Chronic risperidone treatment preferentially increases rat erythrocyte and prefrontal cortex omega-3 fatty acid composition: Evidence for augmented biosynthesis

Abstract

Prior clinical studies suggest that chronic treatment with atypical antipsychotic medications increase erythrocyte and postmortem prefrontal cortex (PFC) omega-3 fatty acid composition in patients with schizophrenia (SZ). However, because human tissue phospholipid omega-3 fatty acid composition is potentially influenced by multiple extraneous variables, definitive evaluation of this putative mechanism of action requires an animal model. In the present study, we determined the effects of chronic treatment with the atypical antipsychotic risperidone (RISP, 3.0 mg/kg/d) on erythrocyte and PFC omega-3 fatty acid composition in rats maintained on a diet with or without the dietary omega-3 fatty acid precursor, alpha-linolenic acid (ALA, 18:3n-3). Chronic RISP treatment resulted in therapeutically-relevant plasma RISP and 9-OH-RISP concentrations (18±2.6 ng/ml), and significantly increased erythrocyte docosahexaenoic acid (DHA, 22:6n-3, +22%, p=0.0003) and docosapentaenoic acid (22:5n-3, +18%, p=0.01) composition, and increased PFC DHA composition (+7%, p=0.03) in rats maintained on the ALA+ diet. In contrast, chronic RISP did not alter erythrocyte or PFC omega-3 fatty acid composition in rats maintained on the ALA− diet. Chronic RISP treatment did not alter erythrocyte or PFC arachidonic acid (AA, composition. These data demonstrate that chronic RISP treatment significantly augments ALA-DHA biosynthesis, and preferentially increases peripheral and central membrane omega-3 fatty acid composition. Augmented omega-3 fatty acid biosynthesis and membrane composition represents a novel mechanism of action that may contribute in part to the efficacy of RISP in the treatment of SZ.

PPARα-L162V polymorphism is not associated with schizophrenia risk in a Croatian population

“…Increased Δ 6 -desaturase mRNA expression, after chronic exposure to atypical antipsychotic medications, has also been demonstrated in recent in vivo study, performed in rats [35]. Furthermore, chronic treatment with both typical and atypical antipsychotic drugs in rats was found to significantly increase PUFA levels, in RBC membranes, as well as in brain tissue [33,35]. The observed inconsistencies regarding effects of antipsychotic treatment on membrane PUFA profile may be linked to several confounding effects of disease-related factors, such as state of illness, its duration, type of antipsychotic medication, etc.…”

“…Thus, the L162V polymorphic variant could possibly modulate more efficiently the ability of PPARα to induce the activity of enzymes that act in PUFA biosynthesis. Several novel findings indicate the possible influence of PPARα genotype in response to antipsychotic medications [33,34]. In fact, the induction of PUFA biosynthesis enzymes has been attributed to the action of antipsychotic drugs as well [34,35].…”

Effects of Risperidone on Learning and Memory in Naive and MK-801-Treated Rats

“…MK-801 was dissolved in 0.9% physiological saline and RIS was dissolved in saline using a few drops of 1% acetic acid [11] . Drugs were freshly prepared and administered by the intraperitoneal (i.p.)…”

Role of lipase-generated free fatty acids in converting mesenteric lymph from a noncytotoxic to a cytotoxic fluid

“…Lipids in the lymph were extracted using the Folch method, and FFAs were separated from the other lipids by thin-layer chromatography, as described in our previous study (28). Then the FFAs were methylated by boron trifluoride in methanol, extracted with hexane, and analyzed by gas chromatography (25). The gas chromatograph (model GC-2014, Shimadzu Scientific Instruments, Columbia, MD) was equipped with an autoinjector (Shimadzu).…”