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

Abstract

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.

Exposure to far‐infrared ray attenuates methamphetamine‐induced impairment in recognition memory through inhibition of protein kinase C δ in male mice: Comparison with the antipsychotic clozapine

“…Phospho‐PKCδ antibody (RRID:http://scicrunch.org/resolver/AB_654730) gave rise to a band of 78 kDa (Shin, Dang, et al, ). ERK 1/2 antibody (RRID:http://scicrunch.org/resolver/AB_330744) and phospho‐ERK 1/2 (RRID:http://scicrunch.org/resolver/AB_331646) recognized two bands corresponding to 42 kDa and 44 kDa (Tu et al, ; Tran et al, ). β‐actin (RRID:http://scicrunch.org/resolver/AB_476697) was detected as a 42 kDa immunoreactive band (Shin et al, ; Shin et al, ).…”

“…All mice were handled and treated in accordance with the NIH Guide for the Humane Care and Use of Laboratory Animals. On the basis of our previous studies, we selected male mice for the current study (Kamei et al, ; Shin et al, ; Tran, Shin, Jeong, et al, ; Tran et al, ). Moreover, in our pilot study (Nguyen et al, ), we observed that male mice were more senstive to MA than female mice.…”

“…We have demonstrated that MA treatment enhances PKCδ expression but does not alter other PKC isoenzymes (Shin et al, ). Moreover, in a recent study we have also demonstrated that repeated treatment with MA results in cognitive impairment via phosphorylation of PKCδ (Tran et al, ), whereas rottlerin, a pharmacological inhibitor of PKCδ, protects against MA‐induced behavioral deficits in mice (Shin et al, ). Importantly, clozapine, an antipsychotic, restores cognitive function by positive modulation of PKCδ, extracellular signal‐regulated kinase (ERK) 1/2, and glutathione peroxidase‐1 (GPx‐1) (Tran et al, ).…”

“…Additionally, magnetic resonance imaging showed that MA abuse leads to prefrontal cortex (PFC) dysfunction, which is associated with cognitive and motor impairment (Chang et al, ; Paulus et al, ; Sekine et al, ). Moreover, we have demonstrated that repeated MA treatment induces recognition memory impairments (Kamei et al, ; Tran et al, ) and can be used as an animal model for schizophrenia and MA psychosis.…”

“…As it is well known that ERK 1/2 plays a significant role in psychostimulant‐induced neural plasticity (Nestler, ; Valjent, Caboche, & Vanhoutte, ), this might be responsible for the cognitive deficit (Zhu et al, ). It has been suggested that activation of the ERK 1/2 pathway in PFC protects against MA‐induced cognitive impairment (Kamei et al, ; Tran et al, ), whereas pharmacologic or genetic inhibition of ERK 1/2 activation impairs memory function in rodents (Blum, Moore, Adams, & Dash, ; Schafe et al, ), indicating that ERK signaling is involved in MA‐induced behavioral and neuronal changes including memory impairment.…”