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


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


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.
Nagai
Taku
T
Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Takuma
Kazuhiro
K
Dohniwa
Misato
M
Ibi
Daisuke
D
Mizoguchi
Hiroyuki
H
Kamei
Hiroyuki
H
Nabeshima
Toshitaka
T
Yamada
Kiyofumi
K
D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000633:toxicity; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D008694:Methamphetamine; D048052:Mitogen-Activated Protein Kinase 3; D003024:Clozapine; D006220:Haloperidol