Inhibition of glycogen synthase kinase-3 attenuates psychotomimetic effects of ketamine.
N-methyl-D-aspartate (NMDA) glutamate receptors mediate fast neurotransmission and regulate synaptic plasticity in the brain. Disruption of NMDA receptor-mediated signaling by noncompetitive antagonists, such as PCP or ketamine, evokes psychotomimetic behaviors, although the cellular mechanisms by which hypofunctional NMDA receptor signaling drives behavioral pathology are still unclear. Activation of glycogen synthase kinase-3 (GSK-3) has been implicated in the cellular neurotoxicity of NMDA receptor antagonists. Accordingly, in the present study we examined the ability of GSK-3 inhibitors, SB216763 and 1-azakenpaullone, to reverse the behavioral aberrations induced by ketamine. Male NMRI mice received intracerebroventricular (i.c.v.) injection of the GSK-3 inhibitors, SB216763 and 1-azakenpaullone, 5 min prior to ketamine administration. Locomotor activity, rotarod performance, prepulse inhibition, novel object recognition, and duration of loss of righting reflex were monitored. GSK-3 inhibitors attenuated ketamine-induced locomotor hyperactivity, motor incoordination, sensorimotor impairment, and cognitive deficits, but did not affect ketamine anesthesia. These data support an important role of GSK-3 in the expression of behavioral aberrations associated with NMDA receptor hypofunction, and suggest that GSK-3 inhibitors may ameliorate certain behavioral and cognitive dysfunctions in patients with schizophrenia.
Department of Pharmacology, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 970, Taiwan.
Ming-Huan
MH
Chan
Pao-Hsiang
PH
Chiu
Chia-Yu
CY
Lin
Hwei-Hsien
HH
Chen
D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001526:Behavioral Symptoms / Q000139:chemically induced*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D007266:Inhibition, Psychological; D007276:Injections, Intraventricular; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D010075:Oxathiins / Q000494:pharmacology; D011571:Psychoacoustics; D021641:Recognition, Psychology / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D008301:Maleimides; D010075:Oxathiins; C417521:SB 216763; C024532:1-azaphenoxathiin; D007649:Ketamine; D038362:Glycogen Synthase Kinase 3