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.     

Effects of two-stage lesions of the medial preoptic area on sexual behavior of male rats

The effects of lesions of the medial preoptic area (MPOA) on sexual behavior of adult male rats were examined. Bilateral lesions were performed in either one or two stages. Bilateral, but not unilateral, destruction of the MPOA virtually eliminated mounts, intromissions, and ejaculation. No sparing of the male rats' sexual behavior was observed after two-stage MPOA lesions.     

Effect of prepuberal medial preoptic area lesions on male rat sexual behavior

Studies have shown that the medial preoptic area (MPOA) is necessary for male sexual behavior in many species. Sparing of function occurs in rats which have MPOA-lesions made prepuberally and are reared in heterosexual group cages. In the present study, male rats with MPOA-lesions made prepuberally and control-operated animals were reared either in group or solitary cages. In three regular mating tests few MPOA-animals reared in isolation displayed sexual behavior, while those reared in groups performed no differently from control animals. Animals with MPOA-lesions that mated exhibited the same frequency and developmental progression of play behaviors as their control peers. In sexual exhaustion and postcastration tests, group-reared MPOA-animals performed at a lower level than control animals. The results are compatible with the hypothesis that play experiences have a role in sparing of copulatory behavior in rats with MPOA-lesions. Deficits in the MPOA-animals in the more challenging tests were discussed in relation to a possible decrease in responsiveness to gonadal or hypothalamic hormones.     

Inhibition of male sexual behavior by serotonin application in the medial preoptic area

The study investigated the possible involvement of serotonin in the medial preoptic area in the regulation of sexual behavior of male rats. Injection of serotonin in the medial preoptic area resulted in an inhibition, whereas cyproheptadine (a serotonin antagonist) produced a slight facilitation, of male sexual behavior.     

Inactivation of the medial preoptic area/anterior hypothalamus by lidocaine reduces male sexual behavior and sexual incentive motivation in male rats

Permanent bilateral lesions of the medial preoptic area anterior hypothalamus (MPOA/AH) produce a drastic inhibition of male sexual behavior in all species studied to date. The present experiment was designed to evaluate if temporal inactivation of the MPOA/AH by infusions of lidocaine also inhibits sexual behavior in male rats. This would allow us to rule out the possibility that the behavioral effects observed after damage of the MPOA/AH could be associated with plastic changes induced by the lesion in other brain regions. We also evaluated sexual incentive motivation in males after the infusion of lidocaine in a test in which copulation is not possible but where males maintain approach behavior to the estrous females despite repeated testing. The percentage of animals displaying mounts, intromissions and ejaculation was significantly reduced while mount and intromission latency were prolonged after infusion of lidocaine. No changes were observed in sexual behavior after infusion of lidocaine in animals with cannulae outside the MPOA/AH suggesting that the inhibitory effects are specific to this brain region. Sexual incentive motivation was also affected by administration of lidocaine. Males consistently showed a clear preference for the sexually receptive female except when infused with lidocaine. After the infusion of the compound a significant reduction in the time spent in the incentive zone of the stimulus female was observed. These results support the hypothesis that neurons of the MPOA/AH are involved in the control of male sexual motivation.     

Orexin A (hypocretin-1) application at the medial preoptic area potentiates male sexual behavior in rats

The medial preoptic area plays an important role in the regulation of male sexual behavior in rats, and this area receives orexinergic inputs. The role of orexinergic inputs in the medial preoptic area in sexual behavior has not been studied, though they have been shown to play a role in some other physiological functions. In this study, the changes in male sexual behavior in rats were studied after local injection of orexin A (Hypocretin-1) at the medial preoptic area. The results of the study showed that orexin A application at the medial preoptic area increased sexual arousal as well as the copulatory performance. Sexual arousal is one of the physiological stimuli, which influences wakefulness. It is possible that the earlier reports showing increased wakefulness, on application of orexin A at the medial preoptic area/basal forebrain, has a contribution from sexual arousal.     

Dorsolateral connections of the medial preoptic area and maternal behavior in rats

The lateral connections of the medial preoptic area (MPOA) are essential for maternal behavior in rats. The purpose of this study was to more exactly specify the nature of this pathway. Experiment 1 found that knife cuts that severed the dorsolateral connections of the MPOA were as effective as complete cuts in disrupting maternal behavior, whereas knife cuts that severed the ventrolateral MPOA connections were ineffective. These results suggest that MPOA efferents and afferents critical for maternal behavior leave or enter the MPOA dorsolaterally. Experiment 2 located possible sources of critical afferent input. Lactating rats received MPOA lateral cuts with a horseradish peroxidase (HRP)-coated wire knife. Full lateral cuts and dorsolateral cuts disrupted maternal behavior and labeled more cells with HRP in the nucleus of the solitary tract and the locus coeruleus than did ventrolateral cuts, which did not disrupt maternal behavior.     

Mating activates NMDA receptors in the medial preoptic area of male rats

Studies have emphasized the role of the medial preoptic area (MPOA) as an important site for the regulation of male sexual behavior. Indeed, ablations of the MPOA impair sexual behavior, whereas stimulation of the MPOA enhances behavior. Furthermore, neural activity in the MPOA increases with mating. The current study tested the hypothesis that activation of N-methyl-D-aspartate (NMDA) receptors occurs in MPOA neurons and is essential for the expression of male sexual behavior in rats. Results indicate that nearly all MPOA neurons that expressed Fos following mating also contained the NR1 subunit of NMDA receptors. Furthermore, mating increased phosphorylation, thus activation, of NR1 in the MPOA. Additionally, blocking NMDA receptors significantly decreased mating-induced Fos expression and mating-induced phosphorylation of NMDA receptors and impaired male sexual behavior. These results provide evidence that mating activates NMDA receptors in the MPOA and that this activation is important for the expression of male sexual behavior.     

Multiple unit activities recorded from the medial preoptic area during copulatory behavior in freely moving male rats

Multiple unit activities (MUAs) were recorded from the medial preoptic area (MPO) during copulatory behavior in freely moving male rats. The baseline firing rate in the male MPO was 19.6 spikes/s +/- 7.1 S.E. (n = 14), and it was increased by 36.7% when a female rat was introduced (26.8 spikes/s +/- 8.9 S.E., n = 14). The firing rate remained elevated until ejaculation. The maximum firing rate (53.5 spikes/s +/- 16.7 S.E., n = 14) was obtained specifically during pursuit-mounting behavior. This high frequency firing with pursuit-mounting behavior was, however, immediately inhibited for 8.2 s +/- 2.1 S.E. (n = 14) when mounting was followed by intromission. The firing-inhibition was further prolonged (120.9 s +/- 44.6 S.E., n = 14) when ejaculation was performed after mounting and intromission. In cases where mounting was elicited alone, a firing-inhibition was not observed and the firing rate after mounting returned to the average firing rate during copulatory behavior. These results suggest that the MPO neurons may play a major role in pursuit-mounting, intromission and ejaculation.     

Facilitation of male rat copulatory behavior by electrical stimulation of the medial preoptic area

Lesion studies have demonstrated that the medial preoptic area (MPO) plays a critical role in male rat copulatory behavior. The present study attempted to better localize the neural elements mediating this behavior pattern and to determine the influence of preoptic area stimulation on particular aspects of copulatory behavior. Monopolar stimulating electrodes were implanted in the medial preoptic-anterior hypothalamic continuum or the lateral preoptic-medial forebrain bundle region. The effects of stimulating a particular locus were measured by comparing each animal's behavior on repeated stimulation and control tests. All measures of copulatory activity taken were facilitated by medial, but not by lateral, preoptic stimulation. The most common change produced by MPO stimulation was a reduction in both the number of mounts and intromissions preceding ejaculation. Short-latency approach and mounting of the female and greatly reduced refractory periods were also seen in two MPO animals. No evidence of a post-stimulation inhibition of copulatory behavior resulting from the stimulation itself was seen in these two animals. Most animals in both the medial and lateral groups learned to self-stimulate (SS) using the same 30-sec trains of stimulation as used in earlier tests of copulatory activity. SS rate, stimulation-bound copulation, and degree of facilitation of ejaculation were positively correlated in MPO, but not in lateral preoptic animals.     

Sexual experience increases nitric oxide synthase in the medial preoptic area of male rats

Nitric oxide in the medial preoptic area (MPOA) is important for the expression and sensitization of male sexual behavior. In this article, the authors report that repeated sexual experience (mating for 2 hr on each of 3 days) increased levels of nitric oxide synthase (NOS) in the MPOA of male rats, regardless of whether they mated on the day they were given an overdose of sodium phenobarbital. This effect resulted from the previous experience and not acute mating, as NOS was not increased 2 hr after the first mating in previously naive males. Experience-induced increases in NOS in the MPOA may be one mechanism through which sexual experience facilitates sexual behavior in male rats.     

GABA receptor agonists in the medial preoptic area and maternal behavior in lactating rats

We studied the effects of injecting agonists of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) muscimol (GABA-A receptor agonist) and baclofen (GABA-B receptor agonist) in the medial preoptic area (MPOA) and neighboring brain regions, the bed nucleus of the stria terminalis (BNST), and lateral preoptic area (LPO) on maternal behavior. Lactating female rats were implanted with bilateral cannulae in the MPOA/BNST on day 1 postpartum. On day 5, a maternal behavior test was conducted in the home cage after females received injections of muscimol or baclofen (0, 12.5, 50 or 200 ng per side). On day 7, after MPOA/BNST injections, a second maternal behavior test was conducted with pups placed at the end of a T-runway projecting from the home cage. Finally, after injections on day 9 maternal aggression, olfaction, and locomotor behavior were tested. The GABA receptor agonists injected in the MPOA/BNST produced dose-dependent deficits in all components of maternal behavior, including maternal aggression, except licking. Muscimol produced deficits in the active component, nest building at lower doses than baclofen, both agonists produced deficits in retrieving, while baclofen produced deficits in passive components (hovering and crouching over pups) at lower doses than muscimol. Both GABA receptor agonists increased locomotor activity and reduced olfactory responsiveness but these were only correlated with deficits in retrieving and crouching in baclofen-treated females.     

Activation of mu opioid receptors in the medial preoptic area following copulation in male rats

The current study tested the hypothesis that sexual behavior is a biological stimulus for release of endogenous opioid peptides. In particular, activation of mu opioid receptors (MOR) in the medial preoptic area (MPOA), a key area for regulation of male sexual behavior, was studied in male rats. MOR endocytosis or internalization was used as a marker for ligand-induced receptor activation, utilizing confocal, electron, and bright microscopic analysis. Indeed, mating including one ejaculation induced receptor activation in the MPOA, demonstrated by increased immunoreactivity for MOR, increased numbers of endosome-like particles immunoreactive for MOR inside the cytoplasm of neurons, and increased percentage of neurons with three or more endosome-like particles inside the cytosol. Moreover, it was demonstrated that MOR activation occurred within 30 min following mating and was still evident after 6 h. Mating-induced internalization was prevented by treatment with the opioid receptor antagonist naloxone before mating, suggesting that mating-induced receptor activation is a result of action of endogenous MOR ligands. i.c.v. injections of MOR ligand [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin resulted in internalization of the MOR in a similar manner observed following mating. Finally, mating induced Fos expression in MOR containing neurons in the MPOA. However, naloxone pretreatment did not prevent Fos activation of MOR neurons, suggesting that Fos induction was not the result of MOR activation. In summary, these results provide further evidence that endogenous opioid peptides are released in the MPOA during male sexual behavior.     

Dopamine D1 receptors and phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein-32 in the medial preoptic area are involved in experience-induced enhancement of male sexual behavior in rats

The medial preoptic area (MPOA) is an integral site for male sexual behavior. Dopamine is released in the MPOA before and during copulation and facilitates male rat sexual behavior. Repeated sexual experience and noncopulatory exposures to an estrous female facilitate subsequent copulation. However, the neurobiological mechanisms that mediate such enhancement remain unclear. Here, we examined the role of dopamine D? receptors in the MPOA in experience-induced enhancement of male sexual behavior in rats. In experiment 1, microinjections of the D? antagonist SCH-23390 into the MPOA before each of seven daily 30-min noncopulatory exposures to a receptive female impaired copulation on a drug-free test on Day 8, compared to vehicle-treated female-exposed animals. Copulatory performance in drug-treated animals was similar to that of vehicle-treated males that had not been preexposed to females. This effect was site specific. There were no group differences in locomotor activity in an open field on the copulation test day. In experiment 2, a separate cohort of animals was used to examine phosphorylation of dopamine- and cAMP-regulated phosphoprotein (DARPP-32) in the MPOA of animals with acute and/or chronic sexual experience. DARPP-32 is a downstream marker of D? receptor signaling and substrate of cAMP-dependent protein kinase (PKA). Western immunoblot analysis revealed that p-DARPP-32 expression was greatest in the MPOA of males that received both acute and chronic sexual experience, compared to all other mated conditions and na?ve controls. These data suggest that D? receptors in the MPOA contribute to experience-induced enhancement of male sexual behavior, perhaps through a PKA regulated mechanism.     

Dopaminergic projections to the medial preoptic area of postpartum rats

Dopamine receptor activity in the rodent medial preoptic area (mPOA) is crucial for the display of maternal behaviors, as well as numerous other physiological and behavioral functions. However, the origin of dopaminergic input to the mPOA has not been identified through neuroanatomical tracing. To accomplish this, the retrograde tracer Fluorogold was iontophoretically applied to the mPOA of postpartum laboratory rats, and dual-label immunocytochemistry for Fluorogold and tyrosine hydroxylase later performed to identify dopaminergic cells of the forebrain and midbrain projecting to the mPOA. Results indicate that the number of dopaminergic cells projecting to the mPOA is moderate (∼90 cells to one hemisphere), and that these cells have an unexpectedly wide distribution. Even so, more than half of the dual-labeled cells were found in either what has been considered extensions of the A10 dopamine group (particularly the ventrocaudal posterior hypothalamus and adjacent medial supramammillary nucleus), or in the A10 group of the ventral tegmental area. The rostral hypothalamus and surrounding region also contained numerous dual-labeled cells, with the greatest number found within the mPOA itself (including in the anteroventral preoptic area and preoptic periventricular nucleus). Notably, dual-labeled cells were rare in the zona incerta (A13), a site previously suggested to provide dopaminergic input to the mPOA. This study is the first to use anatomical tracing to detail the dopaminergic projections to the mPOA in the laboratory rat, and indicates that much of this projection originates more caudally than previously suggested.     

Inhibition of nitric oxide synthase within the medial preoptic area impairs pup retrieval in lactating rats

Central suppression of nitric oxide (NO) production by administering 250 microg of Nitro-superw--subL-Argenine Methyl Ether (L-NAME), an inhibitor of NO synthase, into the 3rd ventricle disrupts both pup retrieval and maternal aggression in postpartum rats. In these studies, the authors examined the ability of varying doses of L-NAME to produce these effects on maternal behavior. Doses of L-NAME that were shown to be ineffective when injected into the 3rd ventricle were administered bilaterally into the medial preoptic area (MPOA) of rats on Day 4 postpartum. To assess the specificity of L-NAME's effect within the MPOA, the authors bilaterally injected Nitro-superw--subD-Argenine Methyl Ether (D-NAME), an inactive isomer of L-NAME, into the MPOA. When administered intracerebroventricularly, the 2 highest doses of L-NAME used, 250 microg and 200 microg, disrupted retrieval behavior and maternal aggression. Bilateral injections of L-NAME into the MPOA at doses of 20 microg and 40 microg/side also disrupted pup retrieval, and D-NAME injections into the MPOA had no effect on the maternal behaviors measured. All rats in these experiments showed normal maternal behavior 24 hr after drug administration. These results suggest that NO acts within the MPOA to facilitate retrieval behavior.     

Dopamine release in the medial preoptic area of female rats in response to hormonal manipulation and sexual activity

Dopamine (DA) is responsive to hormonal manipulations and has been implicated in the regulation of female rat sexual behavior. In the present studies, extracellular DA levels were assessed in the medial preoptic area (MPOA) of ovariectomized female rats in response to exogenous ovarian hormones and during sexual activity. In female rats primed with a low dose of estradiol benzoate (2 microg), but not with a higher dose (20 microg), a 500-microg progesterone injection increased extracellular DA and facilitated copulatory behavior. Extracellular DA levels in the MPOA were further augmented during sexual interactions with a male rat in a nonpacing copulatory chamber by either perineal or vaginal stimulation. However, in a pacing chamber, DA efflux did not increase, although the metabolites rose significantly during copulation. Together, these findings suggest that extracellular DA in the MPOA responds to the hormonal state of the female rat and may contribute to her expression of sexual behavior.     

Effect of medial preoptic lesions on sexual behavior of female rats is determined by test situation

The sexual behavior of female rats with bilateral lesions in the medial preoptic area (MPOA) was examined in two testing conditions. In the first condition, in which the female could not leave the vicinity of males (no-exit test), lordosis quotients (LQs) were elevated in relation to baseline levels. In the second condition, in which the female could control her proximity to males (exit test), LQs were not different from control levels, and experimental subjects permitted fewer copulatory contacts, exhibited less frequent solicitational behavior, and spent less time with males than the controls did. These findings suggest that the higher LQs seen in no-exit tests as a result of MPOA damage are not due to a lesion-induced potentiation in the females' preference to engage in sexual contacts with males.     

GABA release in the medial preoptic area of cyclic female rats

GABA is a potent regulator of gonadotropin-releasing hormone neurons in the hypothalamus. To determine the profile of GABA release in the medial preoptic area where the gonadotropin surge generator resides, an in vivo microdialysis study was performed in cyclic female rats. The microdialysis samples were collected and sequential blood samples (150 microl each) were also obtained, at 1-h intervals. During estrus and diestrus 1, GABA release in the medial preoptic area was relatively low. A small increase in the GABA release began in the afternoon of diestrus 1 and attained its peak in the morning of diestrus 2, but declined in the afternoon of that day. The GABA release markedly increased from late in the night of diestrus 2 through the morning of proestrus, when it attained its peak, and thereafter it declined sharply until the critical period of proestrus. A distinct preovulatory luteinizing hormone surge was observed in the afternoon of proestrus in all proestrous rats. From these results we suggest that the preovulatory elevation of the GABA release from the night through to the morning of proestrus, followed by a sharp decline, is closely associated with the onset of the preovulatory luteinizing hormone surge in cyclic female rats. The present study is the first to report the 4-day profile of GABA release in the medial preoptic area during the estrous cycle.     

Pre- and postpuberal medial preoptic area lesions and maternal behavior in the rat

The ability of female rats to express maternal behavior following pre- or postpuberally-administered lesions of the medial preoptic area (MPOA) was investigated. Female Sprague-Dawley rats were electrolytically or sham-lesioned at either 28-30 days of age or 65-70 days of age and housed together in groups of 6-8 in "enriched" environments. Subsequently, the animals were mated and moved to individual cages just prior to parturition. Indices of maternal proficiency included nest ratings, pup retrieval time, percentage of pups with milk in their stomachs, and percentage of pup mortality. All animals in which lesions had substantially damaged the MPOA demonstrated significant deficits in all indices. Age at which the lesion was administered had no effect. In contrast to the recovery of male sexual behavior that has been reported for rats following prepuberally administered MPOA lesions, no recovery of maternal behaviors was seen in this study. Reasons for this lack of recovery may include the greater complexity of physiological and behavioral processes involved in maternal behavior in comparison to the rather stereotypical response patterns of male sexual behavior.