Chronic fluoxetine suppresses circulating estrogen and the enhanced spatial learning of estrogen-treated ovariectomized rats

Behavioral Neuroscience Group, University of Missouri--St. Louis, 8001 Natural Bridge Road, St. Louis, MO 63121, USA.
Psychoneuroendocrinology (Impact Factor: 4.94). 12/2004; 29(10):1241-9. DOI: 10.1016/j.psyneuen.2004.03.001
Source: PubMed


We are interested in developing animal models to evaluate cognitive processes as influenced by the interplay of steroidal hormones and drugs commonly used in psychotherapy. Two experiments with female rats were conducted to evaluate the interaction of estrogen with the serotonin specific reuptake inhibitor (SSRI) fluoxetine on spatial learning and memory and on the endocrine system. In experiment 1, estrogen (50 microg estradiol benzoate/kg body weight) was administered SC to young adult, ovariectomized (OVX) rats either alone or in combination with fluoxetine (2 mg/kg SC). After a month, the groups were compared with appropriate OVX and gonadally intact controls on trials to criterion in a hole board spatial memory task using massed training trials. Experiment 2 was a dose-response study of the influence of fluoxetine (0.5-5 mg/kg) on circulating estrogen in OVX, estrogen treated females. Results were that the OVX females administered estrogen only reached the learning criterion significantly faster than the other groups. All other groups, including the estrogen + fluoxetine animals, performed no better than the controls. Combining fluoxetine with estrogen also lowered circulating estrogen titers, with the least estrogen reductions being in the group receiving the highest dosage of fluoxetine. No differences among groups were found on measures of activity in an open field or for anxiety in a plus maze. Conclusions were that administration of estrogen improved spatial learning and memory in OVX rats, whereas concurrent fluoxetine exposure suppressed the levels of estrogen in circulation and eliminated the gains in spatial performance obtained from chronic estrogen exposure.

4 Reads
  • Source
    • "In other vertebrates, fluoxetine treatment suppressed E 2 levels in ovariectomised rats (Rattus norvegicus) treated with oestrogen (Taylor et al., 2004). It reduced the number of female rats displaying oestrous behaviour (Matuszczyk et al., 1998a) and decreased sexual motivation in male rats (Matuszczyk et al., 1998b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pharmaceuticals are increasingly being used in human and veterinary medicine, and their presence in the aquatic environment may present a threat to non-target aquatic organisms. The selective serotonin reuptake inhibitor fluoxetine (Prozac) has been reported to affect diverse behaviours (feeding, aggression, and reproduction) and also the endocrine system (steroid biosynthesis pathway) in fish. To investigate these claims further, and in particular effects on androgen synthesis, male three-spined sticklebacks (Gasterosteus aculeatus) were exposed to fluoxetine at 0, 3.2, 10 and 32μg/L in a flow-through system for 21 days. Their sex was determined prior to exposure using a non-invasive method to collect DNA for determining the genetic sex, reported here for the first time. This was necessary as the exposure required males of a non-breeding status which had not developed secondary characteristics. Post exposure a number of biochemical (serotonin, steroid and spiggin levels) and apical (aggressive behaviour) endpoints were measured. No effects were detected on morphometric parameters, spiggin or androgen (11-ketotestosterone) levels. However, all fluoxetine-exposed male fish had higher cortisol levels in comparison to the control fish, although this effect only persisted throughout the whole exposure duration at the highest concentration (32μg/L). In addition, the ratio of 5-HIAA/5-HT (serotonin metabolite/serotonin) was significantly lower in the brains of males exposed to fluoxetine at all concentrations tested. Although we found no differences in the number of nests built by the males, the quality of the nests produced by the fluoxetine-exposed males was generally inferior consisting only of a basic, rudimentary structure. Males exposed to 32μg/L of fluoxetine displayed a delayed response to a simulated threat (rival male via own mirror image) and were less aggressive (number of bites and attacks) toward their mirror image, but these differences were not statistically significant. In summary, fluoxetine exposure resulted in reduced serotonergic activity in the male three-spined stickleback brain suggesting that the mechanism of action between humans and fish is at least partially conserved. Furthermore, this study provided additional evidence of cross-talk between the serotonergic and stress axes as demonstrated by the perturbations in cortisol levels. This potentially complex interaction at brain level may be responsible for the effects observed on nest quality, an endpoint with serious ecological consequences for this species. Finally, despite our hypothesis (an effect on steroid biosynthesis, based on limited literature evidence), we observed no effects of fluoxetine exposure (at the concentrations and duration employed) on male stickleback androgen levels.
    Aquatic toxicology (Amsterdam, Netherlands) 09/2015; 168. DOI:10.1016/j.aquatox.2015.09.009 · 3.45 Impact Factor
  • Source
    • "In female rats fluoxetine has been shown to influence the estrous cycle, sexual behaviour, progesterone (PRO) levels and 17b-estradiol (E2) levels (Matuszczyk et al., 1998; Taylor et al., 2004; Uphouse et al., 2006). Also, in other vertebrates such as fish, fluoxetine has been shown to influence E2 levels (Foran et al., 2004; Lister et al., 2009; Mennigen et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Selective serotonin reuptake inhibitors are known to have a range of disorders that are often linked to the endocrine system e.g. hormonal imbalances, breast enlargement, sexual dysfunction, and menstrual cycle disorders. The mechanisms behind most of these disorders are not known in details. In this study we investigated whether the endocrine effect due to SSRI exposure could be detected in well adopted in-vitro steroidogenesis assays, two versions of the aromatase enzyme inhibition assay and the H295R cell assay. The five drugs citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, were shown to inhibit the aromatase enzyme in both types of aromatase assays. The IC50 values ranged from 3 to 600 μM. All five SSRIs, were further investigated in the H295R cell line. All compounds altered the steroid secretion from the cells, the lowest observed effect levels were 0.9 μM and 3.1 μM for sertraline and fluvoxamine, respectively. In general the H295R cell assay was more sensitive to SSRI exposure than the two aromatase assays, up to 20 times more sensitive. This indicates that the H295R cell line is a better tool for screening endocrine disrupting effects. Our findings show that the endocrine effects of SSRIs may, at least in part, be due to interference with the steroidogenesis. Copyright © 2015. Published by Elsevier Ltd.
    Toxicology in Vitro 07/2015; 29(7). DOI:10.1016/j.tiv.2015.07.005 · 2.90 Impact Factor
  • Source
    • "Additionally, much experimental and epidemiological data have demonstrated adverse endocrine and reproductive effects of FLX exposure. Studies in rodents reported that FLX treatment affected estrous cyclicity, sexual receptivity [21] [22] [23], and gonadal hormone levels [24], decreased the number of corpora lutea and implants [25], decreased litter size and increased spontaneous losses [26], decreased male fertility [25] [27] and decreased sertoli cell population [28]. Clinical studies found preterm birth after in utero exposure to FLX [29] and side effects, such as endometrial hyperplasia and menorrhagia, in children who were exposed to FLX [30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent years have seen an increase in the use of antidepressant drugs, especially fluoxetine (FLX), in sensitive populations, such as pregnant and lactating women. Although some evidence suggests a possible endocrine action of FLX, no specific studies have been performed to investigate this hypothesis. In the present study, we investigated the possible (anti)androgenic and (anti)estrogenic actions of FLX using Hershberger, uterotrophic (0.4, 1.7, and 17 mg/kg), and reporter gene (7.6–129 μM) assays. In the Hershberger assay, no differences were observed in androgen-dependent organ weights. However, the uterotrophic and gene reporter assays indicated a possible estrogenic action of FLX. Uterine weight increased in the 1.7 and 17 mg/kg/day groups in the 3-day uterotrophic assay in immature rats. Additionally, noncytotoxic concentrations of FLX induced estrogenic responses and increased the estrogenic response of estradiol in MCF-7 breast cancer cells transfected with luciferase.
Show more