Neurochemical and molecular characterization of ketamine-induced experimental psychosis model in mice.
Ketamine, an NMDA receptor antagonist has been shown to induce aberrant behaviour phenotypes in rodents, some of which are known to simulate the behaviour abnormalities observed in patients suffering from schizophrenia. Thus, developing ketamine-induced animal models became an important tool of choice to study the mechanistic details of some critical symptoms associated with schizophrenia. In this study, our goal was to characterize and correlate the ketamine-induced changes in the behavioural phenotypes to the changes in neurochemical and molecular profile(s) in the brain tissues implicated in the pathophysiology of schizophrenia. We studied the effects of ketamine in mice using 'acute' and 'chronic' treatment regimens along with the 'drug withdrawal' effects on their biochemical and molecular parameters in the pre-frontal cortex, hippocampus, and striatum. Our results demonstrated that the acute and chronic ketamine administration, differentially and site specifically, modulated the levels of acetylcholine, dopamine, serotonin and noradrenaline. In addition, the chronic ketamine doses dramatically suppressed the levels of glycine among some of the amino acids examined and induced alternations in gene expression of the key neurotransmitter receptor systems, including some members of the dopamine and the serotonin receptor families. The acute and chronic ketamine treatment induced "signature" neurochemical and gene-expression patterns that are implicated in the pathophysiology of schizophrenia. Our analyses tend to support the "chronic ketamine" mice model for experimental psychosis as a tool for deeper investigation of the mechanistic paradigm associated with the schizophrenia spectrum disorder and for screening next-generation antipsychotic drugs.
Division of Pharmacology, Central Drug Research Institute, Lucknow - 226001, Uttar Pradesh, India.
Manavi
M
Chatterjee
Rajkumar
R
Verma
Surajit
S
Ganguly
Gautam
G
Palit
D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D015415:Biomarkers; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D008297:Male; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011605:Psychoses, Substance-Induced / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000235:genetics
D000596:Amino Acids; D015306:Biogenic Monoamines; D015415:Biomarkers; D017931:DNA Primers; D018691:Excitatory Amino Acid Antagonists; D009573:Nitrites; D011978:Receptors, Nicotinic; D012313:RNA; D007649:Ketamine; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase; D000109:Acetylcholine