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Repeated methamphetamine treatment impairs spatial working memory in rats: reversal by clozapine but not haloperidol

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Abstract

Rationale

Although chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans, there are few reports about an animal model that reflects METH-induced impairment of working memory.

Objectives

In this study, we investigated the effect of repeated METH treatment on spatial working memory in rats.

Materials and methods

Rats were repeatedly administered METH (2 mg/kg) once a day for 7 days, and their memory function was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay.

Results

METH-treated animals showed an impairment of performance in the test phase when the delay time was increased from 5 to 30 min or longer. The effect of METH persisted for at least 14 days after the drug withdrawal. METH-induced impairment of working memory was reversed by clozapine (3 and 10 mg/kg, for 7 days), but not haloperidol (1 and 2 mg/kg, for 7 days). The improving effect of clozapine diminished 7 days after the withdrawal. Phosphorylated extracellular signal-regulated kinase1/2 (ERK1/2) levels were significantly increased in the hippocampus of saline-treated control rats from 5 to 60 min after the training phase. In contrast, hyperphosphorylation of ERK1/2 was abolished in the hippocampus of rats treated with METH.

Conclusions

These findings suggest that repeated METH treatment induces impairment of working memory, which is associated with a dysfunctional ERK1/2 pathway in the hippocampus. Furthermore, clozapine may be effective for the treatment of METH-induced cognitive dysfunction.

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Acknowledgements

This study was supported in part by Grants-in-aid for Scientific Research and for the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Grant-in-aid for Health Science Research from the Ministry of Health, Labour and Welfare of Japan, and grants from the Smoking Research Foundation, Japan.

Conflict of interest statement

There are no conflicts of interest in this study.

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Authors and Affiliations

  1. Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

    Taku Nagai, Kazuhiro Takuma, Misato Dohniwa, Daisuke Ibi, Hiroyuki Mizoguchi & Kiyofumi Yamada

  2. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Taku Nagai & Toshitaka Nabeshima

  3. Laboratory of Clinical Pharmacy Practice and Health Care Management, Faculty of Pharmacy, Meijo University, Nagoya, Japan

    Hiroyuki Kamei

Authors
  1. Taku Nagai
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  2. Kazuhiro Takuma
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  3. Misato Dohniwa
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  4. Daisuke Ibi
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  5. Hiroyuki Mizoguchi
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  6. Hiroyuki Kamei
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  7. Toshitaka Nabeshima
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  8. Kiyofumi Yamada
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Corresponding author

Correspondence to Kiyofumi Yamada.

Additional information

Taku Nagai and Kazuhiro Takuma contributed equally to the work.

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Nagai, T., Takuma, K., Dohniwa, M. et al. Repeated methamphetamine treatment impairs spatial working memory in rats: reversal by clozapine but not haloperidol. Psychopharmacology 194, 21–32 (2007). https://doi.org/10.1007/s00213-007-0820-1

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  • DOI: https://doi.org/10.1007/s00213-007-0820-1

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