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Chronic lamotrigine does not alter the turnover of arachidonic acid within brain phospholipids of the unanesthetized rat: implications for the treatment of bipolar disorder

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Abstract

Rationale

Drugs that are effective in treating the manic phase of bipolar disorder (lithium, carbamazepine, and valproate) upon chronic administration to rats decrease the turnover of arachidonic acid in their brain phospholipids. Lamotrigine may not be effective in the manic phase, but is effective in delaying the depressive phase and for treating rapid cycling bipolar disorder. Thus, lamotrigine provides a pharmacological tool to differentiate if downregulation of arachidonic acid turnover is specific to drugs effective in the manic phase of bipolar disorder.

Materials and methods

To test this hypothesis, rats were administered lamotrigine (10 mg kg−1 day−1) or vehicle intragastrically once daily for 42 days. In the unanesthetized rat, [1-14C]arachidonic acid was infused intravenously and arterial blood plasma was sampled until the animal was killed at 5 min, and its microwaved brain was subjected to chemical and radiotracer analysis.

Results

Using equations from our fatty acid model, we found that chronic lamotrigine compared with vehicle did not alter the net incorporation rate of plasma arachidonic acid into brain phospholipids, nor did it alter the turnover of arachidonic acid within brain phospholipids.

Conclusion

Chronic lamotrigine, which is effective in the depressive phase or rapid cycling bipolar disorder does not alter brain arachidonic acid turnover in the unanesthetized rat. These results are consistent with the hypothesis that drugs effective in treating the manic phase of bipolar disorder decrease brain arachidonic acid turnover.

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Abbreviations

cPLA2 :

calcium-dependent cytosolic phospholipase A2

5-HT:

serotonin

sn:

stereospecifically numbered

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Acknowledgment

We would like to thank Dr. Bjornar Hassel for his valuable comments on the study design. This work was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

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Authors and Affiliations

  1. Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA

    Ho-Joo Lee, Jagadeesh S. Rao, Lisa Chang, Stanley I. Rapoport & Richard P. Bazinet

  2. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, FitzGerald Building, 150 College St., Room 306, Toronto, ON, M5S 3E2, Canada

    Richard P. Bazinet

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  1. Ho-Joo Lee
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  2. Jagadeesh S. Rao
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  3. Lisa Chang
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  4. Stanley I. Rapoport
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  5. Richard P. Bazinet
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Correspondence to Richard P. Bazinet.

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Lee, HJ., Rao, J.S., Chang, L. et al. Chronic lamotrigine does not alter the turnover of arachidonic acid within brain phospholipids of the unanesthetized rat: implications for the treatment of bipolar disorder. Psychopharmacology 193, 467–474 (2007). https://doi.org/10.1007/s00213-007-0803-2

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