Daily male exposure attenuates estrous cycle disruption by fluoxetine

Abstract

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...

Pharmacology of serotonin and female sexual behavior

“…The strain difference reported for the acute treatment is consistent with a similar strain difference in subchronic effects of fluoxetine on lordosis behavior and estrous cyclicity (Maswood et al, 2008; Sarkar et al, 2008b; Uphouse et al, 2006). Daily treatment of Fischer females with 10 mg/kg fluoxetine reduced lordosis behavior and estrous cyclicity within the first 5 days of treatment (Uphouse et al, 2006) while the effects in Sprague-Dawley females were considerably more modest and less consistent (Maswood et al, 2008).…”

“…However, this possibility is inconsistent with the finding that, relative to the acute effects, the lordosis-inhibiting effects of fluoxetine were reduced, not increased, after Fischer females were treated for 10 days with the SSRI (Sarkar et al, 2008a). Because Matuszcyk et al (Matuszczyk et al, 1998) tested the rats at least weekly, the repeated mating, and not just exposure to male pheromones/odors, may have increased the effect of fluoxetine because daily exposure to soiled bedding from the male reduced the effect of fluoxetine in naturally cycling Fischer female rats (Sarkar et al, 2008b). …”

Modest effects of repeated fluoxetine on estrous cyclicity and sexual behavior in Sprague Dawley female rats

“…It is particularly interesting that the proportion of Sprague Dawley female rats affected by fluoxetine is not inconsistent with the reported incidence of sexual dysfunction in the human population [10,20]. That a smaller proportion of the outbred Sprague Dawley strain (current experiment) than the inbred Fischer strain (100% affected) [53,60] show sexual dysfunction after fluoxetine may indicate the existence of a genetic predisposition to occurrence of SSRI-induced sexual dysfunction in females. A consideration of published differences between Fischer and Sprague Dawley rats may provide clues to the underlying mechanisms responsible for fluoxetine-induced sexual dysfunction.…”

“…Because olfactory cues from the male’s urine can alter female reproductive function in a variety of mammalian species [39–41,48], it was hypothesized that male exposure might reduce the estrous cycle disruption during fluoxetine treatment. In support of this hypothesis, Sarkar et al [53] reported that fluoxetine’s effect on vaginal estrus of Fischer rats was attenuated by daily exposure to a male. However, this attenuation was evidenced as a delay in the onset rather than a complete elimination of the estrous cycle disruption.…”

“…Subsequently, Heisler et al [22] and van de Kar et al [62] reported that daily fluoxetine treatment did not disrupt estrous cyclicity. To explore potential explanations for these contrasting findings, Sarkar et al [53] compared the effect of fluoxetine in female rats, exposed daily to males, to that in female rats that were isolated from males. Distinct from the experiment by Uphouse et al [60], Matuszczyk et al [34] had housed fluoxetine-treated female rats in the presence of males and had tested female rats daily with a sexually active males.…”