Repeated methamphetamine treatment impairs spatial working memory in rats

Reversal by clozapine but not haloperidol

Taku Nagai, Kazuhiro Takuma, Misato Dohniwa, Daisuke Ibi, Hiroyuki Mizoguchi, Hiroyuki Kamei, Toshitaka Nabeshima, Kiyofumi Yamada

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)21-32
Number of pages12
JournalPsychopharmacology
Volume194
Issue number1
DOIs
Publication statusPublished - 01-09-2007
Externally publishedYes

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Methamphetamine
Clozapine
Haloperidol
Short-Term Memory
Hippocampus
Spatial Memory
Animal Models

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Nagai, Taku ; Takuma, Kazuhiro ; Dohniwa, Misato ; Ibi, Daisuke ; Mizoguchi, Hiroyuki ; Kamei, Hiroyuki ; Nabeshima, Toshitaka ; Yamada, Kiyofumi. / Repeated methamphetamine treatment impairs spatial working memory in rats : Reversal by clozapine but not haloperidol. In: Psychopharmacology. 2007 ; Vol. 194, No. 1. pp. 21-32.
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Repeated methamphetamine treatment impairs spatial working memory in rats : Reversal by clozapine but not haloperidol. / Nagai, Taku; Takuma, Kazuhiro; Dohniwa, Misato; Ibi, Daisuke; Mizoguchi, Hiroyuki; Kamei, Hiroyuki; Nabeshima, Toshitaka; Yamada, Kiyofumi.

In: Psychopharmacology, Vol. 194, No. 1, 01.09.2007, p. 21-32.

Research output: Contribution to journalArticle

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AU - Takuma, Kazuhiro

AU - Dohniwa, Misato

AU - Ibi, Daisuke

AU - Mizoguchi, Hiroyuki

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AU - Nabeshima, Toshitaka

AU - Yamada, Kiyofumi

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