Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice.
BACKGROUND
Recent clinical studies have suggested that chronic use of methamphetamine (METH) induces long-term cognitive deficits. To clarify the mechanism of METH-induced cognitive impairment, we investigated the effect of METH on cognitive function in mice.


METHODS
Mice were repeatedly administered METH for 7 days, and their cognitive function was assessed using a novel-object recognition task. Therapeutic effects of clozapine and haloperidol on METH-induced cognitive impairment were investigated. Western blotting and specific inhibitors were employed to determine the role of extracellular signal-regulated kinase 1/2 (ERK1/2).


RESULTS
Repeated METH treatment induced an impairment of recognition of novel objects and behavioral sensitization. These effects persisted for at least 28 days after the drug withdrawal. Clozapine, but not haloperidol, reduced METH-induced cognitive impairment. Hyperphosphorylation of ERK1/2 was found in the prefrontal cortex of mice exposed to the novel objects, but was abolished in mice treated with METH. Inhibition of ERK1/2 by the microinjection of PD98059 into the prefrontal cortex resulted in cognitive impairment.


CONCLUSIONS
These results suggest that repeated METH treatment induces cognitive impairment, which is associated with the dysfunction of the ERK1/2 pathway in the prefrontal cortex.
Kamei
Hiroyuki
H
Laboratory of Neuropsychopharmacology, Graduate School of Natural Science and Technology, Kanazawa University.
Nagai
Taku
T
Nakano
Hiroko
H
Togan
Yuriko
Y
Takayanagi
Masanori
M
Takahashi
Kenji
K
Kobayashi
Kana
K
Yoshida
Shigeru
S
Maeda
Kenji
K
Takuma
Kazuhiro
K
Nabeshima
Toshitaka
T
Yamada
Kiyofumi
K
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005106:Exploratory Behavior / Q000502:physiology*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000503:physiopathology*; D008694:Methamphetamine / Q000008:administration & dosage* / Q000009:adverse effects; D051379:Mice; D008813:Mice, Inbred ICR; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
D014150:Antipsychotic Agents; D018765:Dopamine Uptake Inhibitors; D008694:Methamphetamine; D019950:Mitogen-Activated Protein Kinase 1