Chronic clozapine reduces rat brain arachidonic acid metabolism by reducing plasma arachidonic acid availability

Authors

  • Hiren R. Modi,

    Corresponding author
    • Brain Physiology and Metabolism Section, National Institute on Aging, Laboratory of Neurosciences, National Institutes of Health, Bethesda, Maryland, USA
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    • Both authors contributed equally to this article.
  • Ameer Y. Taha,

    1. Brain Physiology and Metabolism Section, National Institute on Aging, Laboratory of Neurosciences, National Institutes of Health, Bethesda, Maryland, USA
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  • Hyung-Wook Kim,

    1. Brain Physiology and Metabolism Section, National Institute on Aging, Laboratory of Neurosciences, National Institutes of Health, Bethesda, Maryland, USA
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  • Lisa Chang,

    1. Brain Physiology and Metabolism Section, National Institute on Aging, Laboratory of Neurosciences, National Institutes of Health, Bethesda, Maryland, USA
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  • Stanley I. Rapoport,

    1. Brain Physiology and Metabolism Section, National Institute on Aging, Laboratory of Neurosciences, National Institutes of Health, Bethesda, Maryland, USA
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  • Yewon Cheon

    1. Brain Physiology and Metabolism Section, National Institute on Aging, Laboratory of Neurosciences, National Institutes of Health, Bethesda, Maryland, USA
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    • Both authors contributed equally to this article.

Errata

This article is corrected by:

  1. Errata: Corrigendum Volume 125, Issue 3, 486, Article first published online: 21 April 2013

Address correspondence and reprint requests to Hiren R. Modi, Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, 9000 Rockville Pike, Bldg. 9, 1S126, Bethesda, MD 20892, USA. E-mail: modihr@mail.nih.gov

Abstract

Chronic administration of mood stabilizers to rats down-regulates the brain arachidonic acid (AA) cascade. This down-regulation may explain their efficacy against bipolar disorder (BD), in which brain AA cascade markers are elevated. The atypical antipsychotics, olanzapine (OLZ) and clozapine (CLZ), also act against BD. When given to rats, both reduce brain cyclooxygenase activity and prostaglandin E2 concentration; OLZ also reduces rat plasma unesterified and esterified AA concentrations, and AA incorporation and turnover in brain phospholipid. To test whether CLZ produces similar changes, we used our in vivo fatty acid method in rats given 10 mg/kg/day i.p. CLZ, or vehicle, for 30 days; or 1 day after CLZ washout. [1-14C]AA was infused intravenously for 5 min, arterial plasma was collected and high-energy microwaved brain was analyzed. CLZ increased incorporation coefficients inline image and rates Jin,i of plasma unesterified AA into brain phospholipids i, while decreasing plasma unesterified but not esterified AA. These effects disappeared after washout. Thus, CLZ and OLZ similarly down-regulated kinetics and cyclooxygenase expression of the brain AA cascade, likely by reducing plasma unesterified AA availability. Atypical antipsychotics and mood stabilizers may be therapeutic in BD by down-regulating, indirectly or directly respectively, the elevated brain AA cascade of that disease.

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