces GPx/GSH-dependent antioxidant systems. More importantly, the antipsychotic drug clozapine significantly protected against cognitive impairment and was associated with alterations in phospho-ERK1/2 and phospho-PKC delta expression. However, GPx-1 KO potentiated MA-induced cognitive deficits and alterations in phospho-ERK1/2 and phospho-PKC delta expression. These results suggest that MA induces cognitive impairment by inhibiting ERK1/2 signaling, activating PKC delta, and inactivating GPx-1 by upregulating Src kinase or the D1 receptor. They also suggest that clozapine requires activation of ERK1/2 signaling via positive modulation between the phospho-PKC delta and GPx-1 genes to restore cognitive function.

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