Mood stabilizer lithium inhibits amphetamine-increased 4-hydroxynonenal-protein adducts in rat frontal cortex

Recent studies indicate that bipolar disorder is associated with mitochondrial dysfunction and oxidative stress. Previous studies in our laboratory have shown that the mood stabilizer lithium inhibits oxidative stress. The alpha,beta-unsaturated aldehyde 4-hydroxy-2-nonenal (4-HNE), a major product of lipid peroxidation, is able to exert cytotoxicity and disturb cellular function by forming protein adducts. The purpose of this study is to determine whether chronic lithium treatment prevents 4-HNE-protein adduction in an amphetamine-induced hyperactive mania-like model. We found that repeated amphetamine stimulation significantly induced hyperactive behaviour, decreased activities of mitochondrial complexes I and III, and increased 4-HNE-protein adducts in rat frontal cortex, and that chronic lithium treatment inhibited both amphetamine-induced hyperactivity and 4-HNE-protein adduction. Monoamine neurotransmitters are involved in the aetiology and pathology of bipolar disorder and other psychiatric diseases, and also contribute significantly to amphetamine-induced behavioural effects. Vesicular monoamine transporter 2 (VMAT2) is critical in packaging monoamine neurotransmitters. We found that 4-HNE can form protein adducts with VMAT2. Repeated amphetamine stimulation significantly increased 4-HNE-VMAT2 adducts, while chronic lithium treatment reduced amphetamine-increased 4-HNE-VMAT2 adducts in rat frontal cortex. Our findings suggest that chronic lithium treatment may inhibit amphetamine-induced hyperactive mania-like behaviour by preventing 4-HNE-VMAT2 adduction. This finding also indicates that prevention of 4-HNE-VMAT2 adduction may contribute in part to the pharmacological action of lithium for the treatment of bipolar disorder.