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Operant Procedures for Assessing Behavioral Flexibility in Rats
Published on: February 15, 2015
Repeated methamphetamine treatment impairs spatial working memory in rats: reversal by clozapine but not haloperidol
Taku Nagai1, Kazuhiro Takuma, Misato Dohniwa
1Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
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.
Insights
Chronic methamphetamine (METH) use impairs spatial working memory in rats, linked to hippocampal ERK1/2 pathway dysfunction. Clozapine shows potential in reversing METH-induced cognitive deficits.
Area of Science:
- Neuroscience
- Pharmacology
- Cognitive Science
Background:
- Chronic methamphetamine (METH) use causes long-lasting cognitive dysfunction in humans.
- Few animal models accurately reflect METH-induced working memory impairment.
Purpose of the Study:
- Investigate the effects of repeated METH administration on spatial working memory in rats.
- Explore the underlying molecular mechanisms, specifically the ERK1/2 pathway.
- Evaluate potential therapeutic interventions for METH-induced cognitive deficits.
Main Methods:
- Rats received daily METH (2 mg/kg) for 7 days.
- Spatial working memory assessed using a delayed spatial win-shift task in a radial arm maze.
- Hippocampal ERK1/2 phosphorylation levels analyzed post-treatment.
Main Results:
- METH treatment significantly impaired working memory performance, especially with longer delays (≥30 min).
- METH-induced deficits persisted for at least 14 days post-withdrawal.
- Clozapine, but not haloperidol, reversed METH-induced memory impairment.
- METH abolished training-induced ERK1/2 phosphorylation in the hippocampus.
Conclusions:
- Repeated METH administration induces persistent spatial working memory impairment in rats.
- This impairment is associated with hippocampal ERK1/2 pathway dysfunction.
- Clozapine demonstrates therapeutic potential for METH-induced cognitive dysfunction.
