Apelin-13 facilitates lordosis behavior following infusions to the ventromedial hypothalamus or preoptic area in ovariectomized, estrogen-primed rats.

In normal hormonal conditions, increased neuronal activity in the ventromedial hypothalamus (VMH) induces lordosis whereas activation of the preoptic area (POA) exerts an opposite effect. In the present work, we explored the effect of bilateral infusion of different doses of the apelin-13 (0.37, 0.75, 1.5, and 15 µg) in both brain areas on the expression of lordosis behavior. Lordosis quotient and lordosis reflex score were performed at 30, 120, and 240 min. Weak lordosis was observed following the 0.37 µg dose of apelin-13 at 30 min in the VMH of EB-primed rats; however, the rest of the doses induced significant lordosis relative to the control group. At 120 min, all doses induced lordosis behavior, while at 240 min, the highest dose of 15 µg did not induce significant differences. Interestingly, only the 0.75 µg infusion of apelin in the POA induced significant lordosis at 120 and 240 min. These results indicate that apelin-13 acts preferably in HVM and slightly in POA to initiate lordosis behavior in estrogen-primed rats.

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.

Flibanserin treatment increases appetitive sexual motivation in the female rat.

INTRODUCTION: Flibanserin is a mixed 5-HT1A agonist/5-HT2A antagonist that has been developed for the treatment of hypoactive sexual desire disorder in women. AIM: To assess the acute and chronic dose-response effects of flibanserin on measures of sexual desire and copulation in ovariectomized rats primed with estradiol benzoate (EB) alone or in combination with progesterone (P). METHODS: In Experiment 1, sexually experienced ovariectomized (OVX) rats at one testing site were rendered fully sexually receptive with EB + P priming and tested weekly with a sexually active male in bi-level pacing chambers following daily flibanserin treatment for 28 days. In Experiment 2, sexually experienced OVX rats at a different testing site received EB alone and were tested weekly with sexually active males following daily flibanserin treatment. MAIN OUTCOME MEASURES: Female appetitive behaviors (solicitations, hops and darts, anogenital investigations), defensive behaviors, pacing, lordosis, and male copulatory responses (intromissions and ejaculations) were measured during each 30-minute copulation test. RESULTS: Acute flibanserin or 1 week of chronic flibanserin treatment did not modify sexual responses in fully (EB + P) or partially (EB-alone) primed females. After 2 weeks of chronic treatment, fully primed females displayed significantly more solicitations than the three other groups. After 3 weeks of chronic treatment, a significant increase in female solicitations was observed in both hormone-treatment groups. CONCLUSION: This study shows the first evidence that chronic, but not acute, flibanserin treatment augments appetitive sexual behaviors in OVX female rats primed with EB + P or EB alone. Given the positive effect of flibanserin in clinical trials, these results confirm previous reports that solicitations in the female rat are a predictive animal model of human female sexual desire.

Vaginocervical stimulation induces Fos in glutamate neurons in the ventromedial hypothalamus: attenuation by estrogen and progesterone.

Vaginocervical stimulation (VCS) induces the immediate-early gene product Fos in the ventromedial hypothalamus (VMH) of female rats. However, this induction is lower in ovariectomized rats that receive estradiol benzoate (EB) and progesterone (P) relative to an oil vehicle. We have observed that a substantial proportion of cells activated in the VMH by VCS stain for glutamate, and infusions of glutamate or its selective receptor agonists to the VMH inhibit both appetitive and consummatory sexual behaviors in females. This raises the possibility that VCS activates an inhibitory glutamate system in the VMH, and that ovarian steroids blunt the activation, although it is not known whether EB or P, alone or in combination, lead to this effect. The present experiment examined the ability of VCS to induce Fos in glutamate neurons in the VMH of ovariectomized rats under 4 hormonal regimens: oil, EB alone, P alone, or EB+P, following 1 or 50 distributed VCSs administered with a lubricated glass rod over the course of 1 h. Treatment with EB or P alone significantly reduced the number of glutamate neurons activated by 1 VCS, with P being more effective than EB. Treatment with EB+P also produced a significant reduction, but not to the extent of EB or P alone. Although EB and P work in synergy to activate sexual behavior in female rats, actions of EB or P alone are sufficient to blunt the ability of VCS to activate glutamate neurons in the VMH. It thus appears that ovarian steroids may "disinhibit" sexual responding, in part, by dampening the ability of VCS to activate glutamate neurons in the VMH. In turn, this may allow females to receive a sufficient number of intromissions for the activation of sexual reward and the facilitation of pregnancy.

Pathways of sexual desire.

INTRODUCTION: Sexual desire is controlled by brain systems involved in sexual excitation and inhibition. Hypoactive sexual desire disorder (HSDD) may result from hypofunctional excitation, hyperfunctional inhibition, or some mix of the two. AIM: This study aimed to identify neurochemical and neuroanatomical systems involved in sexual excitation and inhibition, their role during normal, and hypoactive sexual expressions. METHODS: A comprehensive review of the human and animal literature is made, and a theory surrounding the ways that HSDD can be manifested and treated is presented. MAIN OUTCOME MEASURES: Drug effects and neural systems derived largely from rat studies that are involved in the stimulation of sexual desire (excitatory system) vs. the stimulation of sexual reward, sedation, and satiety (inhibitory system). RESULTS: Brain dopamine systems (incertohypothalamic and mesolimbic) that link the hypothalamus and limbic system appear to form the core of the excitatory system. This system also includes melanocortins, oxytocin, and norepinephrine. Brain opioid, endocannabinoid, and serotonin systems are activated during periods of sexual inhibition, and blunt the ability of excitatory systems to be activated. CONCLUSIONS: Drugs that stimulate the activation of hypothalamic dopamine or that blunt endocannabinoid or serotonin release and/or postsynaptic binding may be effective in stimulating sexual desire in animals and humans. The characterization of how those drugs work will help generate a rational approach to drug development in the treatment of HSDD.

High-dose methadone maintenance in rats: effects on cocaine self-administration and behavioral side effects.

It has been demonstrated that high-dose methadone maintenance is efficacious in reducing cocaine abuse in opioid-dependent individuals, but it is not clear whether this is caused by an action of methadone on the direct reinforcing properties of cocaine or on cocaine seeking. Also, it is not clear whether high-dose methadone maintenance may induce behavioral side effects, which could limit its clinical use. Here, we report that high-dose methadone maintenance (20-40 mg/kg/day) does not reduce, and even enhances cocaine (10-30 mg/kg, i.p.)-induced elevation in dopamine concentration in the ventral striatum measured by in vivo microdialysis. In parallel, however, rats maintained on high-dose methadone (30 mg/kg/day) seek and consume significantly less cocaine than controls when tested for intravenous cocaine (0.5 mg/kg/infusion) self-administration on a progressive ratio schedule of reinforcement. This reduction in cocaine self-administration does not result from impaired sensory-motor functioning as rats maintained on high-dose methadone show normal locomotor activity. Furthermore, the reduction in responding for cocaine does not seem to result from general behavioral deficits as male rats maintained on high methadone doses respond normally to palatable food and thermal pain, although their sexual responses to receptive females are greatly suppressed. Taken together, these results from studies in rats support the usefulness of larger doses of methadone to reduce severe cocaine abuse in opioid-dependent individuals and possibly in the management of pure-cocaine addiction.

Role of glutamate receptors in the ventromedial hypothalamus in the regulation of female rat sexual behaviors. II. Behavioral effects of selective glutamate receptor antagonists AP-5, CNQX, and DNQX.

Bilateral infusions of glutamate or its selective ionotrophic receptor agonists to the ventromedial hypothalamus (VMH) produce a rapid inhibition of both appetitive and consummatory sexual behavior in hormone-primed female rats. The present study examined whether infusion of selective ionotrophic glutamate receptor antagonists to the VMH can facilitate female sexual behavior in females treated with estradiol benzoate (EB) and progesterone (P), or EB alone. Ovariectomized, sexually experienced female rats were implanted bilaterally with guide cannulae aimed at the ventrolateral VMH. After recovery from surgery, females were primed either with EB+P or EB alone, and infused with saline, or one of two doses each of AP-5 (to target NMDA receptors), CNQX, or DNQX (to target AMPA/kainate receptors), immediately before tests with sexually vigorous male rats in bilevel chambers. In general, the drug infusions had a more powerful effect in females primed with EB alone compared to females primed with EB+P. AP-5 increased lordosis in females primed with EB alone. CNQX had a similar facilitative effect on lordosis, and also increased solicitations. DNQX increased solicitations in both hormone-priming conditions, increased lordosis quotients and magnitudes, and decreased pacing and defensive responses in the EB-alone condition. These results indicate that antagonism of glutamate receptors in the VMH resembles the effect of P, and that the addition of P to an EB baseline eliminates most of the effects of glutamate receptor antagonists. These data support the notion that glutamate receptors in the VMH contribute a strong inhibitory influence in the control of female sexual behavior.

Role of glutamate receptors in the ventromedial hypothalamus in the regulation of female rat sexual behaviors I. Behavioral effects of glutamate and its selective receptor agonists AMPA, NMDA and kainate.

Bilateral infusions of glutamate or kainate to the ventromedial hypothalamus (VMH) have been shown previously to produce a rapid inhibition of lordosis in estrogen-primed female rats induced by manual flank stimulation. The present study examined whether glutamate or selective ionotrophic glutamate receptor agonists can disrupt appetitive and consummatory sexual behaviors following bilateral infusions to the VMH of females during copulation with male rats. Ovariectomized, sexually experienced female rats were implanted bilaterally with guide cannulae aimed at the ventrolateral VMH. After recovery from surgery, females were primed with estradiol benzoate and progesterone and infused with different doses of glutamate, AMPA, NMDA or kainate (n=9-10 in each dose group) 3 min prior to a test with sexually vigorous males in bilevel chambers. Glutamate infusions decreased the display of hops and darts and produced a trend toward decreased lordosis. AMPA infusions decreased the display of solicitations, hops and darts, and lordosis. NMDA infusions decreased lordosis and increased defensive behaviors and pacing. Kainate infusions decreased solicitations, hops and darts, and lordosis, and increased defensive behaviors and pacing. These data indicate that the activation of glutamate receptors in the VMH is inhibitory for both appetitive and consummatory aspects of sexual behavior in the female rat.