Chronic olanzapine treatment decreases arachidonic acid turnover and prostaglandin E₂ concentration in rat brain

Abstract

The atypical antipsychotic, olanzapine (OLZ), is used to treat bipolar disorder, but its therapeutic mechanism of action is not clear. Arachidonic acid (AA, 20:4n-6) plays a critical role in brain signaling and an up-regulated AA metabolic cascade was reported in postmortem brains from bipolar disorder patients. In this study, we tested whether, similar to the action of the mood stabilizers lithium, carbamazepine and valproate, chronic OLZ treatment would reduce AA turnover in rat brain. We administered OLZ (6 mg/kg/day) or vehicle i.p. to male rats once daily for 21 days. A washout group received 21 days of OLZ followed by vehicle on day 22. Two hours after the last injection, [1-¹⁴C]AA was infused intravenously for 5 min, and timed arterial blood samples were taken. After the rat was killed at 5 min, its brain was microwaved, removed and analyzed. Chronic OLZ decreased plasma unesterified AA concentration, AA incorporation rates and AA turnover in brain phospholipids. These effects were absent after washout. Consistent with reduced AA turnover, OLZ decreased brain cyclooxygenase activity and the brain concentration of the proinflammatory AA-derived metabolite, prostaglandin E₂, In view of up-regulated brain AA metabolic markers in bipolar disorder, the abilities of OLZ and the mood stabilizers to commonly decrease prostaglandin E₂, and AA turnover in rat brain phospholipids, albeit by different mechanisms, may be related to their efficacy against the disease.

Figure 1. Time course of arterial plasma radioactivity during 5 minute [1-¹⁴C] AA infusion

Arterial plasma radioactivity (nCi/ml) was measured in total lipid extracts of plasma from control and olanzapine-treated rats during intravenous infusion of 170 µCi/kg [1-¹⁴C] AA over 5 min at a rate of 0.223 (1 + e ^−0.032t) ml/min (t=second). OLZ rats received OLZ (6 mg/kg/day, i.p.), once daily for 21 days and were euthanized 2 hours after the last drug injection. OLZ-W rats received full period of olanzapine followed by a 24-hour washout. A control group received the same volume of vehicle under parallel conditions. Values are mean ± SD (control, n=10; OLZ, n=12; OLZ-W, n=7).