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

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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

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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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T2 - Reversal by clozapine but not haloperidol

AU - Nagai, Taku

AU - Takuma, Kazuhiro

AU - Dohniwa, Misato

AU - Ibi, Daisuke

AU - Mizoguchi, Hiroyuki

AU - Kamei, Hiroyuki

AU - Nabeshima, Toshitaka

AU - Yamada, Kiyofumi

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N2 - 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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