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Selegiline enhances erectile activity induced by dopamine injection in the paraventricular nucleus of the hypothalamus in anesthetized rats
Abstract
Apomorphine delivered in the paraventricular nucleus of the hypothalamus (PVN) induces penile erection in rats, suggesting a role of dopaminergic projection to the PVN in the control of penile erection. We assessed whether the selective inhibitor of monoamine oxidase B, selegiline, could enhance the erectile activity induced by dopamine delivery in the PVN. Intracavernous and blood pressure (ICP and BP) were monitored in anesthetized rats to quantify ICP rises (number and percentage of ICP maximum/mean BP (ICPmax/BP x 100)) elicited by 10 micro g dopamine injection in the PVN after saline or 3 mg/kg i.v. selegiline (8 rats per group). The number of ICP rises (mean+/-s.d.: 4.5+/-2.9 vs 1.4+/-1.9; P=0.017) and their ICPmax/BP x 100 (49+/-8% vs 34+/-9%; P=0.015) were significantly greater upon dopamine injection in the PVN than upon vehicle. Compared to saline i.v., 3 mg/kg selegiline pretreatment significantly increased the number of ICP rises induced by dopamine injection in the PVN (9.4+/-2.6 vs 4.5+/-2.9; P<0.001), without affecting their amplitude. This suggests that drugs potentiating dopaminergic responses in the central nervous system might enhance proerectile commands of supraspinal origin.
... Selegiline undergoes metabolism to amphetamine and methamphetamine, which may also contribute to the pharmacological effects on erectile function as described above for amphetamine and methamphetamine. Selegiline enhances the effect of dopamine in the PVN in rats [94]. Therefore, selegiline or vehicle was applied for 3 weeks for the treatment of sexual dysfunction in patients in antipsychotic treatment in placebo-controlled, crossover study. ...
The currently recommended first-line treatments of erectile dysfunction, phosphodiesterase type 5 inhibitors (PDE5i), e.g. sildenafil, are efficacious in many patients with erectile dysfunction of vascular origin, but this therapy is insufficient in approximately 30-40% of men with erectile dysfunction where there is also a neuronal affection. There is a demand of novel approaches to treat the condition. We review the possibility of modulating the dopaminergic pathways to improve erectile function. Dopamine D1 (D1 , D5 )-and D2 (D2 -D4 )-like receptors in the paraventricular area, the medial preoptic area, the spinal cord, and in the erectile tissue are involved in erection, and several agonists developed for treatment of Parkinson's disease are associated with increased libido. A therapeutic window for treatment of erectile dysfunction was found by sublingual administration of the general dopamine receptor agonist apomorphine, but it failed mainly due to less efficacy on erectile function compared to PDE5i. To avoid the dose-limiting side effects mediated by D2 receptors, nausea and emesis, dopamine D4 receptor agonists were developed, and they induce erection in rodents, but these drugs were never introduced clinically. The β-lactamase inhibitor clavulanic acid increases dopamine and serotonin and was found to increase sexual arousal and erections, but the dose-response curve is bell-shaped. Bupropion has selectivity for inhibition of the dopamine reuptake transporter and can be used to alleviate sexual symptoms caused by other antidepressant medication, hence providing an interesting approach to treat erectile dysfunction. In summary, modulation of the dopaminergic pathways provides a possibility to improve treatment of erectile dysfunction. This article is protected by copyright. All rights reserved.
... In addition, apomorphine in the PVN elicited increases in intracavernous pressure in anesthetized rats, a response that was enhanced by systemic administration of the monoamine oxidase B inhibitor, selegiline. 598 An oxytocin antagonist administered ICV, but not into the PVN, inhibited NCE, 599 suggesting that axons from the PVN, terminating perhaps in the hippocampus, 600 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter TNQ Books and Journals Pvt Ltd. It is not allowed to publish this proof online or in print. ...
... It has been shown that amphetamine-like drugs, such as SEL and its major metabolites, L-methamphetamine and L-amphetamine, cause tachycardia [35,36], hypotension [37,38] or hypertension [39]. Allard et al. report that 3 mg/kg of SEL induces only a transient decrease in blood pressure, which returns to its baseline value after 4 min [40]. In addition, anorexia/nausea, musculoskeletal injuries, and cardiac arrhythmias occurred more often in patients receiving SEL compared with those receiving placebo [41]. ...
Selegiline, an anti-Parkinson drug, has antioxidant and anti-apoptotic effects. To explore the effect of selegiline on sepsis, we used a clinically relevant animal model of polymicrobial sepsis. Cecal ligation and puncture (CLP) or sham operation was performed in male rats under anesthesia. Three hours after surgery, animals were randomized to receive intravenously selegiline (3 mg/kg) or an equivalent volume of saline. The administration of CLP rats with selegiline (i) increased arterial blood pressure and vascular responsiveness to norepinephrine, (ii) reduced plasma liver and kidney dysfunction, (iii) attenuated metabolic acidosis, (iv) decreased neutrophil infiltration in liver and lung, and (v) improved survival rate (from 44% to 65%), compared to those in the CLP alone rats. The CLP-induced increases of plasma interleukin-6, organ superoxide levels, and liver inducible nitric oxide synthase and caspase-3 expressions were ameliorated by selegiline treatment. In addition, the histological changes in liver and lung were significantly attenuated in the selegiline -treated CLP group compared to those in the CLP group. The improvement of organ dysfunction and survival through reducing inflammation, oxidative stress and apoptosis in peritonitis-induced sepsis by selegiline has potential as an adjuvant agent for critical ill.
Copulation and the physiological mechanisms of erection and ejaculation are described. In most rodents, testosterone's behavioral effects are mediated mostly by conversion to estrogen in neurons, whereas in primates, including humans, and some other animals, testosterone itself is the major hormone. Brain areas that control mating include the amygdala, bed nucleus of the stria terminalis, medial preoptic area, paraventricular nucleus, mesolimbic and nigrostriatal tracts, central tegmental field, lateral and ventromedial hypothalamus, and motor outputs, including the spinal cord. Drugs affecting dopamine, norepinephrine, serotonin, glutamate, gamma-aminobutyric acid, opioids, nitric oxide, oxytocin, and orexin/hypocretin administered systemically or into specific brain areas influence mating.
Major areas controlling sexual motivation and performance in males include the mesolimbic dopamine (DA) system, the medial preoptic area (MPOA), the amygdala, and the bed nucleus of the stria terminalis (BST). Genital reflexes are controlled by the MPOA, paraventricular nucleus (PVN), brainstem, and spinal cord areas. Mating is integrated by the MPOA, amygdala, BST, PVN, and mesolimbic and nigrostriatal tracts, which are also important for other social behaviors. Perinatal and adult hormones predispose the network to produce specific behaviors. Steroid hormones have primarily slow, genomically mediated effects, although they may also have rapid effects mediated by membrane receptors.
Elaine M. Hull has been professor in the Department of Psychology and the Program in Neuroscience at Florida State University, in Tallahassee, Florida, since 2004. She was previously professor of psychology at the University at Buffalo, State University of New York, for many years. She earned a PhD in psychology from Indiana University. She is author or co-author of 84 peer-reviewed articles and 11 chapters. For 25 years she has studied the roles of neurotransmitters in the medial preoptic area, mesocorticolimbic tract, and lateral hypothalamus in the control of male rat sexual behavior, as well as the influence of hormones on those neurotransmitters and behavior.
This chapter discusses the neurobiology of male sexual behavior. Sexual behavior in animals, including the courtship that precedes it, is characterized by enormous diversity. This diversity assures that mating will occur with the optimal partner at the most appropriate time and place, in order to pass parental genotypes onto the next generation. Male animals use species-specific displays to advertise their fitness and suitability as a partner. As they approach the female, they also gain information about her desirability and willingness to mate. In rodents, both partners may emit ultrasonic vocalizations, which are mutually arousing. A receptive female typically remains immobile while the male approaches from her rear, clasps her flanks with his forepaws, and initiates a series of shallow thrusts with his pelvis. Intromission is the defining event of copulation. If the male detects the female's vagina, he will perform a deeper, intravaginal thrust, followed by a rapid, springing dismount. This behavior pattern is reliably associated with penile insertion and is used as the measure of intromission in rats and many other rodents. Most male mammals ejaculate only after receiving stimulation from multiple intromissions. Ejaculation is characterized behaviorally by a deeper, longer thrust, and a slow, relaxed dismount. Rhythmic contractions of skeletal and striated perineal muscles, including the bulbospongiosus, ischiocavernosus, and anal sphincter, usually accompany ejaculation. In human males and females, such muscle contractions are associated with orgasm, the subjective correlate of the culmination of sexual excitement.
Introduction
Advances in understanding of the biochemistry and physiology of penile erection have led to breakthroughs in pharmacotherapy of erectile dysfunction.
Aim
To provide recommendations/guidelines concerning state‐of‐the‐art knowledge for the putative molecular and cellular mechanisms of action of centrally and peripherally acting drugs currently utilized in pharmacotherapy of erectile dysfunction.
Methods
An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state‐of‐the‐art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a two‐year period. Concerning the Pharmacotherapy for Erectile Dysfunction Committee there were 25 experts from 10 countries.
Main Outcome Measure
Expert opinion was based on grading of evidence‐based medical literature, widespread internal committee discussion, public presentation and debate.
Results
Selective and potent oral PDE5 inhibitors have significantly more affinity than cGMP and form broader molecular interactions with multiple amino acids, thereby blocking access to cGMP in the catalytic sites of the PDE5 enzyme. PDE5 inhibitors, which vary as to biochemical potency, selectivity and pharmacokinetics, lead to cGMP elevation and relaxation facilitation of penile corpus cavernosum smooth muscle cells following sexual stimulation. Various centrally acting drugs influence sexual behaviour. In particular, the dopaminergic substance apomorphine is a central enhancer that acts in the paraventricular nucleus of the hypothalamus as a dopamine (D2) receptor agonist, induces and increases penile erection responses via disinhibition, following sexual stimulation.
Conclusions
There is a need for more research in the pharmacotherapeutic development of central and peripheral agents for safe and effective erectile dysfunction treatment.
Steroid hormones regulate male sexual behavior, in part, by orchestrating the production and release of neurotransmitters
in brain areas that control sexual motivation and copulatory performance. Major facilitative neurotransmitters are dopamine,
glutamate, and, in some cases, norepinephrine. Serotonin, GABA, and opioid peptides provide primarily inhibitory influence,
although low levels of some of these neurotransmitters, acting via specific receptor subtypes, may facilitate certain aspects
of behavior. Other neuropeptides, including oxytocin, orexin/hypocretin, α-melanocyte stimulating hormone, gonadotropin releasing hormone, and galanin-like peptide may facilitate mating, whereas neuropeptide
Y, prolactin, corticotropin releasing hormone, and angiotensin II may have inhibitory effects. Brain areas that are especially
important for the control of male sexual behavior include the medial preoptic area, the medial amygdala, the paraventricular
nucleus of the hypothalamus, the mesocorticolimbic dopamine tract, several midbrain and brainstem nuclei, and nuclei in the
spinal cord that control the erectile and ejaculatory reflexes. Some dopaminergic and serotonergic receptor subtypes promote
parasympathetically mediated erection, and other subtypes facilitate sympathetically mediated seminal emission and ejaculation.
Epidemiological studies in the US, the UK and Sweden indicate that approximately 40% of women aged 18 - 59 have significant complaints about their sexual lives. The majority of complaints concern low sexual desire. Other common problems include difficulty reaching orgasm, insufficient lubrication and painful coitus. A vacuum erection device which increases blood flow to the clitoris has been approved by the US Food and Drug Administration. There are no pharmacological agents with approval for the treatment of female sexual dysfunction. Phosphodiesterase inhibitors and other drugs which cause genital vasocongestion in women appear to have minimal clinical efficacy. Although many of these agents increase the vasocongestive response to sexual stimulation, there is minimal correlation between subjective and objective measures of sexual arousal in women. Trials with androgens have clearly and convincingly demonstrated that supraphysiological doses of testosterone increase libido in postmenopausal women. The long-term safety of such doses is unclear. To date, no studies have shown lower doses of androgens to be beneficial. There have been minimal studies of drugs targeting the central nervous system to date. Bupropion may have a beneficial effect on orgasm attainment in women with hypoactive sexual desire disorder.
Many monoamine oxidase inhibitors (MAOIs) have been used to treat major depressive disorder (MDD). However, the prescription of MAOIs has decreased considerably as a result of side effects such as tyramine-induced hypertensive crisis, which is also known as the 'Cheese Effect'. The drug delivery system itself can affect the bioavailability of certain drugs, which might influence the efficacy and tolerability of medications, as well as improve the compliance and reduce the incidence of recurrence and relapse. Therefore, there is a need for advanced drug delivery techniques that can evade the potentially hazardous toxic effects of the parent compound, including extended-release oral, cutaneous, intravesical and intravaginal routes, etc. In this context, the selegiline transdermal system (STS, EMSAM) was introduced with improved side effect profiles and efficacy compared with the conventional form of the selegiline oral tablet. STS allows the targeted inhibition of the monoamine A (MAO-A) and MAO-B isoenzymes with minimal effects on the MAO-A in the gastrointestinal and hepatic systems. Hence, STS can reduce the risk of interactions with tyramine-rich foods. Many fundamental clinical and preclinical studies have reported that 6 mg/24 h of STS is effective against MDD without the need for dietary restrictions with an equal efficacy and improved safety profile. In addition, STS might benefit MDD patients with atypical features or who are resistant to other antidepressants. Overall, familiarity with the properties and indications of STS will have the clinicians another option of biological treatments for MDD patients but subsequent more data including actual post-market clinical experiences will be mandatory.
A dialysis cannula was implanted into rat striatum while the animals were anesthetized, and the area was perfused with Ringer solution while the animals were unanesthetized after at least 3 days following surgery. Concentrations of the metabolites of 3,4-dihydroxy-phenylethylamine (DA) and 5-hydroxytryptamine (5-HT) in the perfusate were determined by HPLC with electrochemical detection. Levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the perfusate significantly decreased after pargyline administration (50 mg/kg i.p.), which may inhibit not only monoamine oxidase (MAO)-B but also MAO-A in these high doses. The level of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) also decreased after pargyline treatment, although change in the relative level of 5-HIAA was less than that of DOPAC or HVA. To clarify the mechanisms for the metabolism of monoamines in rat striatum, highly specific MAO-A and -B inhibitors were used in the following experiments. Treatment with l-deprenyl (10 mg/kg), a specific inhibitor for MAO-B, did not cause any statistically significant change in DOPAC, HVA, and 5-HIAA levels. No significant change was found in rat striatal homogenates at 2 h after the same treatment with l-deprenyl. In contrast, low-dose treatment (1 mg/kg) with clorgyline, a specific inhibitor for MAO-A, caused a significant decrease in levels of these three metabolites in both the perfusates and tissue homogenates. In addition to the above three metabolites, the level of 3-methoxytyramine, which is an indicator of the amount of DA released, greatly increased after treatment with a low dose (1 mg/kg) of clorgyline. These results suggest that DA and 5-HT in rat striatum may be preferentially deaminated by MAO-A in vivo.
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.
The activity of beef heart mitochondrial monoamine oxidase towards 5-hydroxytryptamine (5-HT) is inhibited by the selective inhibitors clorgyline, PCO [5-phenyl-3-(N-cyclopropyl)-ethylamine-1,2,4-oxidiazole] and Deprenyl with a biphasic dependence on the inhibitor concentration. The activities towards tyramine, dopamine and tryptamine were also inhibited in a biphasic manner, but the apparent proportions of the two enzyme species active on dopamine and tryptamine depended on the inhibitor used. Phenethylamine oxidation was inhibited in a monophasic manner suggesting that only a single enzyme species was responsible for the oxidation of this substrate. The biphasic response of 5-HT oxidation to inhibition by clorgyline persisted when functionally competent mitochondria were used and was unaffected by the soluble amine oxidase inhibitors semicarbazine and aminoguanidine. These results indicate that the behaviour of the beef heart enzyme towards selective inhibitors is considerably different from that of any preparations previously studied and suggest that the classification of monoamine oxidase activites into A and B types may be only of limited usefulness.
In vivo microdialysis was used to concurrently measure the behavioral and caudate dopamine (DA) responses to the alleged irreversible type B monoamine oxidase inhibitor deprenyl. The effects were contrasted to those of the type A monoamine oxidase inhibitor, clorgyline. Consistent with its effects as an irreversible monoamine oxidase inhibitor, clorgyline produced an increase in DA concentration that remained elevated for at least 6 h. In contrast, the deprenyl-induced elevation in DA concentration occurred more rapidly, achieved a higher peak response, and then returned to baseline within 2 h following drug administration. The two drugs also produced distinctive changes in DA metabolite levels. Whereas the pattern of clorgyline-induced effects were consistent with irreversible monoamine oxidase inhibition, deprenyl produced an amphetamine-like response profile. Further, deprenyl but not clorgyline significantly increased locomotor activity. These results suggest that deprenyl does not augment caudate DA levels through monoamine oxidase inhibition. Rather, the pattern of its effects on caudate DA dynamics and behavior supports previous evidence that deprenyl produces its effects through its metabolism to amphetamine-like substances.
This report describes experiments designed to determine whether (-)-deprenyl potentiates dopaminergic transmission and whether its mechanism involves the inhibition of dopamine catabolism. Intraperitoneal administration of (-)-deprenyl (0.5-8 mg kg-1) produced a dose-dependent inhibition of striatal monoamine oxidase type B activity whereas monamine oxidase type A activity in the striatum was inhibited only by 8 mg kg-1 of (-)-deprenyl. Intraperitoneal administration of (-)-deprenyl (0.5-4 mg kg-1) did not alter the striatal concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or homovanillic acid. DOPAC concentrations were decreased by 8 mg kg-1 of (-)-deprenyl. In contrast, administration of clorgyline (2 mg kg-1), a monoamine oxidase type A inhibitor, increased the striatal concentrations of DA and decreased the striatal concentrations of DOPAC and homovanillic acid. The striatal concentrations of 2-phenylethylamine (PE), a putative modulator of striatal DA transmission, were increased by (-)-deprenyl (1-8 mg kg-1) but were unaffected by clorgyline (2 mg kg-1). In electrophysiological studies, single caudate neuron responses to iontophoretically applied (-)-apomorphine and (+/-)-2-(N-phenethyl-N-propyl) amino-5-hydroxytetralin were potentiated by intracarotid injections of PE (30 micrograms kg-1) and i.p. injections of (-)-deprenyl (2 mg kg-1). Both PE and (-)-deprenyl reduced the IT50 of responses to apomorphine and (+/-)-2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain microdialysis was used to examine the in vivo efflux and metabolism of dopamine (DA) in the rat striatum following monoamine oxidase (MAO) inhibition. Relevant catecholamines and indoleamines were quantified by HPLC coupled with a electrochemical detection system. The MAO-B inhibitor selegiline only affected DA deamination at a dose shown to inhibit partially type A MAO. Alterations in DA and metabolite efflux were not observed when using the MAO-B-selective dose of 1 mg/kg of selegiline. At 10 mg/kg, selegiline reduced the efflux of DA metabolites to approximately 70% of basal values without affecting DA efflux. K(+)- and veratrine-stimulated DA efflux was not affected by selegiline. Experiments using amphetamine and the DA uptake inhibitor nomifensine demonstrated that the effect of selegiline on DA metabolism was unlikely to be mediated either by inhibition of DA uptake or by an indirect effect of its metabolite amphetamine. The possibility that the effect of selegiline is mediated via a nonspecific inhibition of MAO is discussed. In contrast, the MAO-A inhibitor clorgyline inhibited basal DA metabolism and increased basal and depolarisation-induced DA efflux. A 1 mg/kg dose of clorgyline reduced basal DA metabolite efflux (40-60% of control values) without affecting DA efflux. At 10 mg/kg of clorgyline, DA efflux increased to 253 +/- 19% of basal values, whereas efflux of DA metabolites was reduced to between 15 and 26% of control values. The release of DA induced by K+ and veratrine was not affected by 1 mg/kg of clorgyline but was increased by approximately 200% following pretreatment with 10 mg/kg of clorgyline. The nonselective MAO inhibitor pargyline caused similar but more pronounced alterations in these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
Bromocriptine (0.5 mg/kg) and apomorphine (0.03 mg/kg) exert moderate aphrodisiac effect in sexually sluggish rats. This effect appears rapidly and reaches its peak within 24 h. Amphetamine (2 mg/kg) acts similarly but with a more rapid onset and offset of the effect. A single dose of (-)deprenyl, a selective inhibitor of MAO-B, exerts a much more potent effect in this test.
Phenethylamine and serotonin were oxidatively deaminated by separate forms of monoamine oxidase of rat brain when studied in vitro. These forms, designated as type A and type B enzyme, have different characteristics. For example, type A enzyme deaminated serotonin, was sensitive to clorgiline, was resistant to deprenyl and was heat stable. In contrast, type B enzyme deaminated phenethylamine, was resistant to chlorgiline, was sensitive to deprenyl and was heat labile. Moreover, type A and type B enzyme activities could be partially separated by centrifugation on a continuous sucrose gradient. Phenethylamine and serotonin are present in mammalian brain. It is concluded from these studies that the amines of brain may be catabolized by specific types of monoamine oxidase in vivo.
It was found that in the rat striatum DA was oxidized extrasynaptosomally to 11% by MAO-A and to 3% by MAO-B. The corresponding intrasynaptosomal oxidations were 84% and 2%, respectively. Those figures were virtually unchanged even if the rat brain MAO-B was selectively inhibited to 87% by deprenyl. In the human brain extrasynaptosomal oxidation was 16% and 66%, respectively, by MAO-A and -B. Intrasynaptosomally the corresponding figures were 12% and 6%, respectively. Selective inhibition of human caudate MAO-B was calculated to give a total reduction of DA oxidation of 63%. The differences between man and rat are due to the proportionately greater oxidation of DA by MAO-B in man, which is a consequence of a higher ratio of concentration of MAO-A/-B in the rat.
1-Deprenil, a potent inhibitor of type B monoamine oxidase, was a weak inhibitor of 3H-dopamine uptake as well as a weak releasing agent for previously accumulated 3H-dopamine in rat neostriatal tissue slices. In similar experiments d-amphetamine as approximately 100 times as potent as 1-deprenil as a releasing agent. When deprenil (20 mg/kg IP) was given to rats with a unilateral 6-hydroxydopamine lesion of the substantia nigra, it brought about a moderate but long-lasting ipsilateral rotational behavior. 1-Dopa (20-40 mg/kg, IP) by itself caused a considerably stronger rotation in the opposite direction (contralateral). When 1-dopa was given to rats 1 hr after 1-deprenil, there was a considerably greater contralateral rotation than after 1-dopa alone. Clorgyline, a type A monoamine oxidase inhibitor, which by itself at 20 mg/kg caused no rotation, also potentiated the contralateral rotation seen after 1-dopa (5-20 mg/kg). In contrast, d-amphetamine, which by itself caused ipsilateral rotation, failed to potentiate the rotation after 1-dopa. Possible mechanisms for these observations will be discussed.
Among central neurotransmitters involved in the control of sexual behavior, dopamine is certainly one of the most extensively studied. Our attempt to review old and recent neuropharmacological, biochemical, electrophysiological, and psychobiological studies performed so far only in rats, monkeys, and humans, provides evidence that dopamine through its different neuronal systems and receptor subtypes plays different roles in the control of several aspects of sexual behavior. In fact, while the nigrostriatal system is necessary for the control of the sensory-motor coordination required for copulation, the mesolimbic-mesocortical system plays a key role in the preparatory phase of the behavior, mainly in sexual arousal, motivation and possibly reward. Conversely, the incertohypothalamic system plays a major role in the consummation of the behavior, mainly in seminal emission and erectile performance, but evidence for its involvement in sexual motivation also exists. The dopaminergic receptors playing the major role in the control of male sexual behavior belong to the D2 receptor subtype. However a D1/D2 receptor interaction is well established and an opposite role for D1 and D2 receptors in the preoptic area suggested. Despite some differences, most studies show that treatments that increase or decrease, respectively, brain dopaminergic activity improve or worsen, respectively, several parameters of copulatory activity, supporting a facilitatory role of dopamine in male sexual behavior. In contrast, no conclusion can be deduced from the available studies on the role of central dopaminergic systems in the control of proceptivity and receptivity, the two main components of female sexual behavior.
(−)−Deprenyl has been shown to potentiate rat striatal neurone responses to dopamine agonists at doses not altering dopamine metabolism. Since there are a number of effects of (−)−deprenyl which could result in this phenomenon, we have investigated the effects of MDL 72,145 and Ro 19–6327, whose only common effect with (−)−deprenyl is an inhibition of monoamine oxidase‐B (MAO‐B), on rat striatal neurone responses to dopamine and on striatal dopamine metabolism.
Using in vivo electrophysiology, i.p. injection of either MDL 72,145 or Ro 19–6327 was found to produce a dose‐dependent potentiation of striatal neurone responses to dopamine but not γ aminobutyric acid.
Neurochemical investigations revealed that this occurred at doses (0.25‐1 mg kg ⁻¹ ) which, while not affecting levels of dopamine or its metabolites, 3,4‐dihydroxyphenylacetic acid or homo vanillic acid, did cause a significant, dose‐dependent, elevation in striatal levels of the putative neuromodulator, 2‐phenylethylamine (PE).
Inhibition of PE synthesis by i.p. injection of the aromatic 1 ‐amino acid decarboxylase inhibitor, NSD 1015, produced a reversal of the effects of MDL 72,145 and Ro 19–6327.
Neurochemical analysis revealed this to occur at a dose of NSD 1015 (10 mg kg ⁻¹ ) selective for reduction of elevated PE levels.
These results suggest that PE can act as a neuromodulator of dopaminergic responses and that MAO‐B inhibitors may potentiate neuronal responses to dopamine via the indirect mechanism of elevation of PE following MAO‐B inhibition.
Intraperitoneal injection of the selective D2 dopamine agonist SND 919 (0.1 and 1 mg kg-1) significantly accelerated the copulatory behaviour of sexually-active rats, diminishing the number of mounts, intromissions and latency to ejaculation. Subchronic (-)deprenyl did not produce any significant effect on the copulatory behaviour of sexually-active and -inactive male rats or modify the sexual stimulation exerted on the same sexually-active rats by SND 919, when acutely injected at 1 mg kg-1.
l-Deprenyl (selegiline), an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is rapidly absorbed from the gastrointestinal tract and distributed into tissues. The reaction between MAO and selegiline takes place in two steps. The initial reversible reaction is followed by an irreversible reaction in which selegiline is bound covalently to the flavin part of the enzyme. Studies with positron emission tomography have shown retention of selegiline in brain areas with high MAO-B activity, including striatal structures, hippocampus, thalamus, and substantia nigra. Inhibition of MAO-B in vivo takes place rapidly; for example, platelet MAO is inhibited almost totally within the first 60 minutes after a single 10 mg oral dose of the drug. The recovery of MAO after inhibition depends on the organ and species in question. In rat brain the half-life of recovery in the brain is approximately 8 to 12 days; in rat liver it is shorter, 1 to 3 days. Selegiline is metabolized into l-(-)-desmethylselegiline, l-(-)-methamphetamine, and l-(-)-amphetamine mainly in the liver through the microsomal P-450 system. The stereoselectivity of the metabolites is maintained; no racemic transformation takes place. All three main metabolites are found in human serum, cerebrospinal fluid, and urine, and l-(-)-methamphetamine accounts for most of the metabolite pool. The metabolites are excreted mainly via urine l-(-)-Desmethylselegiline has been shown to be an irreversible inhibitor of MAO-B in the rat and in humans.
Out of 1600 sexually inexperienced 28-week old Wistar-Logan male rats 94 sexually inactive ('low performing', LP) and 99 highly active ('high performing', HP) rats were selected. The rats were treated from the 8th month of their life three times a week, subcutaneously, with either 0,9% NaCl or 0,25 mg/kg (-)deprenyl until they died. Their copulatory activity was tested once a week and their learning performance was measured in the shuttle box once in three months. The salt treated LP rats (n=44) never displayed ejaculation during their life time, they were extremely dull in the shuttle box and lived 134.58+/-2.29 weeks. Their (-)deprenyl-treated peers (n=48) became sexually active, their mating performance was substantially increased and lived 152.54+/-1.36 weeks, significantly longer than their salt-treated peers and as long as the salt-treated HP rats. The salt treated HP rats (n=49) displayed 14.04+/-0.56 ejaculations during the first 36-week testing period and due to aging they produced 2.47+/-0.23 ejaculations between the 73-10th week of testing. Their learning performance was high. They displayed 78.45+/-3.01 conditioned avoidance responses (CAR) during the first 36-week testing period, and this dropped to 50.67+/-2.99 (p<0.01) during the 73-108th week of testing. They lived 151.24+/-1,36 weeks, significantly (p<0.001) longer than their LP peers. The (-)depre-nyl-treated HP rats (n=50) were sexually much more active than their salt-treated peers. They displayed 30.04+/-0.85 ejaculations during the first 36-week testing period and 7.40+/-0.32 ejaculations between the 73-108th week of testing. Also their learning performance was substantially increased. They produced 113.98+/-3.23 CARs during the first 36-week-testing period and 81.68+/-2.14 CARs during the 73-108th week of testing. They Lived 185.30+/-1.96 weeks, significantly more than their salt-treated peers and out of the 50 rats 17 lived longer than the estimated technical life span (TLS).
Administration of L-DOPA (50 mg/kg) elicits a significant increase in extracellular dopamine in striata of rats treated with the catecholaminergic neurotoxin 6-hydroxydopamine but not in striata of intact rats. To assess the role of dopaminergic nerve terminals in determining the effects of exogenous L-DOPA on extracellular dopamine levels in striatum, we examined the relative contributions of monoamine oxidase A and monoamine oxidase B to the catabolism of dopamine synthesized from exogenous L-DOPA. Extracellular concentrations of dopamine and its catabolite, 3,4-dihydroxyphenylacetic acid, were monitored with in vivo dialysis in striata of intact rats and of rats with unilateral 6-hydroxydopamine lesions of striatal dopamine. Clorgyline (2 mg/kg), an inhibitor of monoamine oxidase A, significantly increased dopamine and decreased 3,4-dihydroxyphenylacetic acid in intact but not in dopamine-depleted striata. Inhibition of monoamine oxidase B with either L-deprenyl (1 mg/kg) or Ro 19-6327 (1 mg/kg) did not significantly affect dopamine or 3,4-dihydroxyphenylacetic acid in striata of intact or dopamine-depleted rats. In intact rats, administration of clorgyline in conjunction with L-DOPA produced a > 20-fold increase in dopamine and prevented the L-DOPA-induced increase in 3,4-dihydroxyphenylacetic acid. Although both L-deprenyl and Ro 19-6327 administered in combination with L-DOPA elicited a small but significant increase in dopamine, levels of 3,4-dihydroxyphenylacetic acid were not affected. In rats pretreated with 6-hydroxydopamine, clorgyline had no significant effect on the increases in dopamine and 3,4-dihydroxyphenylacetic acid elicited by L-DOPA. Furthermore, neither L-deprenyl nor Ro 19-6327 affected L-DOPA-induced increases in dopamine and 3,4-dihydroxyphenylacetic acid in dopamine-depleted striata. The present findings indicate that deamination by monoamine oxidase A is the primary mechanism for catabolism of striatal dopamine, both under basal conditions and after administration of exogenous L-DOPA. Loss of dopaminergic terminals eliminates this action of monoamine oxidase A but does not enhance deamination by monoamine oxidase B. These data support a model in which exogenous L-DOPA elicits enhanced extracellular accumulation of dopamine in the dopamine-depleted striatum because some transmitter synthesis occurs at nondopaminergic sites and the dopamine terminals that normally take up and catabolize this pool of transmitter are absent.
In vivo microdialysis was used to investigate the effect of beta-phenylethylamine on extracellular levels of monoamines and their metabolites in the nucleus accumbens of conscious rats. At all doses tested (1, 10 and 100 microM), infusion of beta-phenylethylamine through the microdialysis probe significantly increased extracellular levels of dopamine in the nucleus accumbens. These increases were dose-related. The increase in dopamine levels induced by 100 microM beta-phenylethylamine was not affected by co-perfusion of 4 microM tetrodotoxin. The ability of 100 microM beta-phenylethylamine to increase the extracellular level of dopamine was comparable to that of the same dose of methamphetamine. On the other hand, beta-phenylethylamine had a much less potent enhancing effect on 5-hydroxytryptamine (5-HT) than dopamine levels. Only the highest dose (100 microM) caused a statistically significant effect on 5-HT levels. Over the dose range tested (1, 10 and 100 microM), beta-phenylethylamine had no effect on extracellular metabolite levels of dopamine and 5-HT. The results suggest that beta-phenylethylamine increases the efflux of monoamines, preferentially dopamine, without affecting monoamine metabolism, in the nucleus accumbens.
Selegiline (deprenyl), a selective, irreversible inhibitor of monoamine oxidase type B (MAO-B) is widely used in the treatment of Parkinson's disease. As the first MAO-B inhibitor approved for the treatment of Parkinson's disease, concerns were raised about the safety of the drug based on the adverse effect profiles of older, nonselective MAO inhibitors. Unlike the nonselective MAO inhibitors, selegiline does not significantly potentiate tyramine-induced hypertension (the 'cheese effect') at the dosages (5 to 10 mg daily) used for the treatment of Parkinson's disease. Selegiline has been well tolerated when given alone. The most frequent adverse events seen during monotherapy have been insomnia, nausea, benign cardiac arrhythmias, dizziness and headache. When combined with levodopa, selegiline can potentiate the typical adverse effects of levodopa, if the dose of levodopa is not reduced sufficiently. Thus, the most common adverse effects associated with this combination are nausea, dizziness, fatigue, constipation and insomnia. At the later stages of Parkinson's disease when fluctuations in disability occur, peak dose dyskinesias, psychiatric complications like hallucinations and insomnia, and orthostatic hypotension are further potentiated by selegiline. Mortality was recently reported to be increased when selegiline and levodopa were given together in comparison with treatment with levodopa alone, but a large meta-analysis of 5 long term studies and 4 separate studies did not support this conclusion. Selegiline seems to be generally well tolerated in combination with other drugs. However, when pethidine (meperidine) has been given to patients who are receiving selegiline therapy, severe adverse effects have been reported. Thus, the concomitant use of these drugs is not recommended. A low tyramine diet is recommended if selegiline is used together with nonselective MAO inhibitors or the selective, reversible MAO-A inhibitor, moclobemide. Several adverse effects have been reported when fluoxetine and selegiline have been used together. A recent survey revealed that the incidence of a true serotonin syndrome is, however, very low with this combination. Concomitant use of selegiline and other selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) like citalopram, which have generally less interactions than fluoxetine, seems to be well tolerated. Nevertheless, caution is advised when combining a SSRI or a tricyclic antidepressant and selegiline.
To investigate whether the paraventricular nucleus of hypothalamus (PVN) is involved in the central regulation of apomorphine-induced penile erection in the rat, and to decipher dopamine receptor subtypes in the PVN that are involved in apomorphine-induced penile erection.
Male adult Sprague-Dawley rats (200 to 300 gm.) anesthetized with pentobarbital sodium were used. The intracavernous pressure (ICP), recorded along with systemic and mean arterial pressure (SAP, MAP) as well as heart rate (HR), was measured via a 26-gauge needle inserted into one corpus cavernosum. The PVN was activated by stereotaxically delivered apomorphine hydrochloride (0.1 nmol./100 nl.). Injection of saline into PVN served as a vehicle control. To investigate the participation of dopamine receptor subtypes in the PVN on apomorphine-induced penile erection, D1 or D2 receptor antagonist, SCH-23390 (100 pmol./100 nl.) or sulpiride (100 pmol./100 nl.) respectively, was administered into the PVN prior to subcutaneous application of apomorphine (80 microg./kg.). The effects on ICP of microinjection of D1, D2 or D3 receptor agonist, SKF-38393 (200 pmol./100 nl.), lisuride (200 pmol./100 nl.) or 7-hydroxy-DPAT (200 pmol./100 nl.) respectively, into the PVN were also evaluated.
The mean resting ICP was 5.2+/-0.4 mm. Hg. Upon administration of apomorphine into the PVN, there was a significant increase in ICP that peaked at 50.7+/-5.3 mm. Hg and persisted for 45.2+/-18.0 minutes after an onset latency of 677.7+/-311.6 seconds. Yawning and teeth gnashing were also observed in most of animals during the period of ICP increase. There was no significant change in SAP, MAP or HR. In addition, there was no elevation in ICP after administration of saline to the PVN or direct injection of apomorphine into the cavernous tissue. Microinjection of D1 or D2 receptor antagonist into the PVN blocked the increase in ICP after subcutaneous administration ofapomorphine. Direct application of D2, but not D1 or D3 receptor agonist into the PVN, on the other hand, increased the ICP.
Our results demonstrate that application of apomorphine to the paraventricular nucleus of hypothalamus elicited penile erection in the rat. Such an increase in ICP to apomorphine was due mainly to activation of the D2 receptor subtype in the PVN. These observations indicate that PVN may be involved in the central regulation of apomorphine-induced penile erection in the rat.
Apomorphine SL (TAP Holdings, Deerfield, IL) is a centrally acting treatment for erectile dysfunction (ED) that has been undergoing phase III trials. Over 3000 men have received apomorphine SL and over 75,000 doses have been taken. In the first three phase III parallel arm cross-over double-blind studies 854 patients were given a total of 8263 tablets of apomorphine SL in 2 and 4 mg doses. The patients were between 18 and 70 y old and outcome measures included per attempt rates of intercourse and erections firm enough for intercourse as well as psychometric instruments and partner responses. The majority (74.1%) had moderate and severe grades of ED on admission to the studies, 31% had hypertension, 16% had documented coronary artery disease, 16% had dyslipidemia and 16% had diabetes. Erections occurred rapidly (10-25 min) and in 54.4% of attempts at 4 mg (vs 33.8% placebo). A majority of the attempts at intercourse (50.6%) were successful at 4 mg in patients when recorded on a per-attempt basis. The most common but infrequent and mild side effect of nausea decreases with use. The phase III trials of apomorphine SL show that there is a clinically important restoration of erectile function from this new formulation of apomorphine. It has a rapid and safe effect through action in the central nervous system. Apomorphine SL brings a new choice to the management of ED that will further benefit the millions of couples affected. International Journal of Impotence Research (2000) 12, Suppl 4, S67-S73.
The effects of administration of monoamine oxidase-B inhibitors on rat striatal neurone responses to dopamine
- M D Berry
- MD Berry