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

Abstract

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 upregulated AA metabolic cascade was reported in postmortem brains from bipolar disorder patients. Here 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 (170 µCi/kg) was infused intravenously for 5 min, and timed arterial blood samples were taken. After the rat was euthanized 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 upregulated 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.

Fatty acid composition of the postmortem prefrontal cortex of patients with schizophrenia, bipolar disorder, and major depressive disorder

“…At present, not much is known about this fatty acid in relation to the pathology of psychosis, and studies are therefore required. Antipsychotic medication has been shown to exert effects on PUFA metabolism in animal studies (Cheon et al, 2011;Modi et al, 2013), an observational study (Khan et al, 2002), and a clinical study (Evans et al, 2003). In the latter it was demonstrated that 6 months of antipsychotic treatment in first-episode psychotic patients normalized peripheral DHA levels.…”

Effects of olanzapine on LPS-induced inflammation in rat primary glia cells

“…These findings are in line with previous reports in which OLZ was found to exert both anti-and pro-inflammatory effects. 10,26,32,[38][39][40]73 In this study we used two concentrations of OLZ: 1 and 50 mM. Unlike most of the drugs used for prophylactic treatment in schizophrenia and bipolar disorder, OLZ is a drug whose plasma concentration is not routinely monitored in treated patients.…”

Glycogen Synthase Kinase-3β: Variation over Time and the Possible Association with Mood and Cognition in Healthy Individuals

“…Verbal memory was investigated using the Rey Auditory Verbal Learning Test (RAVLT) [38,39], assessing total recall across five learning trials, immediate recall following a distractor list, 30-min delayed recall and recognition. Executive function was assessed with the Trail Making Test (TMT) part B, the Wechsler Adult Intelligence Scale-III (WAIS-III) letter-number sequencing test [40], the Repeatable Battery of the Assessment of Neuropsychological Status (RBANS) digit span test [41] and the Spatial Working Memory (SWM) from the Cambridge Neuropsychological Test Automated Battery (CANTAB; using the variables ‘between-search errors' and ‘strategy').…”