Omega-3 fatty acid deficiency during perinatal development increases serotonin turnover in the prefrontal cortex and decreases midbrain tryptophan hydroxylase-2 expression in adult female rats: dissociation from estrogenic effects.
A dysregulation in central serotonin neurotransmission and omega-3 fatty acid deficiency have been implicated in the pathophysiology of major depression. To determine the effects of omega-3 fatty acid deficiency on indices of serotonin neurotransmission in the adult rat brain, female rats were fed diets with or without the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during perinatal (E0-P90), post-weaning (P21-P90), and post-pubescent (P60-130) development. Ovariectomized (OVX) rats and OVX rats with cyclic estrogen treatment were also examined. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content, and fatty acid composition were determined in the prefrontal cortex (PFC), and tryptophan hydroxylase-2 (TPH-2), serotonin transporter, and 5-HT(1A) autoreceptor mRNA expression were determined in the midbrain. ALA deficiency during perinatal (-62%, p=0.0001), post-weaning (-34%, p=0.0001), and post-pubertal (-10%, p=0.0001) development resulted in a graded reduction in adult PFC docosahexaenoic acid (DHA, 22:6n-3) composition. Relative to controls, perinatal DHA-deficient rats exhibited significantly lower PFC 5-HT content (-65%, p=0.001), significant greater 5-HIAA content (+15%, p=0.046), and a significant greater 5-HIAA/5-HT ratio (+73%, p=0.001). Conversely, post-weaning DHA-deficient rats exhibited significantly greater PFC 5-HT content (+12%, p=0.03), no change in 5-HIAA content, and a significantly smaller 5-HIAA/5-HT ratio (-9%, p=0.01). Post-pubertal DHA-deficient and OXV rats did not exhibit significant alterations in PFC 5-HT or 5-HIAA content. Only perinatal DHA-deficient rats exhibited a significant reduction in midbrain TPH-2 mRNA expression (-29%, p=0.03). These preclinical data support a causal link between perinatal omega-3 fatty acid deficiency and reduced central serotonin synthesis in adult female rats that is independent of ovarian hormones including estrogen.
McNamara
Robert K
RK
Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati OH 45267-0559, United States. robert.mcnamara@psychiatry.uc.edu
Able
Jessica
J
Liu
Yanhong
Y
Jandacek
Ronald
R
Rider
Therese
T
Tso
Patrick
P
Lipton
Jack W
JW
D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002849:Chromatography, Gas / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004032:Diet / Q000379:methods; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005260:Female; D008297:Male; D008636:Mesencephalon / Q000201:enzymology*; D010052:Ovariectomy; D017397:Prefrontal Cortex / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012701:Serotonin / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000378:metabolism*; D017962:alpha-Linolenic Acid / Q000008:administration & dosage
D015415:Biomarkers; D004967:Estrogens; D015525:Fatty Acids, Omega-3; D017962:alpha-Linolenic Acid; D012701:Serotonin; D004958:Estradiol; D012313:RNA; D014365:Tryptophan Hydroxylase; C504569:tph2 protein, rat