The effects of repeated administrations of MK-801 on ERK and GSK-3beta signalling pathways in the rat frontal cortex.
Repeated administrations of NMDA receptor antagonists induce behavioural changes which resemble the symptoms of schizophrenia in animals. ERK and GSK-3beta associated signalling pathways have been implicated in the pathogenesis of psychosis and in the action mechanisms of various psychotropic agents. Here, we observed the phosphorylations of ERK and GSK-3beta and related molecules in the rat frontal cortex after repeated intraperitoneal injections of MK-801, over periods of 1, 5, and 10 d. Repeated treatment with 0.5, 1, and 2 mg/kg MK-801 increased the phosphorylation levels of the MEK-ERK-p90RSK and Akt-GSK-3beta pathways and concomitantly and significantly increased CREB phosphorylation in the rat frontal cortex. However, single MK-801 treatment did not induce these significant changes. In addition, the immunoreactivities of HSP72, Bax, and PARP were not altered, which suggests that neuronal damage may not occur in the rat frontal cortex in response to chronic MK-801 treatment. These findings suggest that chronic exposure to MK-801 may induce pro-survival and anti-apoptotic activity without significant neuronal damage in the rat frontal cortex. Moreover, this adaptive change might be associated with the psychotomimetic action of MK-801.
Seo
Myoung Suk
MS
Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
Kim
Se Hyun
SH
Ahn
Yong Min
YM
Kim
Yeni
Y
Jeon
Won Je
WJ
Yoon
Se Chang
SC
Roh
Myoung-Sun
MS
Juhnn
Yong-Sung
YS
Kim
Yong Sik
YS
D000818:Animals; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
D017362:Cyclic AMP Response Element-Binding Protein; D018691:Excitatory Amino Acid Antagonists; D050884:HSP72 Heat-Shock Proteins; D051028:bcl-2-Associated X Protein; D016291:Dizocilpine Maleate; D011065:Poly(ADP-ribose) Polymerases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3