Mood stabilizer lithium inhibits amphetamine-increased 4-hydroxynonenal-protein adducts in rat frontal cortex
Open accessAbstract
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 α,β-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.
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Oxidative stress metabolism appears to have important implications in the evolution of replicated affective disorder aspects in animal models.
“oxidative stress metabolism appears to have important implications in the evolution of replicated affective disorders aspects in animal models [94]”
From Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches (2016) · cites this paper as [94]
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Balmus, I. M., Ciobica, A., Antioch, I., Dobrin, R., & Timofte, D. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/3975101 · Cited by 103 · see citing works
“Bipolar disorder Manic phase, induced with amphetamine Brain: ↑ SOD production; ↑ TBARS [90] ↑ protein and lipid oxidative damage [91] ↓ SOD: ↓ CAT specific activity [92] ↑ lipid peroxidation [93] ↑ protein aggregation of 4-HNE (a major product of lipid peroxidation) [94]”
BackgroundDeline, M. L., Straub, J., Patel, M., Subba, P., Grashei, M., van Heijster, F. H. A., Pirkwieser, P., Somoza, V., Livingstone, J. D., Beazely, M., et al. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1200119 · Cited by 8 · see citing works
- Authors
- Tan, H., Young, L. T., Shao, L., Che, Y., Honer, W. G., & Wang, J.-F.
- Affiliations
- University of British Columbia (CA)
- University of Toronto (CA)
- Venue
- The International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-09-23
- Volume
- 15
- Issue
- 09
- Pages
- 1275-1285
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- OpenAlex
- W2119341005
- Cited by
- 40
- References
- 61
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 6 · 2017: 1 · 2016: 4 · 2015: 6 · 2014: 1 · 2013: 6 · 2012: 4
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- AstraZeneca
- National Alliance for Research on Schizophrenia and Depression
- Canadian Institutes of Health Research
- Division of Chemistry
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- lithium, 4-hydroxynonenal, protein adducts, amphetamine-induced hyperactivity, bipolar disorder, oxidative stress, mitochondrial dysfunction, mitochondrial complex I, mitochondrial complex III, vesicular monoamine transporter 2, lipid peroxidation, frontal cortex, monoamines
- MeSH terms
- Aldehydes, Amphetamine, Central Nervous System Stimulants, Animals, Bipolar Disorder, Immunohistochemistry, Lithium, Male, Motor Activity, Nerve Tissue Proteins, Electron Transport Complex III, Blotting, Western, Rats, Sprague-Dawley, Prefrontal Cortex, Antimanic Agents, Electron Transport Complex I, Immunoprecipitation, Vesicular Monoamine Transport Proteins, Rats
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