The stimulation of central kappa opioid receptors decreases male sexual behavior and locomotor activity.

Systemic injections of the kappa (kappa) opioid receptor agonist U-50,488H decreased male sexual behavior, locomotor activity, body temperature and bodily grooming, and induced body flattening. The U-50,488H-induced inhibitions of male sexual behavior were prevented by systemic injections of naloxone and by intra-cranial injections of the kappa opioid antagonist nor-binaltorphimine (NBNI). Injections of NBNI to either the ventral tegmental area (VTA) or the nucleus accumbens septi (NAS) increased female-directed behavior, and prevented the U-50,488H-induced decreases in female-directed behavior. Intra-VTA NBNI prevented U-50,488H-induced decreases in the mean number of ejaculations, intra-NAS NBNI prevented U-50,488H-induced increases in copulation latencies. Intra-medial preoptic area (mPOA) injections of NBNI increased female-directed behavior, and attenuated U-50,488H-induced decreases in female-directed behavior as well as U-50,488H-induced increases in both copulation and ejaculation latencies. Injections of NBNI dorsal to the mPOA were ineffective. Two of 26 days following the central injection of NBNI, systemic injections of U-50,488H remained behaviorally ineffective, leaving both sexual behavior and locomotor activity undiminished. These results suggest that the stimulation of central kappa opioid receptors inhibits sexual behavior in the male rat; perhaps endogenous kappa opioid agonists induce sexual refractory periods.     

Midbrain lesions, dopamine and male sexual behavior

Destruction of the medial preoptic area (MPOA) eliminates mating in male rats and this region is believed to play a major role in the control of male sexual behavior. Efferents from the MPOA pass through and/or terminate in 4 midbrain regions: the dorsolateral tegmentum (DLT), the central gray, and the A9 and A10 areas. The present study reports the effects of bilateral destruction of each of these midbrain regions on brain catecholamines and sexual behavior in male rats. DLT lesions eliminated mating, reproducing the effect of bilateral preoptic lesions. The sexual activity of males with central gray lesions was accelerated in the sense that the mounting rate for these males was significantly faster than for controls and lesioned males ejaculated more frequently and with shorter latencies than did controls. A9 lesions impaired mating--lesioned males mounted at a slower rate and ejaculated less frequently than controls. Males with A10 lesions took longer to re-initiate mating after an ejaculation than controls, but copulation per se (as reflected in mount rate, ejaculation frequency and latency to ejaculate) was not affected by A10 damage. Brain catecholamine levels were not affected by either DLT or central gray lesions. A9 lesions produced a significant depletion in neostriatal dopamine which was highly correlated with mount latency, mount rate, ejaculation latency and ejaculation frequency. A10 lesions produced a significant depletion of dopamine in the nucleus accumbens and cingulate cortex, but these effects were not significantly correlated with any measure of sexual behavior.     

Sexual behavior in male rhesus monkeys elicited by electrical stimulation of preoptic and hypothalamic areas

Electrical stimulation of the preoptic area, lateral hypothalamus or dorsomedial nucleus of the hypothalamus (DMH) has produced sexual behavioral responses in 11 male rhesus monkeys. At a short latency following the onset of each train of stimulation, the stimulated males would mount estrogen-treated, receptive females. Quantitative measures of the elicited sexual behavior, in 4 males, were applied to describe differences between the effect of preoptic and DMH stimulation on male sexual performance. As compared to spontaneous sexual activity, stimulation of the DMH produced mounts of longer duration, with more thrusts per mount, higher thrusting rates and a greater number of ejaculations per test session; refractory periods between successive ejaculatory episodes were shortened as a result of stimulation-induced mounting behavior. Preoptic stimulation also induced mounts of longer than normal duration characterized by a slightly increased number of thrusts per mount. In contrast to DMH stimulus effects, however, thrusting rate was decreased significantly by preoptic stimulation and ejaculation did not occur even after multiple stimulus-induced mounts. Penile erections were elicited by stimulation of the anterior hypothalamus, ventromedial nucleus and the posterior hypothalamus in socially isolated or restrained males; however, stimulation of these same sites was ineffective for provoking sexual behavioral responses when tests were performed while the males were paired with receptive females.     

Dopaminergic control of male sex behavior in rats: Effects of an intracerebrally-infused agonist

Systemically-administered dopaminergic drugs have been found to facilitate sexual behavior of men and male rats. The present experiments investigated the localization within the brain of dopaminergic effects on copulation of male rats. Apomorphine, a dopamine agonist, was microinfused into the medial preoptic area, caudate-putamen, nucleus accumbens, lateral septum and lateral ventricle. The lowest dose of apomorphine (0.2 microgram) infused into the ventricle reduced the number of ejaculations, slowed the rate of intromitting and decreased the percentage of mounts on which the male gained vaginal intromission. The higher two doses (0.5 and 2.0 micrograms) infused into the medial preoptic area and, in some cases, the ventricle, increased the number of ejaculations and the percentage of mounts with vaginal intromission, increased the rate of intromitting and decreased the latency to ejaculate and the postejaculatory interval before resuming copulation. Infusions into the caudate-putamen and lateral septum were without effect. Those into nucleus accumbens produced only a slight dose-related decrease in latency to begin copulating. The copulatory impairments associated with infusions of the lowest dose into the ventricle may have resulted from stimulation of autoreceptors, or from preferential stimulation by low doses of an undetermined area. The facilitative effects of the two higher doses into the medial preoptic area and lateral ventricle may have been due to stimulation of dopaminergic postsynaptic receptors.     

The medial and lateral cell groups of the sexually dimorphic area of the gerbil hypothalamus are essential for male sex behavior and act via separate pathways

Male reptiles, birds and mammals do not copulate if the medial preoptic area (MPOA) is destroyed but the MPOA cell groups necessary for male sexual behavior were not known. Here, two cell groups essential for copulation are identified in the sexually dimorphic area (SDA) of the gerbil (Meriones unguiculatus) MPOA. Bilateral cell-body lesions of either the medial or lateral SDA eliminated mating in sexually experienced male gerbils given testosterone. Nearby MPOA lesions did not. The medial and lateral SDA affect sex behavior via separate pathways since lesioning the medial SDA on one side of the brain and the lateral SDA on the other did not stop sexual behavior.     

Sexual behavior reduces hypothalamic androgen receptor immunoreactivity

Male sexual behavior is regulated by limbic areas like the medial preoptic nucleus (MPN), the bed nucleus of the stria terminalis (BST), the nucleus accumbens (nAcc) and the ventromedial hypothalamic nucleus (VMN). Neurons in these brain areas are rich in androgen receptors (AR) and express FOS-immunoreactivity in response to mating. In many species sexual satiation, a state of sexual behavior inhibition, is attained after multiple ejaculations. The mechanisms underlying sexual satiation are largely unknown. In this study we show that sexual activity reduces androgen receptor immunoreactivity (AR-ir) in some of the brain areas associated with the control of male sexual behavior, but not in others. Thus, one ejaculation reduced the AR-ir in the MPN and nAcc, but not in the BST and VMN. Copulation to satiation, on the other hand, reduced AR-ir in the MPN, nAcc and VMN, and not in the BST. The AR-ir reduction observed in the MPN of sexually satiated rats was drastic when compared to that of animals ejaculating once. Serum androgen levels did not vary after one ejaculation or copulation to exhaustion. These data reveal that sexual activity reduces AR in specific brain areas and suggest the possibility that such a reduction underlies the sexual inhibition that characterizes sexual satiety.     

Anatomical interrelationships of the medial preoptic area and other brain regions activated following male sexual behavior: A combined Fos and tract-tracing study

The medial preoptic nucleus (MPN) is an essential site for the regulation of male sexual behavior. Previous studies using c-fos as a marker for neural activation have shown that copulation increased c-fos expression in the MPN. Neural activation was also present in brain regions that are connected with the MPN and are involved in male sexual behavior, including the posteromedial bed nucleus of the stria terminalis (BNSTpm), posterodorsal preoptic nucleus (PD), posterodorsal medial amygdala (MEApd), and parvocellular subparafascicular thalamic nucleus (SPFp). The present study investigated whether the copulation-induced, activated neurons in these brain regions are involved in the bidirectional connections with the MPN. Therefore, mating-induced Fos expression was combined with application of anterograde (biotinylated dextran amine) or retrograde (cholera toxin B subunit) tracers in the MPN. The results demonstrated that neurons in the BNSTpm, PD, MEApd, and SPFp that project to the MPN were activated following copulation. However, in males that displayed sexual behavior but did not achieve ejaculation, few double-labeled neurons were evident, although both retrogradely labeled neurons and Fos-immunoreactive cells were present. In addition, retrograde neurons that expressed Fos were located in discrete subdivisions within the brain regions studied, where Fos is induced after ejaculation. Likewise, anterogradely labeled fibers originating from the MPN were not distributed homogeneously but were particularly dense in these discrete subdivisions. These results demonstrate that copulation-induced Fos-positive neurons in specific subdivisions of the BNSTpm, PD, MEApd, and SPFp have bidirectional connections with the MPN. Taken together with previous findings, this supports the existence of a discrete subcircuit within a larger neural network underlying male sexual behavior. J. Comp. Neurol. 397:421–435, 1998. © 1998 Wiley-Liss, Inc.     

Medial preoptic and hypothalamic neuronal activity during sexual behavior of the male monkey

Neuronal activity changes in the medial preoptic area of the male monkey were related to the commencement of sexual behavior, penile erection and the refractory period following ejaculation.Increased neuronal activity in the dorsomedial hypothalamic nucleus was found to be synchronized to each mating act.The involvement of medial preoptic neurons in sexual arousal, initial penile erection and that of dorsomedial hypothalamic neurons in the copulatory act are suggested by the present findings.     

Regional brainstem expression of Fos associated with sexual behavior in male rats

This study utilized Fos expression to map the distribution of activated cells in brainstem areas following masculine sexual behavior. Males displaying both appetitive and consumatory sexual behaviors (Cop) were compared to animals prevented from copulation (NC) and to socially isolated (SI) animals. Following copulation, Fos was preferentially augmented in the caudal ventral medulla (CVM), a region mediating descending inhibition of penile reflexes, and which may be regulated by a forebrain circuit that includes the medial preoptic area (MPOA). Copulation-induced Fos was observed in the medial divisions of both the dorsal cochlear nucleus (DC) and trapezoid bodies (Tz), areas which are part of a circuit processing auditory information. In addition, the medullary linear nucleus (Li) displayed comparable amounts of Fos in Cop and NC as compared to the SI animals. Other regions of the pontomedullary reticular system, which may mediate sleep and arousal, did not exhibit Fos expression associated with consumatory sexual behavior. We suggest that Fos is associated with the inhibition of sexual behavior following ejaculation in the CVM, and that auditory information arising from the DC and Tz is combined with copulation-related sensory information in the subparafasicular nucleus and projected to the hypothalamus. In addition, equal amounts of Fos expression observed in the Li in both the Cop and NC animals suggests that this region is involved in sexual arousal. Overall, the data suggest that processing by brainstem nuclei directly contributes to the regulation of mating behavior in male rats.     

Endocrine,neural and pharmacological aspects of sexual satiety in male rats

Sexual satiety is the inhibition of masculine mating behavior produced by copulation itself. This inhibition is manifested in different ways depending upon the species, the time and the amount of sexual behavior prior to sexual satiety. Pharmacological studies indicate that monoaminergic and opioidergic compounds modify this phenomenon in the rat and other species, possibly via a final dopaminergic pathway involving sexual motivation. Reduced androgen receptor expression and/or increased estrogen receptor alpha expression in specific brain areas are associated with the inhibition of mating behavior that characterizes rat sexual satiety. Androgen receptor over-expression in the same and other brain areas coincides with a partial recovery of rat male copulatory behavior after sexual satiety. The lateral septum, medial amygdala and medial preoptic area may participate in the neuroendocrine regulation of sexual satiety, based on changes in the expression of c-Fos, androgen receptor and estrogen receptor alpha in these cerebral regions. These data suggest that changes in steroid receptors, possibly triggered by modifications in neurotransmitters, underlie at least partly the inhibition of copulatory behavior characteristic of rat sexual satiety.     

Effects of ibotenic acid-induced neuronal degeneration in the medial preoptic area and the lateral hypothalamic area on sexual behavior in the male rat

It is well known that electrolytic lesions in the medial preoptic area (MPOA) and the lateral hypothalamic area (LHA) seriously impair masculine sexual behavior in the rat. We here report that bilateral infusions of the neurotoxin, ibotenic acid (IBO), in the MPOA were as effective as electrolytic lesions in eliminating copulation whereas no behavioral effects were detected following similar infusions in the LHA. Histological examination of MPOA and LHA following IBO exposure revealed extensive degeneration of neuronal cell bodies with little evidence of non-specific damage. Also, immunohistochemical studies suggested that the serotonergic innervation of the MPOA remained largely intact in spite of IBO treatment; similarly, the damage inflicted by IBO in LHA on tyrosine hydroxylase-immunoreactive fibers in the medial forebrain bundle was insignificant. These data suggest that: (i) the functional integrity of MPOA nerve cell bodies is necessary for the expression of sexual behavior, and (ii) disruption of mating produced by electrolytic LHA lesions is due to disruption of medial forebrain bundle fiber systems.Behavioral observations of non-copulating males suggested that the MPOA injury did not interfere with all aspects of their sexual interaction with the estrous female; rather, they appeared specifically unable to perform the reflexive pelvic thrust pattern normally associated with mounting. We here report, however, that the ability to perform mounts with pelvic thrusts was temporarily restored in the vast majority of MPOA-injured males by the i.p. administration of the ergot derivative, lisuride. About 50% of these MPOA-damaged males even ejaculated, often after a low number of intromissions and short ejaculation latencies. On the other hand, injections of naloxone (an opiate receptor antagonist) failed to activate mounting in MPOA- lesioned or castrated rats. On the basis of these findings the possible ways in which steroid hormone-sensitive brain areas might interact with monoamine-containing pathways are discussed.     

Neurons containing tuberoinfundibular peptide of 39 residues are activated following male sexual behavior

Tuberoinfundibular peptide of 39 residues (TIP39)-immunoreactive (IR) neurons are present in the medial subdivision of the parvocellular subparafascicular thalamic nucleus (mSPFp) where ejaculation-specific Fos expression is localized. The mSPFp is reciprocally connected to the medial preoptic area (MPOA), bed nucleus of the stria terminalis (BNST) and the medial nucleus of the amygdala (Me), all of which are critical for the regulation of male sexual behavior. The mSPFp also receives galanin and enkephalin containing projections from a region in the lumbar spinal cord, thought to be a central ejaculation center. Therefore, we hypothesized that TIP39 neurons in the mSPFp may be part of the neuronal circuitry activated by male sexual behavior. To test this hypothesis, we examined induction of Fos in TIP39 containing neurons in the mSPFp following male sexual behavior. Mating-induced Fos expression was evaluated in sexually experienced male rats under four experimental conditions: animals that (1) remained in their home cage without any interaction with females, (2) interacted with stimulus females and displayed intromission without ejaculation, (3) displayed one ejaculation, or (4) displayed 2 ejaculations. We found that Fos was induced in TIP39-IR neurons in the mSPFp in male rats following ejaculation but much less so following intromission without ejaculation. This suggests that TIP39-IR neurons in the mSPFp are part of the afferent circuits that process genital-somatosensory information related to ejaculation, and which contribute to mating and mating-induced changes in reproductive behavior.     

E-series prostaglandins and arginine vasopressin in the modulation of male sexual behavior

Studies carried out recently in the author's laboratory have suggested that fever accompanies copulation in the male rat. Given the action of prostaglandin-E (PGE) in the genesis of fever and given the integrative role of the medial preoptic area (MPOA) in the expression of both fever and male sexual behavior, two hypotheses were advanced concerning male copulation. The first concerns PGE in facilitating transmission in MPOA pathways mediating mounting, intromission and ejaculation. The second concerns arginine vasopressin, a presumed "natural antagonist" of PGE, in inhibiting such transmission and eventually making the male refractory to the receptive female. Several experiments were suggested for testing each hypothesis.     

Testosterone stimulation of the medial preoptic area and medial amygdala in the control of male hamster sexual behavior: redundancy without amplification

Receptors for gonadal steroids are present in an interconnected network of limbic nuclei. The existence of this network structure has important implications for how steroids control reproductive physiology and behavior. In 1986, Cottingham and Pfaff proposed that properties of a steroid-responsive neural network could include redundancy, amplification, stability and selective filtering. The present study tested the concept of steroid amplification, using male hamster sexual behavior as a model. In the male hamster, the medial amygdaloid nucleus (Me) and medial preoptic area (MPOA) are essential for mating behavior, and both nuclei transduce steroid cues to facilitate copulation. To determine if steroid action at multiple interconnected nuclei amplifies mating, the present study compared sexual behavior in castrated male hamsters bearing unilateral intracranial implants of testosterone in Me or MPOA with that of males with dual testosterone implants in Me and MPOA. Implants that stimulated androgen receptor-containing neurons in Me or MPOA stimulated copulatory behavior above castrate levels. However, behavior of males with dual implants was not significantly different from that of males with single implants. This suggests that steroid action at either MPOA or Me is sufficient to facilitate mating, but dual stimulation of these reciprocally-connected nuclei does not amplify sexual behavior.     

Fos expression in rat pontine tegmental neurons following activation of the medial preoptic area

Fos immunohistochemistry was used to map the distribution of pontine neurons excited by activation of the medial preoptic area (MPO). Although we have previously shown that Barrington's nucleus receives a very dense focal input from the MPO, electrical stimulation of the preoptic area unexpectedly induced very little Fos expression in Barrington's neurons. These results suggest that the MPO→Barrington's projection utilizes a transmitter(s) that does not involve transduction of the Fos protein; alternatively, MPO afferents to Barrington's nucleus may be inhibitory in nature. As Barrington's nucleus plays a critical role in micturition, MPO projections to Barrington's nucleus may regulate voiding reflexes during sexual behavior. Interestingly, while the locus coeruleus (LC) proper receives only a sparse projection from the MPO, extensive Fos expression was present in LC. The finding of Fos immunoreactive LC neurons suggests that the excitatory influence of MPO may regulate LC neuronal activity and NE release during reproductive behaviors.     

Reactions of neurons of the preoptic area in the presence of serial cortical stimuli]

Evoked potentials (EPs) and neuronal responses of the medial (MPO) and lateral (LPO) preoptic region (RPO) and adjacent areas of the anterior hypothalamus to serial (6-300 s) stimulation of the prefrontal (area 8), cingulum (area 24), periamygdaloideus (RPA) cortex and hippocampus (field CA3) were studied on experimental cats anesthetized by ketamine. Cortical areas were selected according to their evolutionary status. Responses of preoptic neurons to serial stimulation were grouped into four main types: excitatory, inhibitory, excitatory on-off-effect and inhibitory on-off-effect. No pronounced changes in the patterns of response reactions were found when frequency of the stimuli increased, only intensity of the reactions changed. Neurons responding to serial cortical stimulation were located mainly in the central part of the MPO and in the basal part of the LPO. These areas of the RPO contained neurons with the most pronounced convergence of different cortical stimuli to the same cell. In serial cortical stimulation inhibitory reactions developed more frequently than excitatory ones (ratio 3.4:1). A gradient of inhibitory reactions to stimulation of different cortical areas was observed while comparing them in terms of evolution from new to old structures. Prevalence of inhibitory responses over excitatory ones was minimal (ratio 1.7:1), when the neocortex (area 8) was stimulated and it was more pronounced (ratio 1.9:1) during stimulation of the evolutionary intermediate cortex (area 24). That prevalence was still more significant (ratio 4.5:1) in case of paleocortical (RPA) stimulation and it was the most pronounced (ratio 10.2:1) during stimulation of the archicortex (hippocampus).     

Ontogeny of lateral preoptic unit activity in rats

Extracellular single unit recordings were made from units within the lateral preoptic area (LPO) of infant rats from 1 day of age through 31 days of age (postweaning). The rats were anesthetized with dial-urethane and basal (spontaneous) spike rates were recorded for 10–20 min. The rats also received pain-arousal stimulation (tail-pinch and sc injection of formalin solution), and osmotic stimulation (sc or ip injection of hyperosmotic NaCl or sucrose solutions). LPO units were spontaneously active in neonatal rats; however, basal spike rates increased during development. Also increasing during development was the percentage of LPO units which displayed alteration of spike rate in response to hyperosmotic injections (osmosensitive). However, LPO units were found that were responsive to severe pain-arousal stimulation at all ages tested. The developmental changes in LPO unit activity characteristics paralleled the morphological development of LPO neurons and the development of osmotically induced drinking behaviors.     

Sexual and social experience is associated with different patterns of behavior and neural activation in male prairie voles

Monogamous prairie voles (Microtus ochrogaster) show mating-induced aggression towards conspecific strangers. This behavior is both selective and enduring. The present study was designed to investigate the behavioral conditions for the emergence of selective aggression (by varying prior experience with a female and identity of intruders) and the limbic activation in response to an intruder (by mapping regional staining for c-fos) in male prairie voles. In a first experiment, males that mated with a female for 24 h exhibited aggression towards a male intruder and had more Fos-immunoreactive (Fos-ir) cells in the medial amygdala (AMYGme) and medial preoptic area (MPO) relative to males that cohabited with a female without mating or that had no prior exposure to a female. Cohabited males did not become aggressive. However, these males along with mated males had an increased number of Fos-ir cells in the lateral septum (LS) and the bed nucleus of the stria terminalis (BST) relative to males without prior exposure to a female. In a second experiment, mated males exhibited more offensive aggression to a male intruder but more defensive aggression to a female intruder. Both types of aggression, however, induced an increase in the number of Fos-ir cells in the AMYGme. In addition, Fos-ir staining in the BST was induced selectively in response to a male intruder and a similar trend was found in the LS. Exposure to a male or female intruder did not increase Fos-ir staining in the MPO. Taken together, our data suggest the neural substrates activated by social/sexual activity and involved in response to intruders. The AMYGme was involved in processing intruder-related cues and/or in the regulation of aggressive response to both male and female intruders. The BST and LS were modulated by social experience with a female (mating or cohabitation) and were responsive to male-related cues even in the absence of aggression. Finally, the MPO was activated at different magnitudes by social or sexual experience but did not respond to intruder-related cues as measured by Fos-ir.     

Central control of sexual behavior

Neuronal activity changes in the medial preoptic area (MPOA) of the male monkey were related to the commencement of sexual behavior, penile erection and the refractory period following ejaculation. Similarly, changes in the female MPOA were related to the commencement of sexual behavior and presentation. Increased neuronal activity in the dorsomedial hypothalamic nucleus (DMH) in the male monkey and in the ventromedial hypothalamic nucleus (VMH) in the female monkey was synchronized to each mating act. Stimulation study and neuronal activity recordings in the MPOA, DMH and VMH suggest involvement of MPOA neurons in sexual arousal, and of male DMH and female VMH neurons in the copulatory act. Stimulation experiment on the various parts in the hypothalamus of the female monkey also supports the conclusion.     

Electrophysiological analysis of corticofugal influences on neurons of the preoptic area]

Evoked potentials (EPs) and neuronal responses of the medial (MPO) and lateral (LPO) preoptic region (RPO) and adjacent areas of the hypothalamus to stimulation of the prefrontal (area 8), cingulum (area 24), periamigdaloideus (RPA) cortex and hippocampus (area CA3) have been studied on cats anesthetized with ketamine. Cortical areas were selected according to their evolutionary status. It is determined that the most pronounced EPs are generated in the RPO to stimulation of the periamigdaloideus and cingulum cortex. A close correlation between responses of single units and EPs waveforms is shown. The majority of neurons responsible for cortical stimuli are located mainly in the basal part of the LPO. It is this area of the RPO where the prevalence of initial excitatory reactions is observed. The MPO contains much less neurons responding to cortical stimulation. In this area of the RPO mainly initial inhibitory reactions are registered. For the LPO a ratio between the inhibitory and excitatory reactions is 0.6:1, for the MPO the same ratio is 5.8:1. In the area of the RPO adjoining the bed nucleus stria terminalis (BST) the initial inhibitory reactions prevail over the initial excitatory ones too (ratio 4.9:1). In the area of the RPO immediately adjoining the nucleus supraopticus the initial excitatory reactions are registered and the ratio between the initial inhibitory reactions and initial excitatory ones is 0.7:1. In the RPO a pronounced convergence of the stimuli from the different cortical areas to the definite cells is found as well. In the RPO which is a zone of wide convergence 3/4 of neurons responded to stimulation of two and more cortical inputs. The combinations of inputs from the prefrontal and cingulum cortex as well as from prefrontal and periamigdaloideus cortex are the most frequent types of convergence of different cortical stimuli to the preoptic neurons.