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

Abstract

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/d), paliperidone (1.5, 3, 6 mg/kg/d), olanzapine (2.5, 5, 10 mg/kg/d), quetiapine (5, 10, 20 mg/kg/d), haloperidol (1, 3 mg/kg/d) or vehicle through their drinking water for 40 d. Effects on liver Fads1, Fads2, Elovl2, and Elovl5 mRNA expression, plasma indices of n-3 (plasma 22:6/18:3 & 20:5/18:3 ratios) and n-6 (plasma 20:4/18:2 & 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.

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.…”

“…One in vitro study detected that treatment with several typical and atypical antipsychotic medications up-regulate Δ 6 -and Δ 5 -desaturase mRNA expression in human cell lines [34]. 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].…”

“…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]. One in vitro study detected that treatment with several typical and atypical antipsychotic medications up-regulate Δ 6 -and Δ 5 -desaturase mRNA expression in human cell lines [34].…”

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

“…Further studies are needed to determinate whether this antiinflammatory/antioxidant profile may be responsible for the protective effects of paliperidone pretreatment on abnormal rat behavior following exposure to the schizophrenia experimental model based on prenatal immune activation using polyriboinosinic-polyribocytidylic acid during pregnancy in rats [31]. It is important to note that other molecules and pathways could be related to the ability of paliperidone to regulate inflammatory homeostasis, as, for example, is the case of systemic levels of omega-3 polyunsaturated fatty acids, which appeared to be increased in rats chronically treated with risperidone or paliperidone [32].…”

Pathways of polyunsaturated fatty acid utilization: Implications for brain function in neuropsychiatric health and disease

“…Postmortem studies have reported altered expression of genes regulating fatty acid biosynthesis in the prefrontal cortex of patients with schizophrenia (Liu et al, 2009a), major depressive disorder (McNamara and Liu, 2011), bipolar disorder (Liu and McNamara, 2011b), and depressed suicides compared with nonpsychiatric controls (Lalovic et al, 2010). Additionally, antipsychotic medications have been shown to upregulate mRNA expression of genes coding for biosynthetic enzymes in rats (Liu et al, 2009a; McNamara et al, 2011) and red blood cell PUFA levels in patients with psychosis (Evans et al, 2003a; Kaddurah-Daouk et al, 2007). FADS2 expression is elevated in prefrontal cortex in schizophrenia, independently of sex or medication usage (Liu et al, 2009b).…”