Molecular Neurobiology

, Volume 55, Issue 5, pp 4136–4159 | Cite as

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

  • The-Vinh Tran
  • Eun-Joo Shin
  • Lan Thuy Ty Nguyen
  • Youngho Lee
  • Dae-Joong Kim
  • Ji Hoon Jeong
  • Choon-Gon Jang
  • Seung-Yeol Nah
  • Kazuya Toriumi
  • Toshitaka Nabeshima
  • Kiyofumi Yamada
  • Hyoung-Chun Kim


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-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-PKCδ expression and phospho-ERK1/2 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-ERK1/2 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-ERK1/2 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-ERK1/2 and phospho-PKCδ expression. However, GPx-1 KO potentiated MA-induced cognitive deficits and alterations in phospho-ERK1/2 and phospho-PKCδ expression. These results suggest that MA induces cognitive impairment by inhibiting ERK1/2 signaling, activating PKCδ, 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-PKCδ and GPx-1 genes to restore cognitive function.


Methamphetamine-induced cognitive impairment Prefrontal cortex Novel object recognition test Protein kinase Cδ Glutathione peroxidasex-1 ERK1/2 signaling Antipsychotic clozapine 



Acetylcholine esterase


Abelson tyrosine kinase


Ca2+/calmodulin-dependent protein kinase II


Choline acetyl transferase


cAMP response binding protein


Dimethyl sulfoxide


DNA-dependent protein kinase


ETS-like gene-1


Extracellular signal-regulated kinases 1/2


Glial fibrillary acidic protein


Glutathione peroxidase-1




Glutathione disulfide


Human checkpoint protein Rad9


Ionized calcium-binding adapter molecule 1






Mitogen-activated protein kinase


Neuronal nuclei


Nuclear factor kappa B


Novel object recognition test


Nuclear factor (erythroid-derived 2)-like 2


Prefrontal cortex


Protein kinase A


Protein kinase C delta


Phospholipid scramblase 3


Src homology 2-containing tyrosine phosphatase 1

Src kinase

Proto-oncogene tyrosine-protein kinase Src


Signal transducer and activator of transcription 1


Trace amine associated receptor 1


Overexpressing transgenic


Wild type



This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea, and in part by JSPS KAKENHI Grants (No. 26460240, 16K10195) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a grant-in-aid of SRF. The-Vinh Tran and Lan Thuy Ty Nguyen were supported by the BK21 PLUS program.

Compliance with Ethical Standards

All the mice were treated in strict accordance with the NIH Guide for the Humane Care and Use of Laboratory Animals.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

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ESM 1 (DOCX 37 kb)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • The-Vinh Tran
    • 1
  • Eun-Joo Shin
    • 1
  • Lan Thuy Ty Nguyen
    • 1
  • Youngho Lee
    • 1
  • Dae-Joong Kim
    • 2
  • Ji Hoon Jeong
    • 3
  • Choon-Gon Jang
    • 4
  • Seung-Yeol Nah
    • 5
  • Kazuya Toriumi
    • 6
  • Toshitaka Nabeshima
    • 7
  • Kiyofumi Yamada
    • 8
  • Hyoung-Chun Kim
    • 1
  1. 1.Neuropsychopharmacology and Toxicology Program, College of PharmacyKangwon National UniversityChunchonRepublic of Korea
  2. 2.Department of Anatomy and Cell Biology, Medical SchoolKangwon National UniversityChunchonRepublic of Korea
  3. 3.Department of Pharmacology, College of MedicineChung-Ang UniversitySeoulRepublic of Korea
  4. 4.Department of Pharmacology, School of PharmacySungkyunkwan UniversitySuwonSouth Korea
  5. 5.Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics CenterKonkuk UniversitySeoulRepublic of Korea
  6. 6.Project for Schizophrenia Research, Department of Psychiatry and Behavioral SciencesTokyo Metropolitan Institute of Medical ScienceTokyoJapan
  7. 7.Advanced Diagnostic System Research LaboratoryFujita Health University Graduate School of Health SciencesToyoakeJapan
  8. 8.Department of Neuropsychopharmacology and Hospital PharmacyNagoya University Graduate School of MedicineNagoyaJapan

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