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Hippocampal oxytocin mediates apomorphine-induced penile erection and yawning.

Repeated episodes of penile erection and yawning can be induced in male rats either by low doses of the dopaminergic agonist apomorphine or by oxytocin given systematically or into a lateral ventricle (ICV), respectively, or after microinjection of the two substances directly in the paraventricular nucleus (PVN) of the hypothalamus. These behavioral responses are prevented in a dose-dependent manner by the ICV administration of the potent oxytocin antagonist d(CH2)5Tyr(Me)-Orn8-vasotocin. In contrast, the PVN injection of d(CH2)5Tyr(Me)-Orn8-vasotocin (1-30 ng), while effective in preventing oxytocin effect, was unable to prevent apomorphine response. On the other hand, apomorphine-, but not oxytocin-induced penile erection and yawning was prevented by electrolytic lesion of the medial septum (MS). Such a lesion decreased oxytocin content by about 45% in the hippocampus. The above results suggest that the hypothalamic-hippocampal oxytocinergic pathway mediates apomorphine-induced penile erection and yawning and that oxytocin is involved at different levels in the CNS for the control of these behavioral responses.

Animals

Effect of 5-HT1C and 5-HT2 receptor stimulation on excessive grooming, penile erection and plasma oxytocin concentrations.

Serotonin (5-HT) receptor agonist-induced excessive grooming, penile erection and oxytocin secretion were studied in chronically cannulated freely moving rats. The 5-HT1C receptor agonist, m-chlorophenylpiperazine (m-CPP), which also binds to other 5-HT receptors, produced dose-dependent excessive grooming, penile erection and increases in circulating oxytocin concentrations. Maximal responses for excessive grooming and penile erection occurred at 0.3-0.6 mg/kg i.v. m-CPP. Higher doses (0.9-2.5 mg/kg i.v.) caused further increases in oxytocin concentrations, but attenuated both behavioral responses. All three responses to m-CPP (0.6 mg/kg) were attenuated by antagonists with high affinity for the 5-HT1C receptor site (mianserin, LY-53857 and metergoline), but not by the 5-HT2 receptor antagonist ketanserin. The 5-HT2/5-HT1C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), increased plasma oxytocin concentrations only. After ketanserin pretreatment, DOI caused penile erection and diminished the oxytocin response. All responses to DOI were blocked completely by pretreatment with LY-53857 plus ketanserin. Excessive grooming and penile erection showed significant bimodal correlations with the oxytocin response. These data suggest that stimulation of 5-HT1C receptors induces excessive grooming, penile erection and increased oxytocin secretion. Stimulation of 5-HT2 receptors causes a further increase in plasma oxytocin concentration, but inhibits both behavioral responses.

Analysis of Variance

Prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning: site of action in the brain.

The effect of morphine administered systemically or into the paraventricular nucleus of the hypothalamus (PVN) on penile erection and yawning induced either by oxytocin or by the dopaminergic agonist apomorphine was studied in male rats. Systemic morphine (0.5 to 5 mg/kg intraperitoneally [IP]) prevented in a dose-dependent manner penile erection and yawning induced by the intracerebroventricular injection (ICV) of oxytocin (30 ng) or by the subcutaneous (SC) administration of apomorphine (80 micrograms/kg). Morphine (0.1 to 5 micrograms), but not U-69,593 (5 micrograms), injected into the PVN 10 minutes before oxytocin or apomorphine, was found to be able to prevent penile erection and yawning induced by the unilateral PVN microinjection of oxytocin (10 ng) or apomorphine (50 ng). The morphine-induced prevention of these behavioral responses was abolished by pretreatment with naloxone (3 mg/kg IP) 15 minutes before morphine. The present results suggest that morphine prevents apomorphine- and oxytocin-induced penile erection and yawning by inhibiting the activity of oxytocinergic neurons through mu-type receptors in this hypothalamic nucleus.

Analgesics

Intracavernous pressure as an experimental index in a rat model for the evaluation of penile erection.

This report communicates our attempt to design a small animal model for the evaluation of penile erection, based on the pharmacological responses of cavernous tissues in the rat that resemble those of human subjects. Male adult Sprague-Dawley rats anesthetized with pentobarbital sodium were used in conjunction with papaverine and prostaglandin E1, two vasoactive drugs most commonly used in clinical management of impotence. Intracavernous administration of papaverine (0.05, 0.1, 0.02, 0.4 or 0.8 mg.) induced a progressive increase in intracavernous pressure that peaked at 0.4 mg. This effect was associated with visible penile erection that became conspicuous when accompanied by additional bursts of transient intracavernous pressure fluctuations. The duration of papaverine-induced increase in intracavernous pressure was significantly shortened by clonidine (15 micrograms, intracavernous). Injection of prostaglandin E1 (1, 2 or 4 micrograms) into the corpus cavernosum also elicited an elevation in intracavernous pressure, but the responses exhibited acute tachyphylaxis. By manifesting a response to papaverine and prostaglandin E1 that is similar to that in human, we conclude that the intracavernous pressure in the rat may represent a suitable index for the evaluation of penile erection in small laboratory animals.

Alprostadil

Effect of excitatory amino acid receptor antagonists on apomorphine-, oxytocin- and ACTH-induced penile erection and yawning in male rats.

The effect of excitatory amino acid receptor antagonists, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5, 10-imine hydrogen maleate ((+)-MK-801), (+/-)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and (+/-)-2-amino-4-phosphonobutanoic acid (AP-4), on penile erection and yawning induced by subcutaneous apomorphine (80 micrograms/kg), intracerebroventricular (i.c.v.) oxytocin (30 ng) and adrenocorticotropin (ACTH)-(1-24) (10 micrograms) was studied in male rats. Intraperitoneal (0.1-0.4 mg/kg) and i.c.v. (10-50 micrograms) (+)-MK-801 prevented dose dependently the penile erection and yawning induced by the three drugs. The (+)-MK-801 effect coincided with the appearance of head weaving, body rolling, hyperlocomotion and ataxia. Haloperidol (0.5 mg/kg i.p.) antagonized the prevention by (+)-MK-801 of oxytocin responses. Penile erection but not yawning was also prevented by high, but not low doses of CPP and CNQX, which impaired motor performance, AP-4 was ineffective at all doses tested. The above compounds were ineffective when injected into the paraventricular nucleus of the hypothalamus, the brain area where apomorphine and oxytocin act to induce penile erection and yawning. The results suggest that excitatory amino acid transmission is not involved in the expression of penile erection and yawning induced by the above compounds.

6-Cyano-7-nitroquinoxaline-2,3-dione

Elicitation of penile erection following activation of the hippocampal formation in the rat.

We explore the possible involvement of the hippocampal formation in penile erection, using male, adult Sprague-Dawley rats that were anesthetized with pentobarbital sodium. The intracavernous pressure (ICP) was used as the experimental index for penile erection. Electrical activation of the hippocampal formation resulted in two patterns, viz, multiple and single episodes of elevation in ICP, along with visible penile erection and ejaculation. The former pattern exhibited an increase in ICP that was more sustained, with higher peak amplitude and longer latency. Furthermore, they originated respectively from the granule cells of the dentate gyrus and pyramidal cells of the CA1 and CA3 fields of the Ammon's horn. Chemical stimulation of the hippocampus with glutamate also elicited significant increase in ICP. These results thus provided direct evidence to establish that the hippocampal formation may be involved in central neural regulation of the erectile process.

Animals

5-HT1A receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists.

The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4-5] décane-7,9 dione), is a high affinity full 5-HT1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10(-8) M affinity for D2 dopamine (DA) receptors, 100 fold lower than for 5-HT1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 micrograms/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT1A receptor antagonist tertatolol (2-5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT1A agonist property opposes to that of D2 dopamine receptor stimulation with regard to yawning and penile erections.

8-Hydroxy-2-(di-n-propylamino)tetralin

Chronic clonidine treatment and its termination: effects on penile erection and ejaculation in the dog.

The effects of chronic administration (4 weeks) of the alpha-2 adrenoceptor agonist clonidine (CL) and its termination on penile erection and ejaculation were investigated in male dogs. Penile erection and ejaculation were elicited by manual penile stimulation (for 5 min). CL (10 micrograms/kg/hr, s.c.) was delivered via osmotic minipump (Alza, 2ML-4). 3 or 7 days after the minipump implantation, CL caused a significant decrease in the amount of ejaculate produced by the genital stimulation without affecting the erectile potency. Ejaculatory ability returned to pretreatment levels despite continued CL administration, becoming evident in tests 14 days after initiation of treatment. Further, chronic CL (23 days) antagonized the inhibitory effects of acute administration of CL (0.05 mg/kg, i.p.). These data indicate tolerance to continued delivery of low doses as well as to acute administration of a higher dose. In the acute drug experiments, the ejaculatory inhibition elicited by CL (0.05 mg/kg, i.p.) was completely antagonized by pretreatment with yohimbine (0.05 and 0.10 mg/kg, i.p.), an alpha-2 adrenoceptor antagonist, but not with naloxone (1.0 mg/kg, i.p.), an opioid receptor antagonist. Furthermore, DG-5128 (1.0 and 2.0 mg/kg, i.p.), a selective alpha-2 adrenoceptor antagonist that poorly penetrates the blood-brain barrier, failed to antagonize the CL-induced ejaculatory inhibition. This study suggests that functional alterations in the central alpha-2 adrenoceptor mechanism may be related to the changes in the ejaculatory capacity during chronic treatment with CL.

Adrenergic alpha-Antagonists

Apomorphine- and oxytocin-induced penile erection and yawning in male rats: effect of pertussis toxin.

The effect of the intracerebroventricular (ICV) administration of pertussis toxin on penile erection and yawning induced by apomorphine and oxytocin was studied in male rats. Pertussis toxin (2 micrograms ICV) prevented the above behavioral responses to apomorphine (80 micrograms/kg SC) and oxytocin (30 ng ICV) on day 3 and 4, but not on day 0 and 1 after treatment. Oxytocin and apomorphine responses were restored on day 6. Similar results were obtained by microinjecting pertussis toxin (0.5 microgram) in the paraventricular nucleus of the hypothalamus, the most sensitive brain area for the induction of penile erection and yawning by oxytocin and apomorphine. The results suggest that G proteins are involved in the expression of above responses to apomorphine and oxytocin.

Animals

Opposite influences of dopaminergic receptor subtypes on penile erection.

1. Mixed D-1/D-2 dopamine agonist apomorphine induced a penile erection (PE) in rats in a biphasic manner. 2. The response was decreased with increasing doses of the drug. 3. The maximum effect was obtained by 0.1 mg/kg of apomorphine. 4. In animals pretreated with D-1 antagonist SCH 23390, high doses of apomorphine showed higher PE response, while D-2 antagonist sulpiride pretreatment decreased the response of the low doses of the drug. 5. The inhibitory effect of sulpiride was dose-dependent. 6. The D-2 agonists bromocriptine or quinpirole induced a dose-dependent PE. 7. The effects of both drugs were decreased by sulpiride or SKF 38393 pretreatment. 8. Cholinergic drugs physostigmine and neostigmine did not induce PE, but antimuscarinic agent atropine decreased the effects of apomorphine, bromocriptine or quinpirole. 9. It is concluded that D-2 dopamine receptor stimulation may induce PE, while D-1 activation elicit an opposite effect. 10. However, cholinergic stimulation is not able to induce PE, cholinergic inhibition may decrease the PE induced by dopaminergic agents.

Animals

Effects of adenosine on canine penile erection.

We investigated the hemodynamic effects of intracavernous injection of adenosine on canine penile erection. In all ten dogs studied, adenosine induced a dose-dependent increase of intracavernous pressure (ICP). Adenosine (0.67 to 15 micrograms/kg., B.W.) increased arterial blood flow by 83 to 325 percent above baseline levels and also increased venous resistance, which resulted in a full erection (ICP = 80 to 140 cm. H2O) for one to 7 minutes. The repeatability of the adenosine effect was confirmed in eight dogs. We found that adenosine, by virtue of its smooth muscle relaxation properties, can induce a dose-dependent increase of ICP and cause a full erection in dogs.

Adenosine

Involvement of the sympathetic nervous system in the urinary bladder internal sphincter and in penile erection in the anesthetized cat.

Male cats were anesthetized with pentobarbital. In one series of experiments a Foley catheter was placed suprapubically in the urinary bladder and physiologic saline, under a constant head of pressure, was allowed to flow at a constant rate through the bladder. Alpha-adrenergic stimulants such as ephedrine, norepinephrine, or methoxamine all caused a decrease or cessation in urinary flow. This effect was reversed by the alpha-adrenergic blocking agent, phentolamine. In addition, phentolamine administration caused penile erection. Erection also occurred after administration of the alpha-adrenergic blocking agent, phenoxybenzamine, or the beta2-adrenergic stimulants terbutaline or salbutamol. In each case the erection could be reversed, and usually terminated completely, by administration of the beta-adrenergic blocking agent, propranolol. Hypotension per se was not the required event to initiate erection because administration of acetylcholine, histamine, or prostaglandin E2 did not result in penile erection. In two of five experiments nitroprusside caused an erection. It was concluded that a predominance of beta2 activity in the penile vasculature is involved in erection.

Animals

Age-related changes in penile erections and circulating testosterone in middle-aged male rats.

The relationship between aging changes in pituitary-testicular function and the penile erection reflex was examined in middle-aged male rats. Significant decline in circulating LH and testosterone is first apparent in male rats during middle-age (13-15 mos). In Experiment 1, middle-aged (13-15 mos) and young (3-4 mos) rats were tested for erections responses. The erections were measured in animals held supine and mechanically stimulated by retraction of the penile shealth. Middle-aged rats had substantially fewer erections than young animals. In Experiment 2, groups of middle-aged and young animals were castrated and provided equivalent levels of circulating testosterone (T) through the use of Silastic capsules. The levels were measured directly by radioimmunoassay of plasma T. In animals with supraphysiological T levels, erection frequency was low, but there was no significant difference between middle-aged and young animals. The results suggest that middle-aged rats do not have irreversible deficiencies in the somatic and neural mechanisms regulating erection nor are they significantly less responsive to androgen stimulation. The decline in circulating testosterone with age may therefore be a primary factor in the reduction of penile erections in middle-aged rats.

Aging

The effect of intracavernosal haemodilution on the radionuclide quantification of penile vascular changes during pharmacologically induced penile erections.

Radionuclide phallography was performed using 99Tcm-labelled red blood cells in conjunction with pharmacologically induced penile erections. The radioactivity content of aliquots of systemic venous blood taken from the antecubital vein was compared with aliquots of blood withdrawn from the penile cavernosa 20 min after an intracavernosal injection of 10 micrograms prostaglandin E1. The cavernosal samples showed significantly lower counts per unit of blood compared to the systemic venous blood indicating a comparatively lower concentration of tagged red blood cells. On haematological analysis, a significant difference in the haematocrit of the two samples was also established. The fall in the cavernosal haematocrit was found to result from dilution of the cavernosal blood pool by the injected volume of the drug since larger volumes of injection produced a greater fall in the haematocrit. Restriction of the cavernosal venous outflow in response to the injection of the vasoactive drug causes sequestration of the diluted blood in the cavernosal compartment. This factor might affect the quantification of penile blood volume using radiotracer methods.

Adult

Nitric oxide: a physiologic mediator of penile erection.

Nitric oxide (NO) is a cytotoxic agent of macrophages, a messenger molecule of neurons, and a vasodilator produced by endothelial cells. NO synthase, the synthetic enzyme for NO, was localized to rat penile neurons innervating the corpora cavernosa and to neuronal plexuses in the adventitial layer of penile arteries. Small doses of NO synthase inhibitors abolished electrophysiologically induced penile erections. These results establish NO as a physiologic mediator of erectile function.

Amino Acid Oxidoreductases

Effect of intracavernous simultaneous injection of acetylcholine and vasoactive intestinal polypeptide on canine penile erection.

We investigated the effects of intracavernous injection of a combination of acetylcholine (ACh) and vasoactive intestinal polypeptide (VIP) on the erectile response in eleven adult male dogs. The minimum dose of ACh which increased the intracavernous pressure in eight dogs varied from 0.2 to 40 micrograms, and the minimum dose of VIP varied from 0.2 to 5 micrograms. When the minimum doses of ACh and VIP were injected simultaneously, a strong increase of intracavernous pressure (the mean increase was 102 cm. H2O from the baseline level) and a sustained erection (mean 5 min.) were observed in all eight dogs. The effect of simultaneous injection of both drugs was not additive but synergistic. Pretreatment with VIP-antibody and atropine intracavernously suppressed the erectile response induced by cavernous nerve stimulation. VIP may increase the affinity of muscarinic receptors for ACh in canine corpus cavernosum because pretreatment with atropine alone before the simultaneous injection of ACh and VIP completely abolished the effect of the combination. We conclude that ACh and VIP may play a cooperative role in canine penile erection.

Acetylcholine

Penile erection induced by apomorphine and N-n-propyl-norapomorphine in rats.

The intraperitoneal injection of apomorphine (APO) or N-n-propyl-norapomorphine (NPA) to adult male rats markedly increases the incidence of episodes of penile erection (PE). The effect is dose related for a dose range of APO from 25 to 500 microgram kg-1 and NPA from 1.25 to 50 microgram kg-1. Higher doses are progressively less effective until 1 and 5 mg kg-1 of APO and NPA, respectively, suppress even the natural occurrence of PE. APO differs from NPA not only on a potency basis but also in that doses of APO which elicit stereotypy no longer evoke PE, while a wide range of doses of NPA (12.5 to 500 microgram kg-1) produces simultaneously strong PE activation and stereotypy. The sexual stimulant response to APO and NPA is prevented by haloperidol (0.3 mg kg-1) and sulpiride (50 mg kg-1) but is not affected by domperidone (3 mg kg-1), an inhibitor of extracerebral dopamine receptors.

Animals