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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