Sherri Lee Jones

Conditioned partner preference in female rats for strain of male

Female rats show conditioned place preference following paced copulation, and we have recently demonstrated that pairing almond odor with paced copulation induces a conditioned partner preference for almond-scented males. The present study examined whether cues of two different strains of male (albino and pigmented) induce a conditioned partner preference for the strain of male associated with paced copulation. Ovariectomized, hormone-primed Wistar (W) or Long-Evans (LE) female rats received 10 conditioning trials at 4-day intervals. In the Wistar-pacing group females copulated with W males in a chamber bisected by a 4-hole partition that only the female could pass through. Four days later, they copulated with LE males without the partition. The Long-Evans-pacing group received the opposite association. In the final preference test all females chose freely between two males tethered in opposite corners of an open field, one W and one LE. Regardless the strain of male, females displayed more solicitations toward the pacing-related male, and most of the females received their first ejaculation from that male. The preference was facilitated if the pacing-related male was of the same strain as the female. These results suggest that female rats have an unconditioned preference for males of the same strain, but this preference can be switched towards males of a different strain if that male is associated with the sexual reward induced by paced copulation.

Sensitization of sexual behavior in ovariectomized rats by chronic estradiol treatment.

The ovariectomized (OVX) rat treated with estradiol benzoate (EB) is used to elucidate neuroendocrine mechanisms of sexual behavior. Chronic behavioral and pharmacological manipulations can be confounded by rising baselines, since females are behaviorally more sensitive to repeated EB injections. The literature lacks a systematic examination of chronic effects of EB administered alone to the sexually experienced OVX rat. Long-Evans rats were repeatedly treated (8 tests) with s.c. injections of 2, 5, or 10 μg EB at different time intervals (4 or 8 days). Female sexual behaviors as well as receipt of mounts, intromissions and ejaculations from the male were observed in the unilevel 4-hole pacing chamber. The effects of adrenalectomy (ADX) and strain (Long-Evans vs. Wistar) were also assessed. Long-Evans OVX rats treated with 5 μg EB every 8 days showed persistently low levels of sexual behavior. Sensitization was most robust following 10 μg EB at 4-day intervals. Very few sexual behaviors were ever induced by 2 μg EB. ADX did not affect the development of behavioral sensitization by 10μg EB. Therefore, to achieve a low steady state of sexual behaviors in sexually experienced Long-Evans OVX rats 5μg of EB administered every 8days is optimal, whereas a persistently high level of sexual behaviors is induced with 10 μg EB administered every 4 days. OVX Wistar rats are behaviorally more sensitive to EB. Behavioral sensitization to EB may serve as a mechanism to optimize reproductive success.

Sensitization of sexual behaviors in ovariectomized Long-Evans rats is induced by a subthreshold dose of estradiol benzoate and attenuated by repeated copulation.

Ovariectomy (OVX) abolishes the expression sexual behaviors in the rat, but they can be fully reinstated by sequential administration of estradiol benzoate (EB) followed by progesterone (P). When administered alone, 5 or 10 μg EB (but not 2 μg) acutely induce only low levels of lordosis, whereas repeated administration potentiates lordosis and induces sexually appetitive behaviors (e.g., hops, darts, solicitations, ear wiggles). The mechanisms mediating this behavioral sensitization are poorly understood, and it is not clear whether stimulation from the male during repeated copulation plays a role. OVX Long-Evans rats were given 4 sexual training sessions with EB (10 μg) and P (500 μg) 48 and 4h prior to testing, respectively, in a unilevel 4-hole pacing chamber followed by a 2-week hormone washout. Females were then treated with 2 μg or 10 μg EB 48 h prior to copulation on Tests 1 and 8. On Tests 2-7, a group of females was treated with 10 μg EB and allowed to copulate with a male (10 μg EB/Male, n = 16), or treated with 2 μg or 10 μg EB and placed in the chamber alone (2 μg EB/Alone, n = 6; 10 μg EB/Alone, n = 18). A negative control group was treated with the oil vehicle and placed in the chamber alone (Oil/Alone, n = 6) on Tests 2-7, but treated with 2 μg EB prior to copulatory Tests 1 and 8. All groups, except Oil, displayed behavioral sensitization to EB, suggesting that repeated administration EB is both necessary and sufficient to induce sensitization. Appetitive behaviors were attenuated in those that copulated on every session. Pacing was disrupted in all groups. Together these results suggest that EB activates excitatory mechanisms to promote the expression of sexual behaviors, which are potentiated across time under certain conditions. In contrast, copulatory stimulation attenuates behavioral sensitization to EB.

Female Sexual Behavior

This chapter reviews the current state of knowledge concerning the neurobiology of female sexual behavior, including sexual arousal, appetitive desire, pacing of sexual stimulation, the receptive postures that allow vaginal penetration to occur, and the inhibitory or refractory states induced by sexual stimulation, sexual nonreward, and/or the steroid hormone milieu. Data from a variety of species, including humans, is discussed at several levels of analysis that link neuroendocrinology, neuropharmacology, and molecular biology. The context in which sexual behavior occurs, especially during an animals first sexual experiences, is considered in terms of culture and experimental conditioning, processes that alter neuronal responses, and ultimately behavior in the presence of external sexual incentive cues that predict sexual pleasure or nonreward. New vistas for further research are discussed.

Partner preference for strain of female in Long-Evans male rats

Although male rats are reported to show greater sexual arousal and mating preference for a novel female compared to a familiar one, we have shown that after repeated copulation to ejaculation with a female bearing a neutral odor in bilevel pacing chambers, or unilevel pacing chambers bisected by a 1-hole divider, male rats display a conditioned ejaculatory preference for a female bearing the odor relative to a female not bearing the odor. The aim of the present study was to examine whether males might also develop a conditioned ejaculatory preference for the strain characteristics of the female after repeated copulation with the same female in a pacing chamber bisected by either a 1-hole or 4-hole divider. In this experiment, male Long-Evans rats were given 10 copulatory trials with the same Long-Evans or Wistar female in either the 1-hole or 4-hole condition. Copulatory preferences were then examined in an open field where males had the choice to copulate with either the familiar female or a novel one of a different strain from the familiar female. Results indicated that Long-Evans males trained in the 1-hole condition with the same Long-Evans female displayed a conditioned ejaculatory preference for the familiar vs. novel female. However, males trained in the 1-hole condition with the same Wistar female at every trial copulated indiscriminately with the familiar and novel females. No preference was detected in males trained in the 4-hole condition. These findings suggest that, following training in a 1-hole pacing chamber, males displayed an ejaculatory preference only if the familiar female is of their own strain.

The effects of chronic administration of testosterone propionate with or without estradiol on the sexual behavior and plasma steroid levels of aged female rats.

Low sexual desire concomitant with feelings of distress is reported in naturally and surgically menopausal women. A combination of estradiol (E2) and testosterone (T) restores sexual desire and interest in these women. The central mechanisms by which E2 and T act to restore desire are poorly understood. Here we examined the effect of chronic treatment with testosterone propionate (TP) administered by a sc SILASTIC brand capsule in aged ovary-intact female rats. Females were first treated with TP alone, followed by a second phase when TP was administered in combination with estradiol benzoate (EB; 10 μg) by sc injection 48 h prior to testing (EB+TP). Each phase consisted of 5 test days at 4-d intervals. Appetitive and consummatory female sexual behaviors were observed in bilevel chambers, and plasma E2 and T concentrations were measured with ELISA. Sexual solicitations and hops and darts were facilitated by the highest TP dose, and the lordosis quotient was increased by the two highest TP doses when administered alone, coinciding with an increase in plasma T, but those behavioral effects were not maintained across time. The lordosis quotient was inversely related to the TP dose in the EB+TP phase. These results suggest that the administration of TP by sc capsules to aged female rats facilitates appetitive and consummatory sexual behaviors; however, chronic treatment appears to be inhibitory. This is the first study to assess sexual behavior after SILASTIC brand implants of TP in the aged female rat. Additional research is needed to elucidate the mechanisms underlying the effects of T on female sexual function.

Repeated administration of estradiol promotes mechanisms of sexual excitation and inhibition: Glutamate signaling in the ventromedial hypothalamus attenuates excitation

Repeated administration of 10 μg of estradiol benzoate (EB) every 4 days to the ovariectomized (OVX) rat induces a behavioral sensitization of sexual behaviors. Repeated copulation or the receipt of vaginocervical stimulation (VCS) attenuates the sensitization of appetitive sexual behaviors, suggesting that VCS acts in opposition to the mechanisms that induce the sensitization. It is known that VCS accelerates the onset of estrous termination (characterized by a decrease in appetitive sexual behaviors, and an increase in defensive behaviors prior to the decline in lordosis), and glutamate transmission in the ventromedial hypothalamus (VMH), particularly via AMPA receptor signaling, is an important regulator of this effect. Thus, the current studies examined whether mechanisms of estrous termination are involved in the attenuated sensitization to EB that occurs with repeated copulation. In the first study, OVX rats received infusions of AMPA to the VMH on tests 2-4, and sexual behavior was measured on tests 1 and 5. Appetitive sexual behaviors were lower in females that received AMPA infusions in place of copulation compared to saline, suggesting that AMPA receptor activation by VCS may be playing a role in the attenuation of sensitization. In the second study, females that were not given the opportunity to copulate on tests 2-4 fell out of behavioral estrus faster than those that did, suggesting that both excitatory and inhibitory mechanisms of sexual behavior become sensitized with repeated administration of EB. Together these findings extend our hypothesis that repeated episodes of heat sensitize the activation of sexual behaviors to increase the probability of eventual fertilization.

Facilitation of sexual behavior in ovariectomized rats by estradiol and testosterone: A preclinical model of androgen effects on female sexual desire

In the United States and Canada, there are no approved treatments for hypoactive sexual desire disorder in postmenopausal women. Testosterone improves female sexual desire in naturally- and surgically-menopausal women maintained on estrogen replacement therapy, and long-term safety data from randomized placebo-controlled clinical trials has yielded promising results. However, the mechanisms associated with its efficacy are not known, and could be addressed using preclinical rodent models; yet there is no systematic evaluation of the effects of estradiol and testosterone on female rat sexual behavior. The aim of these studies was to assess whether testosterone propionate (TP) facilitates sexual behaviors, particularly appetitive sexual behaviors, in Long-Evans and Wistar ovariectomized (OVX) rats primed with estradiol benzoate (EB). In Experiment 1, Long-Evans OVX rats were treated with Oil (O), 10μg EB+O, O+200μg TP, 10μg EB+500μg progesterone (P), or 10μg EB+200μg TP. In Experiment 2a, Wistar OVX rats were treated with varying doses of EB (2.5, 5, or 10μg) 48h prior, and TP (0, 200, or 400μg) 4h prior to testing in a Latin-Square design. A subset of animals was used in Experiment 2b and treated sequentially with EB (0, 2.5, 5, or 10μg) followed by TP (0, 200, or 400μg, in a Latin-Square design) 48h prior to sexual behavior testing. All tests occurred in the bilevel pacing chamber. Frequencies of female appetitive (hops/darts, solicitations, level changes) and consummatory (lordosis quotient and magnitude) sexual behaviors as well as the number of defensive behaviors towards males were scored. Number of mounts, intromissions and ejaculations from males were also scored. In EB-primed OVX Long-Evans rats, 200μg TP administered 4h prior to testing facilitated hops/darts and lordosis ratings beyond EB alone, and to levels equivalent to EB+P. In contrast, that regimen was not successful in EB-primed OVX Wistar rats. When EB and TP were co-administered 48h prior to testing, 10μg EB+200μg TP significantly increased hops/darts and level changes beyond that observed by 10μg EB alone. In summary, the administration of EB and TP to OVX Long-Evans and Wistar rats facilitates appetitive measures of sexual behavior. Strain differences exist that likely reflect underlying differences in sensitivities to EB, and the EB-primed OVX Long-Evans rat may be useful for studying mechanisms of TP-facilitation of desire due to higher baseline sexual inhibition.

RU486 facilitates or disrupts the sensitization of sexual behaviors by estradiol in the ovariectomized Long-Evans rat: Effect of timecourse.

An acute injection of estradiol benzoate (EB) to the ovariectomized (OVX) rat activates low levels of lordosis, and subsequent progesterone (P) administration augments lordosis and recruits a complete pattern of sexual behavior including appetitive behaviors (e.g., hops/darts and solicitations). However, repeated injections of 5μg or 10μg EB (but not 2μg EB), administered every 4days to sexually-experienced OVX rats results in a behavioral sensitization, such that lordosis quotients (LQs) and appetitive behaviors progressively increase. We have shown that adrenal P does not play a critical role because behavioral sensitization to EB is not prevented by adrenalectomy. Here we tested whether P receptors play a role by examining the effect of chronic administration of the P receptor antagonist RU486 at a dose that reliably inhibits sexual behavior in fully primed OVX rats. Females were treated with EB (5 or 10μg), and 5mg RU486 dissolved in 0.4mL vehicle (VEH; 80% sesame oil, 15% benzyl benzoate, 5% benzyl alcohol) 48h and 5h prior to each of 7 tests, respectively, occurring at 4-day intervals in unilevel 4-hole pacing chambers. Control animals were treated with 2, 5, or 10μg EB+VEH. As expected, sensitization did not occur in females treated with 2μg EB+VEH, and those females received fewer intromissions and ejaculations than all other groups. RU486 did not prevent the sensitization of LQ, moderate and high lordosis magnitudes (LM2 and LM3) or appetitive sexual behaviors on early tests, and in fact potentiated appetitive behaviors, LQ, LM2 and LM3, consistent with its facilitative actions in females treated with EB-alone, as we and others have reported previously. However, despite the initial facilitation, blocking P receptors by chronic administration of RU486 inhibited the maintenance of behavioral sensitization to EB.

Vaginocervical stimulation attenuates the sensitization of appetitive sexual behaviors by estradiol benzoate in the ovariectomized rat.

The acute administration of estradiol benzoate (EB) to the ovariectomized (OVX) rat induces low levels of lordosis while sexually appetitive behaviors (e.g., hops, darts, solicitations) are absent, yet the repeated administration of EB results in a behavioral sensitization in which lordosis is potentiated and sexually appetitive behaviors are induced. We have shown that repeated copulation attenuates the sensitization of appetitive sexual behaviors. Here, we assessed which component of male stimulation during copulation is involved in the attenuation. On 8 occasions, sexually experienced OVX Long-Evans rats were treated with 10μgEB and 48h later assigned to one of six groups that differed in their experience on intermediates tests (2-7). One was given repeated access to a male (EB/Male), and another was placed in the copulation chamber alone (EB/Alone) on intermediate tests. Three groups were given one of three somatosensory stimuli by the experimenter: manual flank stimulation (FLS), clitoral stimulation (CLS), or vaginocervical stimulation (VCS). Finally, the control group was left undisturbed in the animal care facility (ACF). Sexual behaviors were measured on Tests 1 and 8. VCS received from the experimenter (VCS) or from the male during copulation (EB/Male) attenuated the magnitude of the sensitization of appetitive sexual behaviors compared with those that were not brought to the testing rooms (ACF), and the effect was most pronounced on sexual solicitations. These results suggest that VCS received during penile intromission inhibits the sensitization of sexually appetitive behaviors by repeated administration of EB. As such, repeated administration of EB may oppose those mechanisms that induce estrous termination, perhaps by sensitizing inhibitory processes within the ventromedial hypothalamus that typically prevent the display of sexual behaviors (i.e., by facilitating disinhibition).