Progesterone and Allopregnanolone Rapidly Attenuate Estrogen-Associated Mechanical Allodynia in Rats with Persistent Temporomandibular Joint Inflammation.

Temporomandibular joint disorder (TMD) is associated with pain in the joint (temporomandibular joint, TMJ) and muscles involved in mastication. TMD pain dissipates following menopause but returns in some women undergoing estrogen replacement therapy. Progesterone has both anti-inflammatory and antinociceptive properties, while estrogen's effects on nociception are variable and highly dependent on both natural hormone fluctuations and estrogen dosage during pharmacological treatments, with high doses increasing pain.

Sex Differences and Estrous Cycle Effects of Peripheral Serotonin-Evoked Rodent Pain Behaviors.

Many persistent pain conditions occur predominantly in women making pain a major women's health issue. One theory for the prevalence in females is hormone modulation of pain mechanisms. The peripheral release of the neurotransmitter serotonin (5HT) has been implicated in various sexually dimorphic pain conditions; yet no studies have examined the effect of ovarian hormones on peripheral 5HT-evoked pain behaviors.

Use of an operant paradigm for the study of antidepressant-induced sexual dysfunction.

These studies were designed to develop a paradigm for the detection of antidepressant-induced sexual dysfunction in female rats. Ovariectomized, Fischer rats were conditioned to nose poke to open a guillotine door to gain access to a sexually active male. To develop the procedure, we examined the acquisition and stability of the response with a 15-s fixed interval, compared rats treated with 10 μg estradiol benzoate and 500 μg progesterone with those that received only estradiol benzoate, and carried out a preliminary analysis of the effects of 5, 10, and 15 mg/kg fluoxetine.

Repeated estradiol benzoate treatment protects against the lordosis-inhibitory effects of restraint and prevents effects of the antiprogestin, RU486.

The following experiment was designed to test two specific questions: (1) Does the antiprogestin, RU486, reduce emergence of lordosis behavior and/or proceptivity in rats given repeated treatment with 10μg estradiol benzoate (EB) and/or a single high dose (40μg) of EB? (2) Does RU486 accentuate the effects of a 5min restraint experience on sexual behaviors in rats given repeated treatment with estradiol benzoate (EB) and/or a high dose of EB? RU486 was used to determine if a high dose and/or repeated treatment with EB enhanced proceptivity and reduced the response to mild stress through an intracellular progesterone receptor-mediated process. Ovariectomized Fischer rats were injected with a single dose of 10 or 40μg estradiol benzoate (EB) or received 4consecutiveweeks of treatment with 10μg EB. Forty-eight hours after the last treatment with EB, rats were injected with 5mg/kg of the antiprogestin, RU486, or the RU486 vehicle.

Dose-dependent effects of the antiprogestin, RU486, on sexual behavior of naturally cycling Fischer rats.

Regularly cycling Fischer female rats were treated with either a low (5mg/kg) or high (5mg/RAT; approximately 30mg/kg) dose of the antiprogestin, RU486, before the morning of proestrus or on the morning of proestrus. The emergence of sexual behavior after treatment with RU486 was examined in a mating test with a sexually active male rat. Lordosis behavior was remarkably resistant to the effects of RU486.

Allopregnanolone's attenuation of the lordosis-inhibiting effects of restraint is blocked by the antiprogestin, CDB-4124.

A brief restraint experience reduces lordosis behavior in ovariectomized females that have been hormonally primed with estradiol benzoate. The addition of progesterone to the priming prevents the lordosis inhibition. Based on prior studies with an inhibitor of progesterone metabolism, we have implicated the intracellular progesterone receptor, rather than progesterone metabolites, as responsible for this protection.

Pharmacology of serotonin and female sexual behavior.

In this review, first a historical perspective of serotonin's (5-HT) involvement in female sexual behavior is presented. Then an overview of studies implicating 5-HT is presented. The effect of drugs that increase or decrease CNS levels of 5-HT is reviewed.

Comparison of female Fischer and Sprague-Dawley rats in the response to ketanserin.

The effects of the 5-HT2A/2C receptor antagonist, ketanserin, on lordosis behavior were examined in hormonally primed, ovariectomized Fischer and Sprague-Dawley females. Rats were primed with 0.067μg/g body weight estradiol benzoate and 3.

Prior hormonal treatment, but not sexual experience, reduces the negative effects of restraint on female sexual behavior.

These experiments were designed to determine if prior sexual experience reduced the negative effect of mild stress on female sexual behavior. In the first experiment, ovariectomized rats were hormonally primed with estradiol benzoate and progesterone for 3 consecutive weeks during which they received six mating experiences in a male's home cage or received no sexual experience. The next week, females were primed with 10 μg estradiol benzoate two days before a 5 min restraint.

An antiprogestin, CDB4124, blocks progesterone's attenuation of the negative effects of a mild stress on sexual behavior.

These experiments were designed to test the hypothesis that a progesterone receptor antagonist would block progesterone's ability to reduce the negative effects of a 5 min restraint on female rat sexual behavior. Ovariectomized Fischer rats were injected with 10 μg estradiol benzoate. Two days later, rats were injected subcutaneously (sc) with the progesterone receptor antagonist, CDB4124 (17α-acetoxy-21-methoxy-11β-[4-N,N-dimethyaminopheny]-19-norpregna-4,9-dione-3,20-dione) (60 mg/kg), or vehicle (20% DMSO+propylene glycol).

Sprague-Dawley and Fischer female rats differ in acute effects of fluoxetine on sexual behavior.

Introduction: The 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.

RU486 blocks effects of allopregnanolone on the response to restraint stress.

These experiments were designed to provide information about the potential involvement of progesterone receptors in the ability of allopregnanolone (3α-hydroxy-5α-pregnan-20-one) to reduce the lordosis-inhibiting effects of restraint stress. Ovariectomized Fischer rats were hormonally primed with 10 μg estradiol benzoate and 4 mg/kg allopregnanolone or vehicle. One hour before allopregnanolone, rats were injected with the progesterone receptor antagonist, RU486 (11β-(4-dimethylamino)phenyl-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one), or vehicle.

Factors influencing fluoxetine-induced sexual dysfunction in female rats.

Treatment with selective serotonin reuptake inhibitors, such as fluoxetine, produces sexual side effects with low sexual desire being the most prevalent effect in females. In few studies have preclinical models for such antidepressant-induced sexual dysfunction been fruitful. In the current manuscript, the effects of fluoxetine on multiple measures of female sexual motivation and sexual receptivity were examined.

Mechanisms responsible for progesterone's protection against lordosis-inhibiting effects of restraint I. Role of progesterone receptors.

Progestins and antiprogestins are widely used therapeutic agents in humans. In many cases, these are indicated for the treatment of reproductive activities. However, progesterone has widespread physiological effects including a reduction of the response to stress.

Mechanisms responsible for progesterone's protection against lordosis-inhibiting effects of restraint II. Role of progesterone metabolites.

When ovariectomized Fischer female rats are hormonally primed with 10 μg estradiol benzoate, a 5 min restraint experience rapidly inhibits lordosis behavior. Addition of progesterone to the hormonal priming prevents this restraint-induced inhibition. In prior work, we reported evidence that progesterone receptors (PR) may contribute to this protective effect of progesterone.

Fluoxetine prevents 8-OH-DPAT-induced hyperphagia in Fischer inbred rats.

Ovariectomized, Fischer rats were hormonally primed with 10 μg estradiol benzoate and 50 μg progesterone or were treated with the sesame seed oil vehicle. Food intake was measured 2 h and 24 h after treatment with 0.25 mg/kg of the 5-HT(1A) receptor agonist, (±)-8-hydroxy 2-(di-n-propylamino) tetralin (8-OH-DPAT), 5 mg/kg of the selective serotonin reuptake inhibitor, fluoxetine, or their combination.

Tropisetron increases the inhibitory effect of mild restraint on lordosis behavior of hormonally primed, ovariectomized rats.

Ovariectomized rats, hormonally primed with 10 μg estradiol benzoate and 500 μg progesterone are resistant to the lordosis-inhibiting effects of a 5 min restraint experience. However, modulation of the serotonergic (5-HT) system alters this resistance to stress. In the following experiment, ovariectomized Fischer inbred rats were hormonally primed with 10 μg estradiol benzoate and 500 μg progesterone.

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

Ovariectomized Fischer inbred rats were hormonally primed with 10μg estradiol benzoate and sesame seed oil (EO rats) or with estradiol benzoate and 500μg 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 200ng 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.

Role of 5-HT(1A) receptors in fluoxetine-induced lordosis inhibition.

The selective serotonin reuptake inhibitor (SSRI), fluoxetine (Prozac(R)), is an effective antidepressant that is also prescribed for other disorders (e.g. anorexia, bulimia, and premenstrual dysphoria) that are prevalent in females.

Progesterone reduces the effect of the serotonin 1B/1D receptor antagonist, GR 127935, on lordosis behavior.

Ovariectomized rats were hormonally primed with 10 microg estradiol benzoate or with estradiol benzoate plus 500 microg progesterone. Rats received a bilateral infusion with 200 ng of the 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-1-1'-biphenyl-4-carboxamide hydrochloride (GR 127935), into the ventromedial nucleus of the hypothalamus (VMN), followed by a 5 min restraint or home cage experience. In estrogen-primed females that had experienced minimal handling between ovariectomy and use in the experiment, infusion with the water vehicle transiently inhibited lordosis behavior, and the 5-HT(1B/1D) receptor antagonist amplified this inhibition.

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

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.

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.

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.

The PKC inhibitor, bisindolymaleimide, blocks DOI's attenuation of the effects of 8-OH-DPAT on female rat lordosis behavior.

Ovariectomized rats with bilateral cannulae near the ventromedial nucleus of the hypothalamus were hormonally primed with 10 microg estradiol benzoate and 500 microg progesterone. Sexually receptive females were infused bilaterally with 200 ng of the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), or with a combination of 200 ng 8-OH-DPAT and 2000 ng of the 5-HT(2) receptor agonist, (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane HCl (DOI). 8-OH-DPAT inhibited lordosis behavior and DOI reduced this inhibition.

8-OH-DPAT attenuates isoproterenol- but not forskolin-stimulated accumulation of cAMP in mediobasal hypothalamus.

Ovariectomized female rats were used to test the possibility that the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), inhibits cyclic AMP (cAMP) accumulation in the mediobasal hypothalamus. Tissue slices were incubated with forskolin or with the beta-adrenergic receptor agonist, isoproterenol, to stimulate accumulation of cAMP. Both compounds increased accumulation of cAMP.