Effects of fluoxetine on the reproductive axis of female goldfish (Carassius auratus)

Mennigen JA, Martyniuk CJ, Crump K, Xiong H, Zhao E, Popesku J, Anisman H, Cossins AR, Xia X, Trudeau VL. 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 mu 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)beta 1 mRNA by 4-fold in both the hypothalamus and the telencephalon and ER alpha mRNA by 1.7-fold in the telencephalon. Fluoxetine had no effect on the expression of ER beta 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 RTPCR verified that isotocin mRNA was downregulated approximately sixfold in the hypothalamus and fivefold in the telencephalon. Intraperitoneal injection of isotocin (1 mu 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.