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Inhibition of glycogen synthase kinase-3 attenuates psychotomimetic effects of ketamine.
- Source :
-
Schizophrenia research [Schizophr Res] 2012 Apr; Vol. 136 (1-3), pp. 96-103. Date of Electronic Publication: 2012 Feb 09. - Publication Year :
- 2012
-
Abstract
- 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.<br /> (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Subjects :
- Acoustic Stimulation
Analysis of Variance
Animals
Behavior, Animal drug effects
Brain enzymology
Dose-Response Relationship, Drug
Drug Interactions
Glycogen Synthase Kinase 3 antagonists & inhibitors
Indoles pharmacology
Inhibition, Psychological
Injections, Intraventricular
Male
Maleimides pharmacology
Mice
Mice, Inbred ICR
Motor Activity drug effects
Oxathiins pharmacology
Psychoacoustics
Recognition, Psychology drug effects
Reflex, Startle drug effects
Behavioral Symptoms chemically induced
Brain drug effects
Excitatory Amino Acid Antagonists pharmacology
Glycogen Synthase Kinase 3 metabolism
Ketamine pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1573-2509
- Volume :
- 136
- Issue :
- 1-3
- Database :
- MEDLINE
- Journal :
- Schizophrenia research
- Publication Type :
- Academic Journal
- Accession number :
- 22325078
- Full Text :
- https://doi.org/10.1016/j.schres.2012.01.024