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. Effects of fluoxetine on the reproductive axis of female goldfish (Carassius auratus). Physiol Genomics 35: 273-282, 2008. First published September 2, 2008; doi:10.1152/physiolgenomics.90263.2008.-We investigated the effects of fluoxetine, a selective serotonin reuptake inhibitor, on neuroendocrine function and the reproductive axis in female goldfish. Fish were given intraperitoneal injections of fluoxetine twice a week for 14 days, resulting in five injections of 5 g fluoxetine/g body wt. We measured the monoamine neurotransmitters serotonin, dopamine, and norepinephrine in addition to their metabolites with HPLC. Homovanillic acid, a metabolite in the dopaminergic pathway, increased significantly in the hypothalamus. Plasma estradiol levels were measured by radioimmunoassay and were significantly reduced approximately threefold after fluoxetine treatment. We found that fluoxetine also significantly reduced the expression of estrogen receptor (ER)␤1 mRNA by 4-fold in both the hypothalamus and the telencephalon and ER␣ mRNA by 1.7-fold in the telencephalon. Fluoxetine had no effect on the expression of ER␤2 mRNA in the hypothalamus or telencephalon. Microarray analysis identified isotocin, a neuropeptide that stimulates reproductive behavior in fish, as a candidate gene affected by fluoxetine treatment. Real-time RT-PCR verified that isotocin mRNA was downregulated approximately sixfold in the hypothalamus and fivefold in the telencephalon. Intraperitoneal injection of isotocin (1 g/g) increased plasma estradiol, providing a potential link between changes in isotocin gene expression and decreased circulating estrogen in fluoxetine-injected fish. Our results reveal targets of serotonergic modulation in the neuroendocrine brain and indicate that fluoxetine has the potential to affect sex hormones and modulate genes involved in reproductive function and behavior in the brain of female goldfish. We discuss these findings in the context of endocrine disruption because fluoxetine has been detected in the environment. brain; estrogen receptors; isotocin; microarray; Prozac FLUOXETINE (PROZAC), a selective serotonin reuptake inhibitor (SSRI) (46), has been used in several studies in fish to investigate the serotonergic modulation of the endocrine system (55). A racemic mixture of two lipophilic enantiomers, fluoxetine is metabolized by cytochrome P-450 isoenzymes to the active metabolite norfluoxetine (46). In humans, fluoxetine is primarily excreted in urine as ϳ20%-30% unchanged parent compound, while metabolites are largely excreted as pharmacologically active norfluoxetine and inactive fluoxetine glucuronide (62).Fluoxetine also has effects on reproduction in several vertebrates. For example, in the goldfish (Carassius auratus), combined intraperitoneal administration of 10 g/g fluoxetine and 10 g/g serotonin (5-HT) elevated luteinizing hormone (LH) levels relative to 5-HT administration alone 2 h after treatment (55). Japanese medaka (Oryzias latipes) exposed to waterborne 0.1 and 0.5 g/l fluoxetine for 4 wk sh...

SUMMARYWild semipalmated sandpipers (Calidris pusilla) eat n-3 fatty acids to prime their muscles for long migrations. Sedentary bobwhite quails (Colinus virginianus) were used as a model to investigate the mechanisms for this natural doping. Our goal was to characterize the stimulating effects of n-3 eicosapentaenoic acid (EPA) and n-3 docosahexaenoic acid (DHA) on oxidative capacity. Mechanisms linked to changes in membrane composition and in gene expression for peroxisome proliferator-activated receptors (PPAR) were investigated. Dietary n-3 fatty acids stimulated the activities of oxidative enzymes by 58-90% (citrate synthase, cytochrome oxidase, carnitine palmitoyl transferase and hydroxyacyl dehydrogenase), and sedentary quails showed the same changes in membrane composition as sandpipers preparing for migration. EPA and DHA have the same doping effect. The substitution of n-6 arachidonic acid by n-3 EPA in membrane phospholipids plays an important role in mediating the metabolic effects of the diet, but results provide no significant support for the involvement of PPARs (as determined by changes in gene expression). The fatty acid composition of mitochondrial membranes and sarcoplasmic reticulum can be monitored by measuring total muscle phospholipids because all phospholipids are equally affected by diet. Only extreme regimes of endurance training can lead to increments in oxidative capacity matching those induced here by diet. As they prepare for long migrations, semipalmated sandpipers improve their physical fitness by eating! Choosing n-3 fatty acid doping over endurance training strikes us as a better strategy to boost aerobic capacity when rapid storage of energy is critical.