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RU 486 is known primarily as an antagonist to progestins and glucocorticoids. However, RU 486 has also been shown to have agonistic progestational properties in biochemical and behavioral studies. In the current study, RU 486 was implanted directly into the ventromedial hypothalamus (VMH) to test for facilitative action on the receptive behavior of female ovariectomized Long-Evans rats primed with 5 micrograms of estradiol benzoate. Cannulae containing RU 486, progesterone (P), or empty cannulae were implanted 48 hr after estrogen priming. The lordosis quotient and the lordosis score were assessed 4 hr after the cannulae were lowered by a standardized test consisting of 10 mounts by a stimulus male. P and RU 486 significantly facilitated receptivity compared to blank implants in terms of lordosis quotient and lordosis score, with no significant difference between the hormone treatments. While only a single dose of each treatment was given in the current study, RU 486 facilitated lordosis when implanted to the VMH as well as progesterone in contrast to our previous results where the steroids were administered systemically.

Two experiments examined the role of the steroid hormones, estradiol (E2), progesterone (P), and testosterone (T), in activating scent marking and 50-kHz ultrasonic vocalizations in ovariectomized Long-Evans rats in response to a devocalized male rat. In Experiment 1, females received, in a counterbalanced order, a series of six hormone treatments consisting of two injections (48-54 and 4 hr before behavioral tests). The six treatments were 8 micrograms E2 followed by 500 micrograms P or oil, 2 micrograms E2 followed by 500 micrograms P or oil, and oil followed by 500 micrograms P or oil. Injections of either the high or low dose of E2 followed by P resulted in high levels of vocalizations. Neither E2 by itself or P by itself were very effective. Surprisingly, none of the hormone treatments were effective in activating marking above the level seen when the females received control injections of oil. Four other hormone treatments were examined in Experiment 2: daily injections of 500 micrograms T, daily injections of 50 micrograms E2, implantation of silastic capsules of E2 (5% E2, 5 mm length) followed by 500-micrograms P injections before behavioral tests, and implantation of silastic capsules of E2 followed by oil injections. Animals receiving E2 by silastic capsule followed by P injection displayed the highest levels of marking and vocalizations across the five weekly tests. These results suggest that while E2 and P synergize for the display of female-typical behaviors similar to the hormonal regulation of lordosis, the mechanism of E2 action may be different for the two signaling behaviors. Scent marking appears to be responsive to the tonic levels of E2 released from silastic capsules.

Two experiments in house mice (Mus domesticus) examined the neural sites at which steroid hormones activate the following male-typical behaviors: 70 kHz ultrasonic mating vocalizations in response to stimulus females or their urine, urinary marking in response to stimulus males or stimulus females, mounting of estrous females, and intermale aggression. In the first experiment, four groups of castrated males received bilateral intracranial implants of testosterone (T) into either the septum (SEPTUM), medial preoptic area (MPO), anterior hypothalamus (AHA), or ventromedial hypothalamus (VMH). Two control groups received subcutaneous silastic capsules of T (TSIL) or empty silastic capsules (BSIL). The TSIL males performed all behaviors at male-typical levels while the BSIL males were unresponsive. MPO males emitted ultrasonic mating vocalizations at high levels while few vocalizations were seen in males of the other brain implant groups. The VMH, AHA, and MPO males urine marked at higher levels than the BSIL males but did not exhibit the high levels of the TSIL males. Mounting was observed only in MPO and TSIL males. Aggression was rare in males from any of the brain implant groups. In the second experiment, the hormone activity of the implants was increased by using testosterone propionate (TP) or a 50% mixture of estradiol (E2) and cholesterol. The six groups were SEPTUMTP, SEPTUME2, MPOTP, MPOE2, TPSIL, and BSIL. The TPSIL males performed all behaviors at male-typical levels while the BSIL males were unresponsive. TP was effective at restoring vocalizations and urine marking only when placed in the MPO; however, E2 was effective at both sites. Again aggression and mounting were less evident in the brain implanted males. In conclusion, implants of T or TP were effective in restoring ultrasonic mating vocalization when placed into the MPO. MPO implants of T and TP were also effective in stimulating urine marking, although VMH and AHA implants also showed some effectiveness. The restorative effects of E2 were not localized which is probably related to the greater hormonal activity of this treatment. Comparisons of the properties of the various brain implants to restore more than one behavior were discussed.

The effects of testosterone (T) and its major metabolites, estradiol (E2) and dihydrotestosterone (DHT), on the restoration of sebaceous scent marking and 50-kHz ultrasonic vocalizations in male rats were measured in two studies (Experiments 1 and 2) employing different hormone levels. Silastic capsule administration of high and low doses of T (10 and 20 mm) or E2 (5%; 5 and 10 mm) completely restored marking to precastration levels. Both doses of DHT (30 and 40 mm) or no hormone replacement were without effect when tested in presence of estrous odor cues. In our testing paradigm, males appeared to mark glass objects with a sebaceous secretion rather than urine. Only the high dose of T (20 mm) restored vocalizations to intact levels, while animals receiving the high or low dose of E2 or DHT showed no restoration of behavior. In Experiment 3, habituation to estrous odor cues over weekly tests was not observed for marking or vocalizations. These results are discussed with respect to similarities and differences in the hormonal control of signaling behaviors by androgen metabolites in male rodents.

Progesterone (P) facilitation of sexual receptivity in rodents has been achieved by intracranial administration to the ventral hypothalamus; the preoptic area; and midbrain areas such as central gray, mesencephalic reticular formation, and ventral tegmental nucleus. In our laboratory, by far the most effective site in rats has been the ventromedial nucleus of the hypothalamus (VMN). However, several reports of sensitivity to P in the midbrain of rats and other rodent species led us to investigate whether stimulation of the ventral midbrain of female rats might contribute to facilitation of sexual receptivity. Ovariectomized Long-Evans rats received one cannula aimed at the VMN, and another aimed at the contralateral ventral mesencephalon. P in both cannulae, following a priming dose of estradiol, caused significantly higher lordosis quotients (LQ) than blank tubes. Controls with bilateral cannulae in the VMN responded when both tubes were filled with P, but did not respond to unilateral VMN P stimulation. P in the VMN and contralateral anterior preoptic area did not result in a greater degree of receptivity than did the empty tubes. These studies indicate that although progesterone stimulation in the midbrain alone is not sufficient to facilitate receptivity in female rats with our methods, the midbrain may play an auxiliary role. P implants in the midbrain appear to facilitate receptivity in the case of VMN implant treatments that are subthreshold for stimulating lordosis. The results are discussed in light of similar studies in other rodent species, and in the context that more than one brain site may be important in the natural stimulation of sexual receptivity by gonadal hormones.

The progestin receptor antagonist RU 38486 (henceforth referred to as RU 486) was tested for facilitative effects on female receptive behavior in ovariectomized Long-Evans rats primed with 2 micrograms estradiol benzoate (EB). RU 486 (0, 0.5, 1.6, or 5.0 mg) was administered 48 hr after estrogen priming. The lordosis quotient (LQ) and lordosis score (LS) were assessed 4 hr after RU 486 administration in a standardized test consisting of a 10-mount test by a stimulus male. A significant dose effect was found by both LQ and LS, with those subjects receiving 5 mg of RU 486 being significantly more receptive than vehicle control animals. Thus RU 486 acted as a weak progestin agonist under testing conditions typical for assessment of progestin facilitation of female sexual behavior in rats. Low levels of proceptive behavior (hops and darts) were seen in a minority of the tests, and did not vary systematically as a function of the dose of RU 486 administered. We also examined the effects of RU 486 given before progesterone (P) on receptivity in a blocking paradigm and confirmed previous reports that the antagonist significantly attenuates facilitation of sexual behavior when given in combination with P. A progestin receptor assay of the cytosols of the hypothalamus-preoptic area in estrogen-primed female rats treated with 5 mg RU 486 revealed a significantly greater depletion of available cytosolic P receptors than when rats were treated with a similarly facilitating dose of P (100 micrograms). The results suggest a possible dual mode of action for RU 486--a weak, receptor-mediated agonistic effect on sexual behavior when given alone to estrogen-primed rats, and a competitive blocking effect on receptivity when administered with P.

The present study was carried out in order to assess the time course of action of progesterone (P) in the facilitation of complete feminine sexual behavior. Female rats (estrogen primed via 5% E2 Silastic capsules) were given 200 micrograms of P either intravenously (iv) or subcutaneously (sc), and tested for estrous behavior at 1/4, 1/2, 1, 2, and 4 hr after treatment. Among iv-treated animals, significant amounts of lordosis behavior were seen as early as 1/2 hr, and a dramatic rise in solicitation behavior was observed at 2 hr. Although sc-treated animals displayed significant amounts of lordosis and solicitation behavior at 2 hr, the behavior was not maximal until 4 hr. Intravenous administration of 400 micrograms P was equipotent to 200 micrograms P, whereas 50 micrograms of iv P was relatively ineffective. A dual mechanism hypothesis pertaining to progesterone's actions in the facilitation of both the receptive and proceptive components of feminine sexual behavior in rats is discussed.

The CNS sites of action for progesterone facilitation of female sexual behavior are disputed. Among the areas most often cited are the ventromedial hypothalamus and the ventral midbrain. There is also a controversy about whether estradiol may substitute for progesterone for the facilitation of receptive behavior when given systemically or intracranially. We tested VMH and ventral midbrain applications of estradiol versus progesterone for the facilitation of female sexual behavior in estrogen-primed, ovariectomized female rats. Subjects were implanted with bilateral guide tubes aimed at ventral hypothalamic or midbrain sites. Estrogen-primed rats received either 28-gauge insert cannulae filled at the lumen with pure progesterone, estradiol, or cholesterol, or empty tubes, and were tested for receptivity with intact, experienced stud males just before, and 1 and 4 hr after, intracranial hormone administration. Significant estrous responsiveness was seen only in the 4-hr test after progesterone was implanted in the VMN in the first intracranial cannula test. We conclude, in contrast to some previous reports, that administration of progesterone to the VMN is more effective in the facilitation of female sexual behavior than when it is implanted in the ventral midbrain, and that administration of estradiol to either site is ineffective.

The present study examined the actions of the antiprogestin RU 38486 on progesterone (P)-induced facilitation and sequential inhibition of estrous behavior and on brain cytosol progestin receptor (PR) levels in ovariectomized, estrogen-primed (0.5 micrograms of estradiol benzoate for 3 days) female rats. RU 38486 suppressed P-facilitated receptive and proceptive responses in a dose-dependent fashion when administered 1 hr prior to P. RU 38486 did not, however, block the sequential inhibitory effect of P. Indeed, when it was administered alone at a dose of 1 mg, animals were rendered behaviorally unresponsive to a P treatment 25 hr later. It is unclear whether RU 38486 is an agonist for P sequential inhibition of estrous behavior or if the apparent agonist action of RU 38486 actually results from a long-term antagonist effect. Estrogen-induced PRs remain elevated (35-55% above basal) in the hypothalamus (HYP) and preoptic area (POA) at 24 and 48 hr following the last estrogen injection. Thus P facilitation of estrous behavior is correlated with increased levels of cytosol PRs. RU 38486 reduced cytosol PRs in both brain regions to basal levels within 2 hr, and the levels remained suppressed 25 hr following the treatment. Hence there is a strong correlation between behavioral inhibition and suppressed cytosol PRs at both short (5 hr) and long (25 hr) intervals after RU 38486 administration. A P treatment which produced sequential inhibition of estrous responsiveness 24 hr later did not reduce the estrogen-induced level of cytosol PRs in either brain region. These results suggest that mechanisms in addition to induction of PRs may be necessary to ensure successful mating.

The objective of the present study was to delineate the period of sensitivity to a single androgen exposure during the initial neonatal hours on the development of masculine and feminine copulatory behavior in female rats. Female rats were injected once with either 500, 50, or 5 micrograms testosterone propionate (TP) at either 1 or 24 hr after birth. Following castration in adulthood and TP replacement, the females were tested four times at weekly intervals in prolonged sessions for masculine copulatory behavior. One month following the masculine copulatory tests the females were tested for 3 weeks for feminine copulatory behavior with weekly increasing levels of estradiol benzoate (2.5, 10, and 25 micrograms) and progesterone (200 micrograms). The results demonstrate that a single injection of TP administered at either 1 or 24 hr after birth can significantly increase the capacity of female rats to exhibit ejaculation patterns and that the amount of androgen that is administered is critical in determining the levels of ejaculatory responding. Similarly, the females given high doses (50 and 500 micrograms) of TP at either 1 or 24 hr neonatally were almost completely defeminized. In contrast, however, the females treated with 5 micrograms TP at 1 and 24 hr showed different levels of lordotic performance indicating a greater sensitivity to androgen immediately after birth than at 24 hr in female rats as has been shown in male rats.

Marked prolactin (PRL) secretion in response to the ultrasonic distress vocalizations of rat pups in lactating dams deprived of their pups for 6 hr was reported by others. In two experiments, this phenomenon could not be confirmed under our testing conditions at either 1 or 2 weeks postpartum, although behavioral responses to the ultrasounds were noted. In addition, suckling-induced PRL secretion did not differ consistently as a function of the tape recording (pup ultrasounds, 45 kHz artificially produced ultrasounds, or blank tape) heard prior to the return of pups. The functional significance of rat pup ultrasounds is considered.

In order to determine the neural site(s) of estradiol (E2) priming of receptive behavior in female Long-Evans rats, we attempted to inhibit the behavioral effects of peripheral injections of E2 by administering the E2 antagonist tamoxifen (TX) to particular brain regions. Crystalline TX was administered unilaterally or bilaterally via 28-gauge cannulae into the ventromedial hypothalamic nucleus (VMN), the preoptic area (POA), or the interpeduncular region (IP) 1 hr prior to the first of three daily E2 benzoate injections. Subjects were tested for the presence or absence of behavioral estrus 5 hr after a 200-micrograms progesterone injection given 4 days after the initial hormone treatment. Results of this experiment showed that TX inhibits lordosis when directed toward the VMN, but not when directed toward the POA or IP. The quality of the lordosis response and the proportion of subjects showing solicitation behavior were both lower in VMN subjects treated with TX than in POA or IP subjects given the same treatment. Unilateral implants were as effective as bilateral implants in inhibiting the behavior of VMN subjects. A second experiment measured uptake of radiolabeled E2 by nuclei of hypothalamic (HYP) and POA tissue following bilateral TX administration to the VMN or POA. TX was capable of inhibiting uptake of [3H]E2 into nuclei of cells located near the implant site. Most subjects which showed behavioral inhibition also showed a reduction in uptake of [3H]E2 by HYP tissue. These data support the hypothesis that exposure of the VMN to E2 is necessary for the priming of estrous behavior in the female rat.