Abstract
Oxidative stress is thought to be involved in the development of behavioral and histopathological alterations in animal models of psychosis. Here we investigate the causal contribution of reactive oxygen species generation by the phagocyte NADPH oxidase NOX2 to neuropathological alterations in a rat model of chronic psychosocial stress. In rats exposed to social isolation, the earliest neuropathological alterations were signs of oxidative stress and appearance of NOX2. Alterations in behavior, increase in glutamate levels and loss of parvalbumin were detectable after 4 weeks of social isolation. The expression of the NOX2 subunit p47phox was markedly increased in pyramidal neurons of isolated rats, but below detection threshold in GABAergic neurons, astrocytes and microglia. Rats with a loss of function mutation in the NOX2 subunit p47phox were protected from behavioral and neuropathological alterations induced by social isolation. To test reversibility, we applied the antioxidant/NOX inhibitor apocynin after initiation of social isolation for a time period of 3 weeks. Apocynin reversed behavioral alterations fully when applied after 4 weeks of social isolation, but only partially after 7 weeks. Our results demonstrate that social isolation induces rapid elevations of the NOX2 complex in the brain. Expression of the enzyme complex was strongest in pyramidal neurons and a loss of function mutation prevented neuropathology induced by social isolation. Finally, at least at early stages, pharmacological targeting of NOX2 activity might reverse behavioral alterations.
Highlights
To define the time course of behavioral alterations induced by social isolation, we isolated rats for 2, 4 or 7 weeks
We focused on behavioral functions that are regulated by nucleus accumbens and prefrontal cortex, such as spontaneous locomotor activity and novel object discrimination
Results from the open field test showed no significant difference in locomotor activity between control and isolated rats after 2 weeks of social isolation (Figure 1a)
Summary
There is increasing evidence that psychosocial stress leads to oxidative stress in the brain, thereby contributing to the development of mental disorders such as anxiety and psychosis. Data from psychotic patients have shown a key role of oxidative stress in the pathogenesis of mental disorders (reviewed in Yao and Ravinder2).NOX enzymes are proteins that transfer electrons across biological membranes to catalyze the reduction of molecular oxygen and generate the superoxide anion O2À.3 In the central nervous system, NOX isoforms are heterogeneously distributed in different regions and cell types, and thought to be involved in redox regulation of cell fate and neuronal activity. From a pathological point of view, NOX enzymes have been implicated in the generation of oxidative stress seen in a variety of brain disorders, from psychiatric to neurodegenerative diseases.4Some progress in the understanding of the mechanistic link between oxidative stress and psychiatric diseases has come from animal models. There is increasing evidence that psychosocial stress leads to oxidative stress in the brain, thereby contributing to the development of mental disorders such as anxiety and psychosis.. Data from psychotic patients have shown a key role of oxidative stress in the pathogenesis of mental disorders (reviewed in Yao and Ravinder). NOX enzymes are proteins that transfer electrons across biological membranes to catalyze the reduction of molecular oxygen and generate the superoxide anion O2À.3. From a pathological point of view, NOX enzymes have been implicated in the generation of oxidative stress seen in a variety of brain disorders, from psychiatric to neurodegenerative diseases.. Some progress in the understanding of the mechanistic link between oxidative stress and psychiatric diseases has come from animal models. In the ketamine-induced model of psychosis, we and others have previously shown that
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
