Differential effects of antipsychotic medications on polyunsaturated fatty acid biosynthesis in rats: Relationship with liver delta6-desaturase expression

Polyunsaturated fatty acids (PUFA), a lipid family comprised of omega-3 (n− 3) and n− 6 fatty acids, are a critical component of cellular membranes, and recent in vitro studies have found that antipsychotic medications up-regulate genes responsible for PUFA biosynthesis. To evaluate this effect in vivo, rats were treated with risperidone (1.5, 3, 6 mg/kg/day), paliperidone (1.5, 3, 6 mg/kg/day), olanzapine (2.5, 5, 10 mg/kg/day), quetiapine (5, 10, 20 mg/kg/day), haloperidol (1, 3 mg/kg/day) or vehicle through their drinking water for 40 day. Effects on liver Fads1, Fads2, Elovl2, and Elovl5 mRNA expression, plasma indices of n− 3 (plasma 22:6/18:3 and 20:5/18:3 ratios) and n− 6 (plasma 20:4/18:2 and 20:3/18:2 ratios) biosynthesis, and peripheral (erythrocyte, heart) and central (frontal cortex) membrane PUFA composition were determined. Only risperidone and its metabolite paliperidone significantly and selectively up-regulated liver delta-6 desaturase (Fads2) mRNA expression, and robustly increased plasma indices of n− 3 and n− 6 fatty acid biosynthesis. In risperidone- and paliperidone-treated rats, plasma indices of n− 3 and n− 6 fatty acid biosynthesis were all positively correlated with liver Fads2 mRNA expression, but not Fads1, Elovl2, or Elovl5 mRNA expression. All antipsychotics at specific doses increased erythrocyte docosahexaenoic acid (DHA, 22:6n− 3) composition, and all except quetiapine increased arachidonic acid (AA, 20:4n− 6) composition. Risperidone, paliperidone, and olanzapine increased heart DHA and AA composition, and no antipsychotic altered frontal cortex DHA or AA composition. These in vivo data demonstrate that augmentation of PUFA biosynthesis is not common to all antipsychotic medications, and that risperidone and paliperidone uniquely increase delta-6 desaturase (Fads2) mRNA expression and most robustly increase PUFA biosynthesis and peripheral membrane composition.