Subchronic Administration of Fluoxetine Impairs Estrous Behavior in Intact Female Rats

Matuszczyk, Josefa Vega; Larsson, Knut; Eriksson, Elias

doi:10.1016/s0893-133x(98)00040-2

Cited by 55 publications

(61 citation statements)

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“…Marvan and co-workers (Marian et al 1996) have thus previously reported that the immobility displayed by female rats in a so-called animal model of depression (the swimming immobility test) is more pronounced in the diestrus phase than in the estrus phase of the cycle, and that the immobility in the diestrus phase is reduced by treatment with a serotonin reuptake inhibitor, clomipramine. Tentatively, serotonin may be a key factor in mediating the effects of cycle-related changes in hormonal levels on various aspects of behavior; supporting this notion, we recently showed that administration of a serotonin reuptake inhibitor reduces sexual receptivity in the estrus phase of normally cycling, female rats (Matuszczyk et al 1998; see also Uphouse et al 1991).A few technical comments are warranted. Albert and co-workers (1991) have reported that aggressive behavior is exaggerated in female rats that have experienced pseudopregnancy; for this reason, the rats used in the first and second experiments had all been the subjects of one period of pseudopregnancy before the resident intruder experiments were started.…”

mentioning

confidence: 70%

The Serotonin Reuptake Inhibitor Fluoxetine Reduces Sex Steroid-Related Aggression in Female Rats An Animal Model of Premenstrual Irritability?

2001

Neuropsychopharmacology

106

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The aggressive behavior displayed by some (but not all) female Wistar rats when an unfamiliar rat is being introduced into their home cage (the resident intruder paradigm) was found to be higher in non-receptive phases (metestrus, diestrus) than in the receptive phases (proestrus, estrus) Premenstrual dysphoric disorder (PMDD) is characterized by a constellation of symptoms appearing regularly in the luteal phase of the cycle, and disappearing within a few days after the onset of menstruation (American Psychiatric Association 1994). Most researchers in the field regard irritability and anger as the cardinal symptoms of PMDD, but sadness, affect lability, and tension also are common complaints (see Steiner 1997;Freeman and Halbreich 1998;Eriksson 1999).The hypothesis that ovarian steroids are of importance for the pathophysiology of PMDD gains support not only from the fact that the onset and disappearance of symptoms are linked to the reproductive cycle, but also from the findings that premenstrual complaints may be reduced by surgical ovariectomy and by druginduced inhibition of ovulation (see Backstrom and Hammarback 1991;Schmidt et al. 1998). Several observations suggest that PMDD subjects do not differ from controls with respect to serum levels of sex steroids, but with respect to how the brain reacts to these hormones. First, most studies suggest that replacing endogenous sex steroid secretion with exogenous hormones in the form of oral contraceptives is usually not an effective treatment for PMDD (Bancroft and Rennie 1993). Second, treatment with progesterone and/or estrogen after administration of an ovulation inhibitor has been shown to elicit PMDD-like symptoms in women with a history From the Department of Pharmacology, Göteborg University, Göteborg, Sweden.Address correspondence to: Hoi-Por Ho, Department of Pharmacology, Göteborg University, POB 431, SE 405 30 Göteborg, Sweden.Received April 25, 2000; revised October 6, 2000; accepted October 18, 2000. N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 24 , NO . 5 Animal Model of Premenstrual Dysphoria? 503 of PMDD, but not in controls . Third, women with a history of PMDD more often than other women experience PMDD-like symptoms when given gestagen intermittently during menopause as part of a hormonal replacement therapy (Bjorn et al. 1999). Animal experiments suggest that the brain neurotransmitter serotonin exerts an inhibitory influence on irritability and aggression (see Eriksson and Humble 1990), and also that brain serotonergic neurotransmission is influenced by sex steroids . The hypothesis that serotonin may be involved in the regulation of premenstrual irritability lends strong support from studies showing that serotonin reuptake inhibitors very effectively reduce the symptoms of PMDD (Sundblad et al. 1992;Eriksson et al. 1995;Steiner et al. 1995;Yonkers et al. 1997;Wikander et al. 1998); moreover, whereas the serotonin precursor tryptophan has been shown to be superior to placebo for the treatment of PMDD (Steinberg et al. 1999), a reduction i...

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confidence: 70%

The Serotonin Reuptake Inhibitor Fluoxetine Reduces Sex Steroid-Related Aggression in Female Rats An Animal Model of Premenstrual Irritability?

2001

Neuropsychopharmacology

106

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Section: Introductionmentioning

confidence: 99%

“…Although fluoxetine has been previously studied in ovariectomized females primed with estrogen and/or progesterone, the results have been equivocal [10,25]. In one report, ovariectomized rats were treated with 10 mg/kg fluoxetine for as long as 42 days [25]. At weekly intervals, females were hormonally primed with estrogen and progesterone and tested for sexual receptivity (measured by the lordosis reflex) and sexual motivation (measured by the percentage of time females spent in the vicinity of a male).…”

Section: Introductionmentioning

confidence: 99%

Subchronic treatment with fluoxetine attenuates effects of acute fluoxetine on female rat sexual behavior

et al. 2008

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These experiments were designed to evaluate the hypothesis that fluoxetine-induced sexual dysfunction in female rats derived from disruption of neuroendocrine events that normally facilitate sexual behavior. If so, exogenous hormonal priming to ovariectomized rats should eliminate fluoxetine's effect. Ovariectomized rats were subchronically treated with 10 mg/kg fluoxetine or distilled/deionized water vehicle for 9 consecutive days. On the 8 th day of treatment, rats were primed with 10 μg estradiol benzoate followed 48 hr later with 500 μg progesterone. In a pretest for sexual behavior on the 10 th day, there was no difference between subchronic treatments. Sexual receptivity was again monitored 30 min after injection on the 10 th day (acute treatment) with distilled/deionized water, 10 mg/kg fluoxetine or 20 mg/kg fluoxetine. Thereafter, the female's behavior was monitored for 20 min in a male preference procedure. After the acute treatment in rats subchronically treated with water, fluoxetine (10 or 20 mg/kg) significantly reduced both lordosis frequency and quality and reduced (but not significantly) time spent with the male. In rats subchronically treated with fluoxetine, the lordosis-inhibiting effect of an acute injection with fluoxetine was significantly attenuated relative to that of the subchronically water-treated rats. In contrast to expectation, subchronic treatment with fluoxetine increased, rather than reduced, the relative time females spent near the male. Activity, as measured by center crossings, and grooming were also reduced by subchronic treatment with fluoxetine. KeywordsSSRI; sexual motivation; lordosis; subchronic IntroductionFluoxetine (Prozac®) is frequently prescribed for depression as well as for a variety of other disorders such as premenstrual dysphoria, anxiety, anorexia and bulemia which are more prevalent in females than in males [4,19,22,33]. A reported undesirable side effect of fluoxetine, as well as other selective serotonin reuptake inhibitors (SSRIs), is a high incidence of sexual dysfunction [8,15,28]. Although such sexual dysfunction occurs in both genders, more experimental emphasis has been placed on identifying the responsible mechanisms in males than in females [17]. Yet, as much as 32% of female patients may experience SSRI-*Corresponding author Department of Biology, Texas Woman's University, Denton, TX 76204, Phone: 940-898-2356, FAX: 940-898-2382.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [32]. The mechanisms responsible for such drug-induced sexual dysfunction in females have been difficult to identify,...

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“…Disruptive effects of 5-HT on female reproduction are well recognized [37,50,56,67]. In addition, several of the effects of fluoxetine (in particular, reduced food intake [3,4,6,23] and activation of the hypothalamic-pituitary-adrenal (HPA) axis [54,68]) might be anticipated to substantially alter the neuroendocrine system and thereby influence the female's reproductive cycle [2,7,26,27,29,53,69].However, in a report by Matuszczyk et al [35], sexual behavior and vaginal cyclicity of female rats were examined during 3 weeks of treatment with 10 mg/kg fluoxetine [35]. Fluoxetine reduced sexual behavior, but had no disruptive effect on the female's vaginal cycle.…”

mentioning

confidence: 99%

“…This was a significant observation since it had been generally assumed that fluoxetine-induced female sexual dysfunction occurred independent of drug-induced modification of the HPG axis controlling estrous cyclicity. According to the NTP-CERHR Expert Panel Report in 2004, "The data in female rats are sufficient to qualitatively demonstrate that fluoxetine treatment with 10 mg/kg bw/day by s.c. or i.p injection results in altered estrous behavior and sexual receptivity, but has no effect on estrous cycle length" [25].Since concurrent vaginal and behavioral estrus have been examined in only two reports [35,63], it is important to identify explanations for the contrasting findings. In the following manuscript, we investigate one such potentially important difference between the two studies.…”

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confidence: 99%

Daily male exposure attenuates estrous cycle disruption by fluoxetine

Sarkar

Hiegel

Maswood

et al. 2008

Behavioural Brain Research

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Fluoxetine (Prozac®) produces sexual dysfunction in a substantial number of patients. In the few animal studies designed to address this sexual dysfunction in females, data have been inconsistent. Some investigators report that the drug disrupts sexual behavior without affecting the estrous cycle while we have reported robust effects of fluoxetine on the estrous cycle. The current studies were designed to initiate examination of procedural differences that may account for these contradictory outcomes. In the first experiment, intact, regularly cycling female rats were injected daily for 10 days with 10 mg/kg fluoxetine (intraperitoneally) or vehicle. Male-exposed, fluoxetine-or vehicle-treated rats were housed in a room with males and placed for 5 min/day into a male's cage. Other fluoxetinetreated females were housed in a room separate from males. In the second experiment, this protocol was repeated for 20 days and an additional group of females were exposed to male bedding for 5 min/day. Without male exposure, fluoxetine rapidly disrupted vaginal estrus and sexual receptivity so that approximately 50% of the rats failed to show vaginal estrus during the first 5 days; and the majority of the rats had a blocked cycle by 10 days of treatment. With male exposure, these reproductive effects were attenuated. The majority of rats cycled normally during the first 5 days of treatment and more than half cycled throughout the experiment. Loss of behavioral receptivity occurred even when normal estrous cyclicity was present. Although exposure to the male's bedding may have delayed the onset of estrous cycle disruption, five min daily exposure to a male's bedding did not prevent the disruptive effects of fluoxetine. These findings are consistent with evidence that fluoxetine's effect on female sexual dysfunction may result, in part, from the drugs' disruption of the hypothalamic-pituitary-gonadal axis. However, the data also evidence dissociation between the effects of fluoxetine on vaginal and behavioral estrus. These findings may also explain why different laboratories have reported the presence or absence of estrous cycle disturbances following daily treatment with fluoxetine. KeywordsSSRIs; intact rats; sexual behavior; pheromones; progesterone; estrus INTRODUCTIONSelective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac®), are effective in the treatment of depression [32,66] but produce sexual dysfunction in a substantial number of patients [12,19,38,39,55,59]. Although the high prevalence of SSRI-induced sexual *Corresponding author: Department of Biology, Texas Woman's University, Denton, TX 76204, Phone: 940-898-2356, FAX: 940-898-2382.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that durin...

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Subchronic Administration of Fluoxetine Impairs Estrous Behavior in Intact Female Rats

Cited by 55 publications

References 39 publications

The Serotonin Reuptake Inhibitor Fluoxetine Reduces Sex Steroid-Related Aggression in Female Rats An Animal Model of Premenstrual Irritability?

The Serotonin Reuptake Inhibitor Fluoxetine Reduces Sex Steroid-Related Aggression in Female Rats An Animal Model of Premenstrual Irritability?

Subchronic treatment with fluoxetine attenuates effects of acute fluoxetine on female rat sexual behavior

Daily male exposure attenuates estrous cycle disruption by fluoxetine

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