Protein Kinase Cδ Gene Depletion Protects Against Methamphetamine-Induced Impairments in Recognition Memory and ERK Signaling via Upregulation of Glutathione Peroxidase-1 Gene.

Accumulating evidence has suggested that repeated treatment with methamphetamine (MA) resulted in cognitive impairments. Importantly, we show that selective upregulation of protein kinase Cδ (PKCδ) 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-PKCδ expression and decrease in phospho-ERK 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-PKCδ expression and phospho-ERK expression. Since PKCδ 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-PKCδ expression and decreased GPx1 expression. In the absence of MA, exposure to novel objects increased phospho-ERK and GPx-1 expression in the PFC; however, these expression levels were decreased in the presence of MA. PKCδ KO and GPx-1 TG mice each exhibited significantly attenuated MA-induced decreases in phospho-ERK and GPx-1 expression. Consistently, PKCδ 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-ERK and phospho-PKCδ expression. However, GPx-1 KO potentiated MA-induced cognitive deficits and alterations in phospho-ERK and phospho-PKCδ expression. These results suggest that MA induces cognitive impairment by inhibiting ERK signaling, activating PKCδ, and inactivating GPx-1 by upregulating Src kinase or the D1 receptor. They also suggest that clozapine requires activation of ERK signaling via positive modulation between the phospho-PKCδ and GPx-1 genes to restore cognitive function.