Chronic valproate does not alter the kinetics of docosahexaenoic acid within brain phospholipids of the unanesthetized rat

Abstract

It has been reported that each of three drugs effective in treating bipolar disorder (lithium, carbamazepine, and valproate) decreases the turnover of arachidonic acid (AA, 20:4n-6) in brain phospholipids of the awake rat. It is also known that lithium and carbamazepine do so without decreasing the turnover of docosahexaenoic acid (DHA, 22:6n-3). The aim of this study was to see whether valproate also specifically targets the turnover of AA but not of DHA in brain phospholipids. Valproate was administered (200 mg kg(-1), i.p.) to rats for 30 days to produce a therapeutically relevant plasma concentration and then determine its effect compared with that of vehicle on incorporation and turnover rates of DHA in brain phospholipids. In unanesthetized rats that had received valproate or vehicle, [1-14C]DHA was infused intravenously, and arterial blood plasma was sampled until the animal was killed at 5 min; and its brain, after being microwaved, was subjected to chemical and radiotracer analysis. Using equations derived from our fatty acid model, it was found that chronic valproate compared with vehicle did not alter the rate of incorporation or turnover of DHA in brain phospholipids. Valproate-treated animals had higher concentrations of linoleic acid (18:2n-6) in several brain phospholipids, supporting the hypothesis that it alters brain n-6 fatty acid metabolism. The results, comparable to published findings following chronic administration of lithium and carbamazepine to rats, support the hypothesis that drugs are effective against mania in bipolar disorder act by downregulating incorporation and turnover of AA, but not of DHA, in brain phospholipids.