Social isolation rearing in rats alters plasma tryptophan metabolism and is reversed by sub-chronic clozapine treatment

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 post-natal 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 liquid-chromatography 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.

► Isolation rearing elevates tryptophan, intermediate metabolites and quinolinic acid.
► Isolation rearing reduces kynurenic acid and lowers the neuroprotective ratio.
► Clozapine reversed all isolation rearing-induced changes in tryptophan metabolism.
► These findings expand on the construct and predictive validity of isolation rearing.
► These findings provide new insight into the biology and treatment of schizophrenia.