Juan M. Dominguez

Dopamine, the medial preoptic area, and male sexual behavior

The medial preoptic area (MPOA), at the rostral end of the hypothalamus, is important for the regulation of male sexual behavior. Results showing that male sexual behavior is impaired following MPOA lesions and enhanced with MPOA stimulation support this conclusion. The neurotransmitter dopamine (DA) facilitates male sexual behavior in all studied species, including rodents and humans. Here, we review data indicating that the MPOA is one site where DA may act to regulate male sexual behavior. DA agonists microinjected into the MPOA facilitate sexual behavior, whereas DA antagonists impair copulation, genital reflexes, and sexual motivation. Moreover, microdialysis experiments showed increased release of DA in the MPOA as a result of precopulatory exposure to an estrous female and during copulation. DA may remove tonic inhibition in the MPOA, thereby enhancing sensorimotor integration, and also coordinate autonomic influences on genital reflexes. In addition to sensory stimulation, other factors influence the release of DA in the MPOA, including testosterone, nitric oxide, and glutamate. Here we summarize and interpret these data.

A Role for Hypocretin (Orexin) in Male Sexual Behavior

The role of hypocretin (orexin; hcrt/orx) neurons in regulation of arousal is well established. Recently, hcrt/orx has been implicated in food reward and drug-seeking behavior. We report here that in male rats, Fos immunoreactivity (ir) in hcrt/orx neurons increases markedly during copulation, whereas castration produces decreases in hcrt/orx neuron cell counts and protein levels in a time course consistent with postcastration impairments in copulatory behavior. This effect was reversed by estradiol replacement. Immunolabeling for androgen (AR) and estrogen (ERα) receptors revealed no colocalization of hcrt/orx with AR and few hcrt/orx neurons expressing ERα, suggesting that hormonal regulation of hcrt/orx expression is via afferents from neurons containing those receptors. We also demonstrate that systemic administration of the orexin-1 receptor antagonist SB 334867 [N-(2-methyl-6-benzoxazolyl)-N″-1,5-naphthyridin-4-yl urea] impairs copulatory behavior. One locus for the prosexual effects of hcrt/orx may be the ventral tegmental area (VTA). We show here that hcrt-1/orx-A produces dose-dependent increases in firing rate and population activity of VTA dopamine (DA) neurons in vivo. Activation of hcrt/orx during copulation, and in turn, excitation of VTA DA neurons by hcrt/orx, may contribute to the robust increases in nucleus accumbens DA previously observed during male sexual behavior. Subsequent triple immunolabeling in anterior VTA showed that Fos-ir in tyrosine hydroxylase-positive neurons apposed to hcrt/orx fibers increases during copulation. Together, these data support the view that hcrt/orx peptides may act in a steroid-sensitive manner to facilitate the energized pursuit of natural rewards like sex via activation of the mesolimbic DA system.

Getting his act together: roles of glutamate, nitric oxide, and dopamine in the medial preoptic area.

Gonadal hormones have primarily slow, genomically mediated effects, but copulation requires rapid interactions with a partner. A major way in which hormones facilitate male sexual behavior is by increasing production of neurotransmitter receptors or of enzymes that regulate neurotransmitter synthesis or release. Dopamine is an important facilitative neurotransmitter, and the medial preoptic area (MPOA) is a critical integrative site for male sexual behavior. MPOA dopamine is released before and during mating and facilitates copulation, genital reflexes, and sexual motivation. Gonadal hormones regulate dopamine release in the MPOA of male rats in part by increasing nitric oxide synthase (NOS) in the MPOA; the resultant increase in production of nitric oxide (NO) increases both basal and female-stimulated dopamine release. Glutamate also increases dopamine release via increased production of NO. At least some of the glutamatergic inputs to the MPOA are from the medial amygdala (MeA) and bed nucleus of the stria terminalis (BNST), which mediate the female-stimulated increase in dopamine, which in turn enhances copulatory ability. Extracellular glutamate in the MPOA increases during copulation, especially during ejaculation, and increased glutamate facilitates copulation and genital reflexes. Previous sexual experience also facilitates copulation and confers resistance to impairment by various lesions, drugs, and stress. Experience enhances processing of sexual stimuli, and its effects require activation of glutamate NMDA receptors and NOS in the MPOA. Neuronal NOS is increased in the MPOA of experienced males. Therefore, glutamate, NO, and dopamine interact in the MPOA to facilitate mating and to enhance future sexual responsiveness.

The roles of nitric oxide in sexual function of male rats

Nitric oxide (NO) may mediate penile erection by inhibiting smooth muscle of the corpora cavernosa, thereby allowing vasodilation of the corpora. In order to test the role of NO in the sexual function of intact male rats, either the precursor of NO (L-arginine, L-Arg) or an inhibitor of its synthesis (NG-nitro-L-arginine methyl ester, NAME) was administered systemically before tests of copulation, ex copula genital reflexes, or sexual motivation/motor activity. NAME impaired copulation in a dose dependent manner. It also decreased the number of ex copula erections, but it increased the number of ex copula seminal emissions and decreased the latency to the first seminal emission. L-Arg marginally increased the number of penile reflexes, but had no other effects. NAME had no effect on sexual motivation or motor activity. The results indicate that nitric oxide promotes erection in intact male rats, probably by mediating filling of the corpora cavernosa. The data also suggest that NO inhibits seminal emission, probably by decreasing sympathetic nervous system activity; this may help prevent premature ejaculation.

Preoptic Glutamate Facilitates Male Sexual Behavior

The medial preoptic area (MPOA) is a critical regulatory site for the control of male sexual behavior. We first measured glutamate in 2 min microdialysate samples from the MPOA before, during, and after copulation by male rats. There was a slight [∼140% of baseline (BL)] rise in extracellular glutamate when the female was presented, a significant increase (∼170% of BL) during periods of mounting and intromitting, and a very large increase in samples collected during ejaculation (∼300% of BL). A precipitous fall in levels occurred in the first postejaculatory sample; the magnitude of this fall was highly correlated with the length of the postejaculatory interval of quiescence. In experiment 2, we reverse-dialyzed a mixture of glutamate uptake inhibitors into the MPOA before and during mating; control animals received artificial CSF. The mixture increased extracellular glutamate (∼280% of BL), increased the number of ejaculations in the 40 min test, decreased ejaculation latency, and decreased the postejaculatory latency to resume copulation. These data, together with other findings that glutamate in the MPOA can elicit genital reflexes in anesthetized rats and that glutamate receptor antagonists in the MPOA impair copulation, strongly suggest that MPOA glutamate is a major facilitator of copulation and that the postejaculatory fall in glutamate regulates the postejaculatory interval.

NITRIC OXIDE MEDIATES GLUTAMATE-EVOKED DOPAMINE RELEASE IN THE MEDIAL PREOPTIC AREA

Dopamine (DA) release in the medial preoptic area (MPOA) of the hypothalamus is an important facilitator of male sexual behavior. The presence of a receptive female increases extracellular DA in the MPOA, which increases further during copulation. However, the neurochemical events that mediate the increase of DA in the MPOA are not fully understood. Here we report that glutamate, reverse-dialyzed into the MPOA, increased extracellular DA, which returned to baseline after the glutamate was removed. This increase was prevented by co-administration of the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME), but not by the inactive isomer, Nw-nitro-d-arginine methyl ester (D-NAME). In contrast, extracellular concentrations of the major metabolites of DA were decreased by glutamate, suggesting that the DA transporter was inhibited. These decreases were also inhibited by L-NAME, but not D-NAME. These results indicate that glutamate enhances extracellular DA in the MPOA, at least in part, via nitric oxide activity. Therefore, glutamatergic stimulation of nitric oxide synthase may generate the female-induced increase in extracellular DA in the MPOA, which is important for the expression of male sexual behavior.

Stimulation of the medial amygdala enhances medial preoptic dopamine release: implications for male rat sexual behavior.

Increased dopamine (DA) in the medial preoptic area (MPOA) facilitates male sexual behavior. A major source of innervation to the MPOA is the medial amygdala (MeA). We now report that chemical stimulation of the MeA enhanced levels of extracellular MPOA DA in anesthetized male rats. These results suggest that DA activity in the MPOA can be regulated by input from the MeA to the MPOA.

Partial antagonism of 8-OH-DPAT'S effects on male rat sexual behavior with a D2, but not a 5-HT1A, antagonist

The serotonin agonist 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), injected systemically or directly into the medial preoptic area (MPOA), reduces the ejaculatory threshold in male rats. While 8-OH-DPAT has been characterized as an agonist at the 5-HT1A receptor, it also acts at other receptor sites including the dopamine D2 receptor. The current experiments investigated whether 8-OH-DPAT injected into the MPOA facilitates male sexual behavior through stimulation of the 5-HT1A receptor or the dopamine D2 receptor. Experiment 1 co-administered 8-OH-DPAT (6 microgram) with either the 5-HT1A antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-ben zamide hydrochloride (MPPI) (10 microgram) or the D2 antagonist raclopride (10 microgram). Raclopride blocked 8-OH-DPATs facilitative effects on ejaculation frequency and latency, while the 5-HT1A antagonist was ineffective. In Experiment 2, 8-OH-DPAT (500 microM), retrodialyzed into the MPOA through a microdialysis probe, enhanced male copulatory behavior similarly to the microinjection, increasing ejaculation frequency and decreasing ejaculation latency, postejaculatory interval and mount frequency. Retrodialyzing 8-OH-DPAT through a microdialysis probe in the MPOA had been previously shown to increase extracellular levels of dopamine and serotonin. The data from the present studies suggest that the effects of 8-OH-DPAT in the MPOA on male rat copulatory behavior may be mediated, at least in part, either directly through 8-OH-DPATs activity at D2 receptors or indirectly through 8-OH-DPATs ability to increase extracellular dopamine.

Intracellular preoptic and striatal monoamines in pregnant and lactating rats: possible role in maternal behavior.

In many mammals, hormonal fluctuations during pregnancy and parturition produce neurochemical events that are necessary for the transition from a non-maternal state to a maternal state that occurs when infants are born. However, the nature of these events is mostly unknown. We investigated whether changes in dopamine (DA) and serotonin (5-HT) activity within the preoptic area (POA) and striatum, neural sites important for some maternal behaviors, could be part of this process. Female rats were sacrificed as either diestrus virgins, on pregnancy day 10 or 20, on the day of parturition, or on day 7 or 17 of lactation. Bilateral tissue punches from the POA, dorsolateral striatum (ST(dl)), and nucleus accumbens (NA) were obtained and levels of intracellular DA and 5-HT analyzed with high-performance liquid chromatography with electrochemical detection (HPLC-EC). In the POA, DA was high in virgins and during early pregnancy, lowest on the day of parturition, and very high during lactation. Although there were no changes in the DOPAC to DA ratio (i.e., turnover), DOPAC levels also followed this pattern. 5-HT turnover in the POA was lower in virgins compared to other groups. In the ST(dl), DA turnover was highest during late pregnancy and on the day of parturition, while no changes in 5-HT measures were found. No significant effects were found in the NA. Therefore, decreased DAergic activity in the POA and increased DAergic activity in the ST(dl) occurs around parturition, the time when maternal behavior emerges, and may influence its onset.

Is sexual motivational state linked to dopamine release in the medial preoptic area

The medial preoptic area (mPOA) is a key site for the dopaminergic enhancement of male sexual behavior. Dopamine release increases in the rat mPOA with mating, supporting the critical stimulatory role played by preoptic dopamine on male sexual behavior. However, it has been questioned whether dopamine is specifically related to the occurrence of male sexual behavior and not simply involved in general arousal. To address this question, we asked whether dopamine release in the mPOA is linked to the production of male sexual behavior in Japanese quail (Coturnix japonica), a species that exhibits a much shorter temporal pattern of copulation than rats and does not have an intermittent organ, resulting in a very different topography of their sexual response. Extracellular samples from the mPOA of adult sexually experienced male quail were collected every 6 min before, during, and after exposure to a female using in vivo microdialysis and analyzed using high-performance liquid chromatography with electrochemical detection. Extracellular dopamine significantly increased in the presence of a female and returned to baseline after removal of the female. However, quail that failed to copulate did not display this increased release. These findings indicate that it is not solely the presence of a female that drives dopamine release in males, but how a male responds to her. Furthermore, in quail that copulated, dopamine release did not change in samples collected during periods of no copulation. Together, these findings support the hypothesis that dopamine action in the mPOA is specifically linked to sexual motivation and not only to copulatory behavior or physical arousal.