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Regional brain dysregulation of Ca(2+)-handling systems in ketamine-induced rat model of experimental psychosis.

ABSTRACT: Chronic N-methyl-D-aspartate receptor (NMDAR) antagonist treatment can provide valuable neurochemical and neuroanatomical models of experimental psychosis. One such antagonist, ketamine, with its short half-time and well-documented psychotomimetic action, has cognitive effects resembling various aspects of schizophrenia-like symptoms. In order to obtain insights into possible relationships between Ca(2+) homeostasis and schizophrenia-related symptoms, we investigate the effects of chronic ketamine administration on intracellular Ca(2+) levels in various brain regions and on the expression level of key members of the neuronal Ca(2+)-handling system in rats. We show increased intracellular [Ca(2+)] in all of the examined brain regions following ketamine treatment but an altered cytosolic Ca(2+) level correlated with hyperlocomotor activity was only established for the cortex and striatum. Our findings also suggest that an imbalance in the expression between the calcium "on" and "off" systems contributes to the deregulation of brain Ca(2+) homeostasis in our ketamine-induced model of experimental psychosis. Identification of the genes whose expression is affected by ketamine treatment indicates their involvement as putative etiological factors in schizophrenia.

SUBMITTER: Lisek M

PROVIDER: S-EPMC4761010 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Regional brain dysregulation of Ca(2+)-handling systems in ketamine-induced rat model of experimental psychosis.

Lisek Malwina M Boczek Tomasz T Ferenc Bozena B Zylinska Ludmila L

Cell and tissue research 20151221 3

Chronic N-methyl-D-aspartate receptor (NMDAR) antagonist treatment can provide valuable neurochemical and neuroanatomical models of experimental psychosis. One such antagonist, ketamine, with its short half-time and well-documented psychotomimetic action, has cognitive effects resembling various aspects of schizophrenia-like symptoms. In order to obtain insights into possible relationships between Ca(2+) homeostasis and schizophrenia-related symptoms, we investigate the effects of chronic ketami ...[more]

PMID: 26685921

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Project description:BackgroundStatus epilepticus (SE) is an acute, prolonged epileptic crisis with a mortality rate of 20-30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant action.Methodology/principal findingsIn a clinically relevant experimental model of temporal lobe SE (TLSE) using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47(phox) subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB), angiotensin AT1 receptor subtype (AT1R), nitric oxide synthase II (NOS II) or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol), a specific antagonist of NADPH oxidase (apocynin) or an AT1R antagonist (losartan) blunted significantly the augmented superoxide anion or phosphorylated p47(phox) subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdnf oligonucleotide significantly potentiated all those events, alongside peroxynitrite. However, none of the pretreatments affected the insignificant changes in heart rate and baroreflex-mediated cardiac responses.Conclusions/significanceWe conclude that formation of peroxynitrite by a reaction between superoxide anion generated by NADPH oxidase in RVLM on activation by AT1R and NOS II-derived NO leads to a reduction in baroreflex-mediated sympathetic vasomotor tone during experimental TLSE; to be ameliorated by the upregulated BDNF/TrkB signaling via inhibition of p47(phox) phosphorylation. This information offers a new vista in devising therapeutic strategy towards minimizing mortality associated with TLSE.

Dataset Information

Regional brain dysregulation of Ca(2+)-handling systems in ketamine-induced rat model of experimental psychosis.

Publications

Regional brain dysregulation of Ca(2+)-handling systems in ketamine-induced rat model of experimental psychosis.

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