Zaprinast, a Phosphodiesterase 5 Inhibitor, Overcomes Sexual Dysfunction Produced by Fluoxetine, a Selective Serotonin Reuptake Inhibitor in Hamsters

Frye, Cheryl A.; Rhodes, Madeline E.

doi:10.1038/sj.npp.1300051

Cited by 16 publications

(22 citation statements)

References 37 publications

(41 reference statements)

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“…Inhibitory effects of an acute treatment with fluoxetine on sexual behavior are consistent with prior reports on lordosis behavior in female rats [10] and lateral displacement in female hamsters [11]. Fluoxetine rapidly increases extracellular 5-HT in a variety of brain areas including the hypothalamus [21,24,29,36].…”

Section: Discussionsupporting

confidence: 89%

“…However, when these same rats were administered an acute injection of 10 or 20 mg/kg fluoxetine, some reduction in sexual behavior did occur, but only at the higher dose of the drug. In contrast, in rats subchronically treated with water, acute treatment with either 10 or 20 mg/kg fluoxetine reduced L/M ratios and lordosis quality.Inhibitory effects of an acute treatment with fluoxetine on sexual behavior are consistent with prior reports on lordosis behavior in female rats [10] and lateral displacement in female hamsters [11]. Fluoxetine rapidly increases extracellular 5-HT in a variety of brain areas including the hypothalamus [21,24,29,36].…”

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confidence: 89%

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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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Section: Discussionsupporting

confidence: 89%

supporting

confidence: 89%

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

et al. 2008

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“…Although highly effective for the treatment of depression, fluoxetine has been reported to produce sexual side effects in 30–60% of the female patient population [2,4,15,20,33,38]. While several suggestions have been made [11,16–18,51,56,57], the mechanisms responsible for SSRI-induced sexual dysfunction, especially in the female population, remain unclear.…”

Section: 0 Introductionmentioning

confidence: 99%

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

2008

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In an earlier study, we reported that daily fluoxetine treatment (10 mg/kg/day) rapidly disrupted estrous cyclicity and sexual receptivity in adult, regularly cycling Fischer rats. The current study was designed to investigate if comparable fluoxetine treatment would similarly affect intact, regularly cycling Sprague Dawley rats. In the first experiment, fluoxetine was injected for 24 days. After 11-14 days of daily fluoxetine treatment, 40% of the rats showed a transient disturbance of the estrous cycle with elimination of sexual receptivity. In these affected rats, reduced sexual receptivity generally preceded disruption of vaginal cyclicity. In a second experiment, a shorter exposure was used to attempt to dissociate effects of fluoxetine on behavior and estrous cyclicity. Nine days of fluoxetine treatment eliminated sexual receptivity and proceptivity (hops/darts) in 40% and 46%, respectively, of rats without altering the estrous cycle. Female rats then received a 10 th fluoxetine injection 30 min prior to assessment of sexual motivation (measured with the male preference paradigm). There was no effect of fluoxetine on male preference, but fluoxetine significantly reduced the number of crossings and seconds of grooming during preference testing. Therefore, effects of fluoxetine on estrous cyclicity and behavior of Sprague Dawley female rats were smaller and required longer to develop than previously reported in Fischer female rats. These findings reinforce a probable relationship between fluoxetine's effect on sexual activity and neuroendocrine disturbances and illustrate the importance of strain selection in attempting to model human disease. KeywordsSSRI; sexual motivation; lordosis; rat strain; food intake; body weight IntroductionSelective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are frequently prescribed for a variety of mood and eating disorders, such as anxiety, depression, anorexia, bulimia, and premenstrual dysphoria [14,33,43,55]. Although highly effective for the treatment of depression, fluoxetine has been reported to produce sexual side effects in 30-60% of the female patient population [2,4,15,20,33,38]. While several suggestions have been made [11,16-18, *Corresponding author Department of Biology, Texas Woman's University, Denton, TX 76204, Phone: 940-898-2356, FAX: 940-898-2382, Email: Luphouse@twu.edu. # Both authors contributed equally to the manuscript 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. Most investigators have assumed that female sexual dysfunction occurs independent of a primary disturbance of the neuroen...

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“…Hormones were administered sc in a sesame oil vehicle. Zaprinast (Sigma) was prepared as described previously in a vehicle of 25% dimethylsulfoxide (DMSO) v/v in saline and administered ip, 20 min before testing [9]. …”

Section: Methodsmentioning

confidence: 99%

“…It is not known how the administration of agents that modulate vaginal blood flow such as PDE-5 inhibitors affect the display of sexual behaviors in female rats. One study suggests that PDE-5 inhibitors can modulate the display of sexual behaviors in female hamsters [9]. Specifically, alterations in the pelvic adjustments made by the female hamster that facilitate penile insertion that occurred following the administration of a specific serotonin reuptake inhibitor were ameliorated by zaprinast (3 mg/kg, ip, 20 min before the test), suggesting cross-talk between the serotonin and NO-cGMP pathways in the regulation of female sexual behaviors [9].…”

Section: Introductionmentioning

confidence: 99%

Zaprinast, a phosphodiesterase type-5 inhibitor, alters paced mating behavior in female rats

Clark¹,

Meerts²,

Guarraci³

2009

Physiology & Behavior

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Nitric oxide (NO) is the primary mediator of blood flow in female genital tissues and drugs that enhance the activity of nitric oxide, such as phosphodiesterase type-5 (PDE-5) inhibitors, increase vaginal blood flow in anesthetized rats. The goal of the present study was to test the effects of one PDE-5 inhibitor, zaprinast, on the display of sexual behaviors in gonadectomized, estrogen and progesterone-treated female rats. Experiment 1 demonstrates that zaprinast alters paced mating behavior by lengthening the contact-return latency to ejaculation; there is a significant relationship between dose of zaprinast (range 1.5 -6 mg/kg) and contact-return latency to ejaculation. Experiment 2 illustrates that zaprinast has no effect on preference for an intact male as measured in a No Contact partner preference test. Rats receiving zaprinast tend to exhibit reduced locomotor activity in both experiments. Collectively, these findings demonstrate that modulation of the NO-cGMP pathway using a PDE-5 inhibitor alters the display of paced mating behaviors in rats.

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Zaprinast, a Phosphodiesterase 5 Inhibitor, Overcomes Sexual Dysfunction Produced by Fluoxetine, a Selective Serotonin Reuptake Inhibitor in Hamsters

Cited by 16 publications

References 37 publications

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

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

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

Zaprinast, a phosphodiesterase type-5 inhibitor, alters paced mating behavior in female rats

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