Both authors contributed equally to this article.
Chronic clozapine reduces rat brain arachidonic acid metabolism by reducing plasma arachidonic acid availability
Article first published online: 6 DEC 2012
Published 2012. This article is a U.S. Government work and is in the public domain in the USA.
Journal of Neurochemistry
Volume 124, Issue 3, pages 376–387, February 2013
How to Cite
J. Neurochem.(2012) 10.1111/jnc.12078
- Issue published online: 7 JAN 2013
- Article first published online: 6 DEC 2012
- Accepted manuscript online: 1 NOV 2012 09:50AM EST
- Manuscript Accepted: 29 OCT 2012
- Manuscript Revised: 12 OCT 2012
- Manuscript Received: 26 JUL 2012
- Research Program of the National Institute on Aging
Vol. 125, Issue 3, 486, Article first published online: 21 APR 2013
- arachidonic acid;
- bipolar disorder;
- rat brain;
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 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.