title: Chronic clozapine reduces rat brain arachidonic acid metabolism by reducing plasma arachidonic acid availability.
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 E(2) 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-(14) C]AA was infused intravenously for 5 min, arterial plasma was collected and high-energy microwaved brain was analyzed. CLZ increased incorporation coefficients ki * and decreased [corrected] rates J(in,i) of plasma unesterified AA into brain phospholipids. [corrected]. 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.
authors.affiliation: Brain Physiology and Metabolism Section, National Institute on Aging, Laboratory of Neurosciences, National Institutes of Health, Bethesda, MD 20892, USA. modihr@mail.nih.gov
authors.forename: Hiren R
authors.initials: HR
authors.lastname: Modi
authors.forename: Ameer Y
authors.initials: AY
authors.lastname: Taha
authors.forename: Hyung-Wook
authors.initials: HW
authors.lastname: Kim
authors.forename: Lisa
authors.initials: L
authors.lastname: Chang
authors.forename: Stanley I
authors.initials: SI
authors.lastname: Rapoport
authors.forename: Yewon
authors.initials: Y
authors.lastname: Cheon
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000097:blood* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003024:Clozapine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D015536:Down-Regulation / Q000235:genetics; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D014150:Antipsychotic Agents; D016718:Arachidonic Acid; D003024:Clozapine