Hormone treatment facilitates penile erection in castrated rats after sleep deprivation and cocaine

Sleep deprivation is associated with cocaine-enhanced genital reflexes in male rats, and castration of the male rat causes a decline in sexual behaviour, which can be reversed by hormone administration. We conducted two experiments to determine whether sleep deprivation and cocaine administration could also induce spontaneous penile erection in castrated rats after hormonal treatment (testosterone, progesterone and oestradiol). Different doses of hormones or vehicle were administered to rats during the 4-day period of sleep deprivation, and in home-cage control rats. Testosterone did not restore penile erection in castrated sleep-deprived rats. Progesterone triggered penile erection, and 100 mg/day of progesterone induced the highest proportion of rats displaying penile erection, and restored the frequency of penile erection observed in noncastrated sleep deprived rats. Penile erection was absent in vehicle as well as oestradiol-treated sleep-deprived castrated rats. Whereas sleep deprivation increased progesterone concentrations in noncastrated rats, sleep deprivation decreased progesterone concentrations in castrated rats. Corticosterone concentrations were lower in the castrated sleep-deprived rats than in respective control group. These data show that progesterone treatment facilitates penile erection in sleep deprived-cocaine castrated rats.     

The cannabinoid CB1 receptor antagonist SR 141716A induces penile erection by increasing extra-cellular glutamic acid in the paraventricular nucleus of male rats

The cannabinoid CB1 receptor antagonist SR 141716A (0.1, 0.5 and 1 microg) induces penile erection when injected into the paraventricular nucleus of the hypothalamus of male rats. The pro-erectile effect of SR 141716A occurs concomitantly with an increase in the concentration of glutamic acid in the paraventricular dialysate obtained by means of intra-cerebral microdialysis. Glutamic acid increase and penile erection did not occur when SR 141716A was given after tetrodotoxin, a voltage-dependent Na(+) channel blocker. Both penile erection and glutamic acid increases were also reduced by the cannabinoid CB1 receptor agonists WIN 55,212-2 or HU 210 given into the paraventricular nucleus before SR 141716A at doses unable to induce penile erection or to modify glutamic acid. In contrast, dizocilpine ((+)MK-801), an antagonist of excitatory amino acid receptors of the N-methyl-d-aspartic acid (NMDA) subtype, given into the paraventricular nucleus reduced penile erection, but was ineffective on the glutamic acid increase induced by the CB1 receptor antagonist. 6-Cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and (+/-)-2-amino-4-phosphono-butanoic acid (AP(4)), antagonists of the excitatory amino acid receptors of the AMPA subtype and of the metabotropic subtype, respectively, were ineffective on both penile erection and glutamic acid increase. SR 141716A responses were also reduced by muscimol, a GABA(A) receptor agonist, but not by baclofen, a GABA(B) receptor agonist, given into the paraventricular nucleus before SR 141716A. The present results show that SR 141716A induces penile erection by activating glutamic acid neurotransmission, which causes in turn the activation of paraventricular oxytocinergic neurons mediating penile erection.     

Brain somatostatin depletion by cysteamine attenuates the penile erection induced by serotonergic and dopaminergic, but not by cholinergic, activation in rats

To clarify the role of brain somatostatin in the expression of penile erection, the effects of cysteamine, a somatostatin depletor, on the penile erection induced by serotonergic, cholinergic and dopaminergic stimulants were investigated in rats. Fenfluramine (0.1–10 mg/kg, i.p.), pilocarpine (0.032–3.2 mg/kg, i.p.) and apomorphine (0.01–1 mg/kg, i.p.) induced penile erection in rats, with bell-shaped dose-response curves. Pretreatment with cysteamine (200 mg/kg, s.c.) significantly attenuated the penile erection induced by fenfluramine and apomorphine, but scarcely affected that induced by pilocarpine. Neurochemical measures revealed that cysteamine pretreatment significantly reduced the somatostatin content in all brain regions examined. These results provide the first pharmacological evidence that the brain somatostatin may play an important role in drug-induced penile erection.     

Some proposals regarding the organization of the central nervous system control of penile erection

Recent research on the central nervous control of penile erection is discussed. A framework for this control is based upon principles put forward by Frank Beach regarding the neuroendocrine regulation of male copulatory behavior. The current discussion is focused primarily on a subset, penile erection. The spinal cord contains all the necessary components for the production of penile erection. This requires a multisegmental coordination among penile vasodilator and vasoconstrictor autonomic neurons, pudendal motoneurons responsible for penile rigidity and autonomic neurons which control extra-penile blood flow. Genital sensory stimulation can activate this spinal network. The spinal cord is also under excitatory and inhibitory control from supraspinal sites. Penile erection can be driven by supraspinal input alone and supraspinal control can inhibit the erectile effects of genital stimulation.An important aspect of the CNS control of penile erection is that there are extensive interconnections between most of the brain sites identified to date. Most of the pathways are characterized by reciprocal connections. A large number of the CNS sites also receive genital sensory information. Thus, descending control may itself be modulated by ascending sensory pathways which relay information from the genitalia. This raises the possibility that penile erection may involve a positive feedback system. Receptors for gonadal hormones have been identified throughout the neuraxis. However, strong evidence for the control of male sexual function by gonadal hormones has been identified only for forebrain sites. The functional role of brainstem and spinal gonadal hormone receptors has not yet been clarified.     

Reduction of drug-induced yawning and penile erection and of noncontact erections in male rats by the activation of GABAA receptors in the paraventricular nucleus: involvement of nitric oxide

The effect of muscimol, a GABAA receptor agonist, injected into the paraventricular nucleus (PVN) of the hypothalamus on drug-induced (apomorphine, oxytocin and NMDA) yawning and penile erection, and on the increase in the concentration of NO2- and NO3- occurring in the paraventricular dialysate in these experimental conditions, was studied in male rats. Muscimol (50, 100 and 200 ng) reduced, in a dose-dependent manner, penile erection and yawning induced by apomorphine (50 ng), oxytocin (30 ng) and NMDA (50 ng) delivered into the PVN. The reduction of penile erection and yawning was parallel to a reduction of the concomitant NO2- and NO3- increase that occurs in the paraventricular dialysate in this experimental condition. In contrast, baclofen (200 ng), a GABAB receptor agonist, was ineffective. The muscimol effects on drug-induced penile erection, yawning and NO2- increase were prevented by the prior administration of bicuculline (250 ng into the paraventricular nucleus). Muscimol (200 ng) but not baclofen (200 ng), injected into the PVN, reduced both noncontact erections in male rats placed in the presence of an inaccessible receptive female, and also the NO2- increase that occurs in the paraventricular dialysate in this experimental condition. As found with drug-induced penile erection, the muscimol reduction of noncontact erections and of NO2- increase was prevented by bicuculline. The present results show that the activation of GABAA receptors in the PVN reduces yawning and penile erection induced by drugs or physiological stimuli by reducing the increase in NO activity that occurs in this hypothalamic nucleus in these experimental conditions.     

Pro-VGF-derived peptides induce penile erection in male rats: possible involvement of oxytocin

The effect of five peptides derived from the C-terminal portion of rat pro-VGF (VGF(577-617), VGF(588-617), VGF(599-617), VGF(556-576) and VGF(588-597)) on penile erection was studied after injection into the hypothalamic paraventricular nucleus of male rats. VGF(577-617), VGF(588-617), VGF(599-617) and, to a lower extent, VGF(588-597) (0.1-2 microg) induced penile erection episodes in a dose-dependent manner when injected into the paraventricular nucleus, while VGF(556-576) was ineffective. VGF(588-617)-induced penile erection was reduced by nitro(omega)-L-arginine methylester (L-NAME; 20 microg), by morphine (5 microg) and by muscimol (1 microg), but not by dizocilpine [(+)MK-801; 1 microg], nor by cis-flupenthixol (10 microg) given into the paraventricular nucleus 10 min before the VGF peptide. d(CH2)5Tyr(Me)-Orn8-vasotocin (1 microg) effectively reduced VGF(588-617)-induced penile erection when given into the lateral ventricles but not when injected into the paraventricular nucleus. Immunocytochemistry with antibodies specific for the C-terminal nonapeptide sequence of pro-VGF (VGF(609-617)) revealed numerous neuronal fibres and terminals within the paraventricular nucleus, including its parvocellular components. Here, many immunostained neuronal terminals impinged on parvocellular oxytocinergic neurons. The present results show for the first time that certain pro-VGF C-terminus-derived peptides promote penile erection when injected into the paraventricular nucleus and suggest that, within this nucleus, these or closely related pro-VGF-derived peptides may be released to influence sexual function by activating paraventricular oxytocinergic neurons mediating penile erection.     

Nocturnal penile tumescence studies in spinal cord injured males

Traditional methods of evaluating sexual function in disabled individuals using neurological examinations, interviews, and psychological screening has been well established. A patient's ability to have erections and ejaculations are recorded through interviews with the patient and his partner. Therefore, to obtain a more objective view of the patient's sexual function, we used a nocturnal penile tumescence monitor in 12 tetraplegics and 12 paraplegics. Patients were interviewed for sexual histories before and after the injury. Their penile size was monitored during sleeping time using two strain gauges attached to each end of the penile shaft. The bridge output from these strain gauges was amplified to a single channel recorder. The spontaneous increase of penile circumference and its duration was recorded. The result showed that: tetraplegics had a greater increase of penile size and longer duration of erection than paraplegics, there is no correlation between incompleteness of spinal lesion and erection, there is no correlation between the presence of bulbocavernosus reflex and erection, and there is no correlation between sex dreams and erections.     

Role of calcium in the expression of ACTH-induced stretching, yawning and penile erection

The effect of omega-conotoxin GVIA, a potent and selective inhibitor of N-type calcium channels and of the organic calcium channel inhibitors nimodipine, verapamil and flunarizine, on stretching, yawning and penile erection induced by ACTH 1-24 was studied in male rats. omega-Conotoxin (1-10 ng ICV 15 min before ACTH, 10 micrograms ICV), but not carboxymethylated omega-conotoxin, induced a dose-dependent prevention of all ACTH effects. In contrast, organic calcium channel inhibitors (20 mg/kg IP 30-60 min before ACTH) failed to modify ACTH-induced stretching and yawning but induced a 25% decrease in the number of penile erection episodes induced by the peptide, and prevented, like ICV omega-conotoxin, oxytocin- and apomorphine-induced yawning and penile erection. When injected in the paraventricular nucleus of the hypothalamus, omega-conotoxin prevented the above behavioral responses induced by apomorphine and oxytocin but not by ACTH 1-24. The present results suggest that ACTH induces stretching, yawning and penile erection by mobilizing calcium through central omega-conotoxin-sensitive calcium channels in brain sites different from those sensitive to oxytocin and apomorphine.     

Simultaneous recording of penile diameter and penile arterial pulse during laboratory-based erotic stimulation in normal subjects

We have assessed erectile responses of normal male subjects to short periods of fantasy and to short erotic films, using simultaneous measurement of penile diameter and penile dorsal arterial pulse amplitude, together with systemic arterial blood pressure, heart rate and skin blood flow. By a variety of criteria, we have satisfied ourselves that penile pulse amplitude reflected local vascular changes in the penis rather than changes in systemic blood pressure, although it is uncertain whether it was primarily determined by the magnitude of arterial flow or that of arterial volume. Penile pulse amplitude usually increased markedly during the stimulation period, and was correlated with penile erection. The temporal relationship between these two parameters was variable. Typically pulse amplitude increase started later than diameter increase but thereafter changed in parallel. In a proportion of responses, however, these two changes were markedly dissociated in time and these responses tended to be slower in reaching their maximum diameter. This variable association suggests that two separate processes involved in erection are being measured. Simultaneous monitoring of penile diameter and penile pulse may therefore provide further information about the basic physiological processes involved in penile erection as well as diagnostic information in patients with erectile dysfunction of uncertain aetiology.     

Penile erection in the rat: stimulation of the hypogastric nerve elicits increases in penile pressure after chronic interruption of the sacral parasympathetic outflow

Penile erection, a vascular event mediated by the autonomic nervous system, is often adversely affected by injury to the spinal cord. To further characterize the laboratory rat as an animal model of penile erection and to investigate erectile responses following neural injury, the present study has examined pressor penile responses in intact rats and in animals deprived of sacral parasympathetic outflow. Increases in penile pressure result from graded stimulation of postganglionic parasympathetic fibers. The vasodilator response is insensitive to blockade with atropine, a cholinergic antagonist. Penile tumescence also results from stimulation of the pelvic nerve, but not the hypogastric nerve. However, beginning 3 days after unilateral interruption of the pelvic nerve, stimulation of the ipsilateral hypogastric nerve results in an increase in penile pressure. This novel response, which is blocked by a ganglionic antagonist, is maximally developed at 1 week post-lesion, is stable for at least 3 months and remains confined to the side of the lesion. These results suggest that the rat, although relatively small, can be used to obtain quantitative data on penile erection. Moreover, the model may lend itself to an analysis of the mechanisms of altered control of visceral tissues following injury to the nervous system.     

Paraventricular nucleus lesion prevents yawning and penile erection induced by apomorphine and oxytocin but not by ACTH in rats

The effect of electrolytic lesion of the paraventricular nucleus of the hypothalamus (PVN) on yawning and penile erection induced by apomorphine, oxytocin and adrenocorticotropic hormone (ACTH1-24) was studied in male rats. In sham-operated rats, apomorphine (50 micrograms/kg s.c.), oxytocin (30 ng i.c.v.), and ACTH1-24 (10 micrograms i.c.v.) significantly increased the number of yawning and penile erection episodes. In PVN-lesioned rats, apomorphine- and oxytocin-, but not ACTH-induced responses were strongly reduced. These results confirm our previous observations showing that the PVN has a crucial role in the expression of yawning and penile erection induced by dopamino-mimetic drugs and oxytocin, and suggest that ACTH-derived peptides induce the above responses by a mechanism not involving PVN hypothalamic dopamine or oxytocin.     

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.     

Neural pathways and central sites involved in penile erection: neuroanatomy and clinical implications

Penile erection occurs in response to tactile, visual, and imaginative stimuli in humans. In animals olfactory and auditory cues are particularly important. The participation of multiple sites with the brain and spinal cord, and coordination of somatic and autonomic pathways make sexual behavior in general, and erection in particular, vulnerable to neurologic injury and disease. Sites within the brain and spinal cord act in concert to process, coordinate, then distribute the neural inputs necessary for sexual behavior including erection. Activation of neurons in some of these regions either pharmacologically or by electrical stimulation has been associated with penile tumescence. This review will provide a geographic framework for understanding the neuroanatomical basis of penile erection based primarily on animal data. Following discussion of the anatomical substrates, a clinical correlation is then provided to confirm and reinforce these experimental observations.     

Localization of Androgen Receptor in Nitric Oxide Synthase- and Vasoactive Intestinal Peptide-Containing Neurons of the Major Pelvic Ganglion Innervating the Rat Penis

Neurons of the rat major pelvic ganglia provide innervation to the pelvic organs and external genitalia. In these ganglia, a subpopulation of neurons containing either nitric oxide synthase or vasoactive intestinal peptide or both molecules, is involved in penile erection. The androgen dependence of penile erection is a well established fact. After castration, decreased testosterone levels have been documented to produce erectile dysfunction possibly resulting from functional alterations in major pelvic ganglion neurons. It was therefore of interest to investigate the presence of androgen receptor within these ganglionic neurons.     

Oxytocin induces penile erection when injected into the ventral tegmental area of male rats: role of nitric oxide and cyclic GMP

Oxytocin (80 ng) injected into the caudal mesencephalic ventral tegmental area (VTA) of male rats induces penile erection. Such an effect occurs together with an increase in nitric oxide (NO) production, as measured by the augmented concentration of NO(2)(-) and NO(3)(-) found in the dialysate obtained from this brain area by means of intracerebral microdialysis. Both effects are abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin (1 microg), an oxytocin receptor antagonist, by S-methyl-l-thiocitrulline acetate (20 microg), a neuronal NO synthase inhibitor, or by omega-conotoxin GVIA (50 ng), a N-type Ca(2+) channel blocker, all injected into the VTA 15 min before oxytocin. In contrast, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (40 microg), a guanylate cyclase inhibitor, given into the VTA 15 min before oxytocin, abolishes penile erection, but not the increase in NO production, while haemoglobin (40 microg), a NO scavenger, injected immediately before oxytocin reduces the increase in NO production, but not penile erection. 8-Bromo-cyclic guanosine monophosphate (0.5-10 microg) microinjected into the VTA induces penile erection with an inverted U-shaped dose-response curve; the maximal effective dose being 3 microg. Immunohistochemistry reveals that in the caudal VTA oxytocin-containing axons/fibres (originating from the paraventricular nucleus of the hypothalamus) contact cell bodies of mesolimbic dopaminergic (tyrosine hydroxylase-positive) neurons containing both NO synthase and guanylate cyclase. These results suggest that oxytocin injected into the VTA induces penile erection by activating NO synthase in the cell bodies of mesolimbic dopaminergic neurons. NO in turn activates guanylate cyclase present in these neurons, thereby increasing cyclic GMP concentration.     

Dopamine–oxytocin interactions in penile erection

Dopamine and oxytocin have established roles in the central regulation of penile erection in rats; however, the neural circuitries involved in a specific erectile context and the interaction between dopamine and oxytocin mechanisms remain to be elucidated. The medial preoptic area (MPOA), supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus may serve as candidate sites because they contain oxytocin cells, receive dopaminergic inputs and have been implicated in mediating masculine sexual behavior. Double immunofluorescence revealed that substantial numbers of oxytocin cells in the MPOA, SON and PVN possess dopamine D₂, D₃ and D₄ receptors. In anaesthetized rats, using intracavernous pressure as a physiological indicator of erection, blockade of lumbosacral oxytocin receptors (UK, 427843) reduced erectile responses to a nonselective dopamine agonist (apomorphine), suggesting that dopamine recruits a paraventriculospinal oxytocin pathway. In conscious males in the absence of a female, penile erection elicited by a D₂/D₃ (Quinelorane) but not D₄ (PD168077) agonist was associated with activation of medial parvocellular PVN oxytocin cells. In another experiment where males were given full access to a receptive female, a D₄ (L‐745870) but not D₂ or D₃ antagonist (L‐741626; nafadotride) inhibited penile erection (intromission), and this was correlated with SON magnocellular oxytocin neuron activation. Together, the data suggest dopamine’s effects on hypothalamic oxytocin cells during penile erection are context‐specific. Dopamine may act via different parvocellular and magnocellular oxytocin subpopulations to elicit erectile responses, depending upon whether intromission is performed. This study demonstrates the potential existence of interaction between central dopamine and oxytocin pathways during penile erection, with the SON and PVN serving as integrative sites.     

Participation of hippocampal formation in negative feedback inhibition of penile erection in the rat

Detailed information on how the central nervous system regulates penile erection, particularly the inhibitory aspect, is sparse. We observed in Sprague–Dawley rats anesthetized and maintained with chloral hydrate that administration of papaverine (400 μg) directly into the corpora cavernosum of the penis produced an increase in intracavernous pressure (ICP). This elicited experimental index for penile erection was accompanied by a transient increase in the root mean square values, concurrent with a shift in the contribution of Θ (increase) and δ (decrease) power to the hippocampal electroencephalographic (hEEG) activity. Reversal blockade of these hEEG responses with xylocaine, given either intrathecally at the L6–S1 spinal levels or unilaterally to the hippocampal formation, significantly heightened and prolonged the ICP response. Pretreatment with xylocaine by itself, however, did not alter appreciably the baseline ICP or hEEG activity. These results suggest the presence of a novel negative feedback inhibitory mechanism in the hippocampal formation, which is triggered by ascending sensory inputs initiated by tumescence of the penis during normal erectile processes.     

Apomorphine-induced penile erection and yawning: site of action in brain

Microinjection of the dopamine (DA) agonist apomorphine into the paraventricular nucleus of the hypothalamus (PVN) induced penile erection and yawning in rats. A significant effect was elicited by a dose of apomorphine as low as 5 ng. The symptomatology usually began within 5 min after the microinjection, lasted for 30-50 min, and was identical to that induced by the systemic administration of the drug. Stereotypy and hypermotility were never observed after apomorphine microinjection into the PVN, even at the highest dose tested (1 microgram). Microinjections of the same doses of apomorphine into the hypothalamic ventromedial and dorsomedial nucleus, preoptic area, caudate nucleus, nucleus accumbens and substantia nigra, were ineffective. LY 171555, a specific D2 Da receptor agonist, and (+)-3-PPP, but not (-)-3-PPP nor the specific D1 DA receptor agonist SKF 38393, were as effective as apomorphine when injected into the PVN. Apomorphine-induced penile erection and yawning were antagonized by pretreatment with neuroleptic drugs, such as haloperidol, (-)-sulpiride, a specific D2 DA antagonist, and SCH 23390, a specific D1 DA antagonist. The present results suggest that the PVN is the brain area where D2 DA agonists act to induce penile erection and yawning. Moreover, since the PVN contains the cell bodies of a group of incerto-hypothalamic DA neurons, the above results suggest for the first time a possible involvement of the incerto-hypothalamic DA system in the expression of penile erection and yawning.     

ACTH- and alpha-MSH-induced grooming, stretching, yawning and penile erection in male rats: site of action in the brain and role of melanocortin receptors

The effect of adrenocorticotropin (ACTH)(1-24) and alpha-melanocyte stimulating hormone (alpha-MSH) on grooming, stretching, yawning and penile erection was studied after injection into different brain areas. Both peptides induce the above responses when injected into the hypothalamic periventricular region of the third ventricle. This region includes the paraventricular nucleus, the dorsomedial nucleus, the ventromedial nucleus and the anterior hypothalamic area. The minimal effective dose of both peptides was 0.5 microg and the maximal effect was seen with 2 microg, the highest dose tested. Irrespective of the injection site, grooming started 5-7 min after injection of either peptide, while stretching, yawning and penile erection started only after 15-35 min and lasted for 90-120 min. In contrast both peptides were ineffective when injected into the preoptic area, the caudate nucleus or the CA1 field of the hippocampus. Grooming, stretching and yawning, but not penile erection, were prevented by cyclic[AcCys(11), D-Nal(14), Cys(18), AspNH(2)(22)]-beta-MSH (11-22) (HS014), a selective melanocortin 4 receptor antagonist, injected into the same periventricular area 10 min before of ACTH(1-24) or alpha-MSH. The results show that ACTH(1-24) and alpha-MSH act in the hypothalamic periventricular region to induce the above responses and that grooming, stretching and yawning, but not penile erection, are mediated by melanocortin 4 receptors.     

Sleep-related penile erections do not occur in rats during carbachol-induced rapid eye movement sleep

This study was undertaken to find out whether sleep-related penile erections occur in the carbachol-induced rapid eye movement sleep model in rats. Bulbospongiosus EMG, as a measure of penile erection, was recorded along with EEG, EMG, and EOG during normal sleep-wakefulness. These parameters were again recorded after injection of carbachol into the pontine tegmentum. Carbachol-induced rapid eye movement sleep was not accompanied by penile erections.