Social isolation rearing in rats alters plasma tryptophan metabolism and is reversed by sub-chronic clozapine treatment
Date
2012Author
Möller, Marisa
Du Preez, Jan L.
Harvey, Brian H.
Emsley, Robin
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Show full item recordAbstract
Schizophrenia is associated with increased oxidative stress, although the source of this redox disequilibrium
requires further study. Altered tryptophan metabolism has been described in schizophrenia,
possibly linked to inflammation and glutamate-directed excitotoxicity. Social isolation rearing (SIR) in
rats induces various behavioural manifestations akin to schizophrenia, as well as altered frontal cortical
glutamate N-methyl-D-aspartate (NMDA) receptor binding and increased oxidative stress, all reversed by
antipsychotic treatment. Tryptophan is catabolized via the kynurenine pathway to kynurenine, 3-
hydroxykynurenine, quinolinic acid (QA), kynurenic acid (KYNA), anthranilic acid and 3-
hydroxyanthranilic acid (3-OHAA), ultimately contributing to neuronal integrity and redox balance in
the brain. We studied tryptophan metabolism and neuroprotective-neurodegenerative balance in postnatal
SIR rats, and its response to clozapine treatment. Male Sprague-Dawley (SD) rats (10 rats/group)
were exposed to SIR or social rearing for 8 weeks, whereupon they received either sub-chronic vehicle or
clozapine (5 mg/kg i.p) treatment. Plasma tryptophan metabolites were analysed by liquidchromatography
electrospray ionization tandem mass spectrometry. Plasma tryptophan, kynurenine,
anthranilic acid, 3-OHAA and QA were significantly elevated in SIR vs. socially housed rats. KYNA and the
neuroprotective ratio were significantly decreased. The latter implies a decrease in KYNA (neuroprotective)
but an increase in QA (neurodegenerative) directed components of the pathway. Clozapine
significantly reversed all the above alterations in SIR animals. Concluding, SIR in rats significantly
disrupts tryptophan metabolism via the kynurenine pathway with increased risk for neurodegenerative
changes in the brain. These changes are reversed by clozapine, emphasising the importance of these
findings for the neurobiology and treatment of schizophrenia
URI
http://hdl.handle.net/10394/17369https://www.sciencedirect.com/science/article/pii/S0028390812000822
https://doi.org/10.1016/j.neuropharm.2012.02.021
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