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

摘要

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 α-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-HT1A 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.