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

• Published in: Journal of neurochemistry Vol. 124; no. 3; pp. 376 - 387
• Main Authors: Modi, Hiren R., Taha, Ameer Y., Kim, Hyung‐Wook, Chang, Lisa, Rapoport, Stanley I., Cheon, Yewon
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.02.2013
• Subjects: Animals; antipsychotic; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - blood; Antipsychotic Agents - pharmacokinetics; arachidonic acid; Arachidonic Acid - antagonists & inhibitors; Arachidonic Acid - blood; Arachidonic Acid - metabolism; bipolar disorder; Brain - drug effects; Brain - metabolism; clozapine; Clozapine - administration & dosage; Clozapine - blood; Clozapine - pharmacokinetics; Down-Regulation - genetics; Male; Metabolism; Neurochemistry; Pharmacology; phospholipid; Psychotropic drugs; rat brain; Rats; Rats, Inbred F344; Rodents; Schizophrenia
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12078

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 ki * 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. The atypical antipsychotic clozapine, like olanzapine, downregulates rat brain arachidonic acid (AA) metabolism (cyclooxygenase activity and PGE2 concentration) by reducing plasma unesterified AA concentration and AA incorporation rate Jin into brain phospholipids. Brain AA incorporation coefficient k* (uptake affinity) is increased. Thus two atypical antipsychotics, like mood stabilizers, may act in bipolar disorder by dampening its upregulated brain AA metabolism.