Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N-acetyl cysteine
Date
2013Author
Möller, Marisa
Du Preez, Jan L.
Viljoen, Francois P.
Harvey, Brian H.
Berk, Michael
Emsley, Robin
Metadata
Show full item recordAbstract
Apart from altered dopamine (DA) function, schizophrenia displays mitochondrial and immune-inflammatory
abnormalities, evidenced by oxidative stress, altered kynure nine metaboli sm and cytokine
release . N-acetyl cysteine (NAC), an antioxidant and glutamate modulator, is effective in the adjunctive
treatment of schizophrenia. Social isolation rearing (SIR) in rats is a valid neurodevelopmental animal
model of schizoph renia. This study evaluated whether SIR-induced behavioural deficits may be explained
by altered plasma pro- and anti-inflammatory cytokines, kynurenine metabolism, and cortico-striatal DA
and mitochondrial function (via adenosine triphosphate (ATP) release), and if clozapine or NAC (alone
and in combination) reverses these chan ges. SIR induced pronounced deficits in social interactive behaviours,
object recogni tion memory, and prepulse inhibition (PPI), while simultaneously increasing striatal
but reducing frontal cortical accumulation of ATP as well as DA. SIR increased pro- vs. anti-inflammatory
cytokine balance and altered kynurenine metabolism with a decrease in neuroprotective ratio. Clozapine
(5 mg/kg/day 14 days) as well as clozapine + NAC (5 mg/kg/day and 150 mg/kg/day 14 days)
reversed these changes, with NAC (150 mg/kg/day) alone significantly but partially effective in some
parameters . Clozapine + NAC was more effect ive than clozapine alone in reversing SIR-induced PPI, mitochondrial,
immune and DA changes. In conclusion, SIR induces mitochondrial and immune-inflammatory
changes that underlie cortico-striatal DA perturbations and subsequent behavioural deficits, and
responds to treatment with clozapine or NAC, with an additive effect following combination treatment.
The data provides insight into the mechanisms that might underlie the utility of NAC as an adjunctive
treatment in schizophrenia.
URI
http://hdl.handle.net/10394/14870https://www.sciencedirect.com/science/article/pii/S0889159112005417
https://doi.org/10.1016/j.bbi.2012.12.011
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