IntroductionBipolar disorder (BD) is characterized by recurrent episodes of mania/hypomania and depression, affects 1.5% of the population, and is associated with high morbidity and mortality. 1 The pathophysiology of BD is linked to a number of factors, including neurotransmitter imbalance, oxidative stress and genetic causes.2 Increased oxidative stress, which could result in oxidative and nitrosative damage to biomolecules, 3 is a consistent finding in patients with BD. For example, mitochondrial dysfunction and decreased expression of genes of the electron transport chain, particularly that of complex I, are reported in patients with BD. 4,5 Decreased efficiency of the electron transport chain could result in increased production of reactive oxygen species (ROS).3 Moreover, increased levels of carbonyl groups, 3-nitrotyrosine (3NT) and decreased levels of antioxidants, such as glutathione, are all reported in patients with BD. [6][7][8][9] It is widely held that dysregulation of the dopamine (DA) system is important in BD, where high levels of DA are thought to underlie mania, a defining feature of the disorder.10 Increasing synaptic DA levels with amphetamine and Levodopa (L-dopa) produces mania-like behaviour, 10,11 and antipsychotics, which act in part by blocking DA receptors, Background: Increased oxidative stress is strongly implicated in bipolar disorder (BD), where protein oxidation, lipid peroxidation and oxidative damage to DNA have been consistently reported. High levels of dopamine (DA) in mania are also well-recognized in patients with BD, and DA produces reactive oxygen species and electron-deficient quinones that can oxidize proteins when it is metabolized. Methods: Using immunohistochemistry and acceptor photobleaching Förster resonance energy transfer (FRET), we examined oxidation and nitration of areas immunoreactive for the DA transporter (DAT) and tyrosine hydroxylase (TH) in the postmortem prefrontal cortex from patients with BD, schizophrenia and major depression as well as nonpsychiatric controls. Results: We found increased oxidation of DAT-immunoreactive regions in patients with BD (F 3,48 = 6.76, p = 0.001; Dunnett post hoc test p = 0.001) and decreased nitration of THimmunoreactive regions in both patients with BD (F 3,45 = 3.10, p = 0.036; Dunnett post hoc test p = 0.011) and schizophrenia (p = 0.027). On the other hand, we found increased global levels of oxidation in patients with BD (F 3,44 = 6.74, p = 0.001; Dunnett post hoc test p = 0.001) and schizophrenia (p = 0.020), although nitration levels did not differ between the groups (F 3,46 = 1.75; p = 0.17). Limitations: Limitations of this study include the use of postmortem brain sections, which may have been affected by factors such as postmortem inter val and antemortem agonal states, although demographic factors and postmortem interval were accounted for in our statistical analysis. Conclusion: These findings suggest alterations in levels of protein oxidation and nitration in DA-rich regions of the prefrontal cortex in pati...

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Chronic N-methyl-d-aspartate (NMDA) administration to rats may be a model to investigate excitotoxicity mediated by glutamatergic hyperactivity, and lithium has been reported to be neuroprotective. We hypothesized that glutamatergic hyperactivity in chronic NMDA injected rats would cause mitochondrial dysfunction and lipid peroxidation in the brain, and that chronic lithium treatment would ameliorate some of these NMDA-induced alterations. Rats treated with lithium for 6 weeks were injected i.p. 25 mg/kg NMDA on a daily basis for the last 21 days of lithium treatment. Brain was removed and frontal cortex was analyzed. Chronic NMDA decreased brain levels of mitochondrial complex I and III, and increased levels of the lipid oxidation products, 8-isoprostane and 4-hydroxynonenal, compared with non-NMDA injected rats. Lithium treatment prevented the NMDA-induced increments in 8-isoprostane and 4-hydroxynonenal. Our findings suggest that increased chronic activation of NMDA receptors can induce alterations in electron transport chain complexes I and III and in lipid peroxidation in brain. The NMDA-induced changes may contribute to glutamate-mediated excitotoxicity, which plays a role in brain diseases such as bipolar disorder. Lithium treatment prevented changes in 8-isoprostane and 4-hydroxynonenal, which may contribute to lithium's reported neuroprotective effect and efficacy in bipolar disorder.