Progesterone attenuates the effect of the 5-HT1A receptor agonist, 8-OH-DPAT,and of mild restraint on lordosis behavior

Ovariectomized, hormone-primed rats were used to test the hypothesis that progesterone treatment attenuated the effects of the 5-HT(1A) receptor agonist, (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on female rat lordosis behavior. Based upon prior evidence that prepriming with estradiol benzoate (EB) reduced the ability of 8-OH-DPAT to inhibit lordosis behavior, rats were preprimed with 10 microg EB 7 days before a second priming with 10 microg EB followed 48 h later with 500 microg progesterone or vehicle. Independent of the presence of progesterone, prepriming with EB attenuated the lordosis-inhibiting effects of systemic treatment with 8-OH-DPAT. However, progesterone also reduced the effects of 8-OH-DPAT and this effect was also seen in females primed only once with EB. In contrast, progesterone was relatively ineffective in attenuating the effects of bilateral infusion with 8-OH-DPAT into the ventromedial nucleus of the hypothalamus (VMN). The failure of progesterone to substantially reduce the effects of VMN infusion with 8-OH-DPAT contrasts with prior studies in which estrogen's protective action against the drug did include the VMN. Thus, while both estrogen and progesterone reduce the lordosis-inhibiting effect of 8-OH-DPAT, the mechanisms responsible for the effects of the two gonadal hormones may be different. Priming with progesterone also prevented the effects of 5 min of restraint. When rats were hormonally primed with EB and oil, rats showed a transient, but significant, decline in lordosis behavior 5 and 10 min after restraint. Rats primed with EB and progesterone were unaffected by the restraint. These results are discussed in terms of their implications for the role of progesterone in altering the 5-HT(1A) receptor modulation of lordosis behavior.     

Serotonin receptor involvement in effects of restraint on female rat lordosis behavior

Ovariectomized Fischer (CDF-344) rats, with bilateral cannulae in the mediobasal hypothalamus (MBH) near the ventromedial nucleus of the hypothalamus (VMN), were used to test the hypothesis that serotonin receptors in the VMN contribute to the lordosis-inhibiting effects of mild restraint. Rats were hormonally primed with 10 microg estradiol benzoate (EB) followed 48 h later with sesame seed oil. Four to six hours later (during the dark portion of the light-dark cycle), rats were pretested for sexual behavior. Thereafter, they were infused with saline, 2 microg of the serotonin (5-HT) 2 receptor agonist, (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane HCl (DOI), or 1 microg of the 5-HT(1A) receptor antagonist, N-{2[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635). After a 5 min restraint, rats were tested for sexual receptivity. Rats infused with saline showed a significant decline in lordosis behavior after restraint. Infusion with either DOI or WAY100635 attenuated these effects of restraint. These findings extend earlier observations that the lordosis-disruptive effects of mild restraint include activation of 5-HT(1A) receptors in the VMN and are the first to implicate VMN 5-HT(2) receptors in protection against mild restraint.     

Restraint accentuates the effects of 5-HT2 receptor antagonists and a 5-HT1A receptor agonist on lordosis behavior

The effect of restraint on lordosis behavior was examined in proestrous and ovariectomized, hormone-primed rats. Restraint durations from 5 to 60 min had no effect on lordosis behavior of proestrous rats. There was also no effect of 5 min restraint on lordosis behavior of ovariectomized rats hormonally primed with 10 microg estradiol benzoate and 500 microg progesterone. However, after intraperitoneal treatment with 1.0 mg/kg ketanserin tartrate (ketanserin), 5 min of restraint significantly reduced lordosis behavior of both groups of rats. The 5-min restraint combined with 0.50 or 0.75 mg/kg ketanserin reduced lordosis to mount (L/M) ratios of ovariectomized rats, while L/M ratios of proestrous rats were inhibited only by the 1.0 mg/kg dose. Increasing the restraint duration (10 or 15 min) reduced the dose of ketanserin necessary to reduce the L/M ratios of proestrous rats. Treatment with the selective serotonin (5-HT)(2C) receptor antagonist, SB206553 (2.5 or 5.0 mg/kg), in combination with 5 min of restraint, also reduced L/M ratios of hormonally primed, ovariectomized rats. The neural sites responsible for ketanserin's additivity with restraint are unknown, but infusion of the drug into the ventromedial nucleus of the hypothalamus (VMN) did not mimic the systemic treatment. However, 5 min of restraint did enhance the effects of VMN infusion with the 5-HT(1A) receptor agonist, 8-OH-DPAT. In contrast, 8-OH-DPAT's systemic potency was not enhanced by restraint. These findings support the hypothesis that a mild stressor increases the lordosis-inhibiting effects of 5-HT(1A) receptor agonists and that 5-HT(2) receptors may protect against such disruption of lordosis behavior.     

Sprague‐Dawley and Fischer Female Rats Differ in Acute Effects of Fluoxetine on Sexual Behavior

IntroductionThe selective serotonin reuptake inhibitor (SSRI), fluoxetine, leads to sexual dysfunction in a substantial proportion of women. In studies with the Fischer inbred rat, the 5‐HT_1A receptor has been implicated in this sexual dysfunction. Whether this association with 5‐HT_1A receptors holds for other rat strains is not known.AimThe effects of acute fluoxetine on sexual behavior in two strains of rats that differ in their response to a 5‐HT_1A receptor agonist were examined. Whether the strain difference is comparable in naturally cycling and hormonally primed, ovariectomized rats was determined.MethodsProestrous rats and ovariectomized rats, hormonally primed with estradiol benzoate and progesterone, were treated with varying doses of fluoxetine. Sexual behavior was examined before and after treatment with the SSRI.Main Outcome MeasuresLordosis to mount ratios, lordosis quality, and proceptive behaviors were quantified. Sprague‐Dawley and Fischer females were compared on each of these measures. The IC₅₀ for inhibition of lordosis behavior was determined.ResultsIn both the intact and the hormonally primed, ovariectomized model, Sprague‐Dawley females were less sensitive to the effects of fluoxetine on sexual behavior. In both groups, fluoxetine showed dose dependency in behavioral inhibition, but a higher dose was required for Sprague‐Dawley than for Fischer females. Naturally cycling, proestrous rats required a higher dose of fluoxetine than hormonally primed ovariectomized rats to produce significant inhibition of sexual behavior. Thus, the strain difference in the response to fluoxetine does not parallel strain differences in the response to a 5‐HT_1A receptor agonist.ConclusionsAcute treatment with fluoxetine inhibits lordosis behavior in both Fischer and Sprague‐Dawley females and the strain difference cannot be explained by reported strain differences in the response to a 5‐HT_1A receptor agonist. Fluoxetine's inhibition of female rat sexual behavior may involve effects of the SSRI in addition to activation of the 5‐HT_1A receptor. Miryala CSJ, Hiegel C, and Uphouse L. Sprague‐Dawley and Fischer female rats differ in acute effects of fluoxetine on sexual behavior. J Sex Med **;**:**–**.     

Progesterone reduces the inhibitory effect of a serotonin 1B receptor agonist on lordosis behavior

Ovariectomized Fischer inbred rats were hormonally primed with 10 μg estradiol benzoate and sesame seed oil (EO rats) or with estradiol benzoate and 500 μg progesterone (EP rats). Four to six hours after progesterone or oil, rats were pretested for sexual behavior and then infused bilaterally into the ventromedial nucleus of the hypothalamus with 0, 50, 100 or 200 ng of the 5-HT_1B receptor agonist, 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrol[3,2-bi]pyridin-5-one-dihydrochloride (CP 93129). Sexual receptivity was monitored by the lordosis to mount (L/M) ratio. EO rats showed a transient decline in lordosis behavior following infusion with the saline vehicle and this was amplified by CP 93129. There were no effects of any infusion in EP rats. These findings are discussed in terms of the possible stress effect of the intracranial infusion in EO rats and their implications for a role of 5-HT_1B receptors in the response to a mild stress.     

Daily male exposure attenuates estrous cycle disruption by fluoxetine

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 fluoxetine-treated 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.     

Female gonadal hormones, mild restraint, and male preference

The partner preference paradigm was used to test the hypothesis that mild restraint reduced sexual motivation of female rats. Ovariectomized rats were primed with 10 µg estradiol benzoate or estradiol benzoate and 500 µg progesterone. Additional rats were injected with sesame seed oil. These three groups of rats (oil–oil, estradiol benzoate–oil, or estradiol benzoate–progesterone; OO, EO, EP) were placed for 10 min in an arena, the ends of which enclosed either a sexually active male or an ovariectomized, unprimed female. Time spent near the sexually active male relative to time spent near either stimulus animal was used as the index of male preference. As expected, hormonal treatment significantly increased male preference. After this first 10 min interval, females were returned to the home cage or restrained for 5 min in a Decapicone®. Thereafter, male preference was recorded for another 10 min. Consistent with the first 10 min period, EP rats spent significantly more time near the male than did OO rats while EO rats were intermediate. There was no effect of restraint, but there was a significant increase in self-grooming. These findings contrast with previous studies and allow the suggestion that a brief, mild restraint fails to influence the female's sexual motivation. The implications of these findings are discussed.