Proerectile effects of apomorphine in mice

doi:10.1016/S0024-3205(03)00122-X

Life Sciences

Volume 72, Issue 21, 11 April 2003, Pages 2329-2336

https://doi.org/10.1016/S0024-3205(03)00122-X Get rights and content

Abstract

Dopaminergic pathways play a key role in the central control of sexual behavior. Stimulation of central dopaminergic receptors elicits penile erection in a variety of species and has been proposed as a treatment option for erectile dysfunction in humans. The present study investigated the proerectile effects of apomorphine in mice. In this species, subcutaneous injection of apomorphine (range: 0.11–110 μg/kg sc) elicited three different behavioral responses: erection, erection-like responses and genital grooming. Proerectile effects of apomorphine were dose-dependent. More than 50% of mice displayed erections after administration of 1.1–11 μg/kg of apomorphine sc. Proerectile effects of apomorphine were blocked by haloperidol, a central D2 antagonist, but not by domperidone, a peripherally active dopaminergic antagonist. We conclude that apomorphine elicits erection in mice. This effect is dose-dependent and due to activation of central D2 dopaminergic receptors. The mouse model may be useful for pharmacological approaches designed to provide a better understanding of the central mechanisms of penile erection and sexual behavior.

Introduction

Penile erection results from relaxation of smooth muscle fibers present in the penis and penile arteries, leading to increased blood flow to the penis and filling of the cavernous and spongiosus spaces with blood [1]. Penile erection is mainly controlled by the autonomic nervous system and enhanced by contractions of the perineal striated muscles [20]. Parasympathetic pathways derived from the sacral spinal cord are proerectile. Sympathetic pathways derived from the thoracolumbar spinal cord are antierectile. Parasympathetic and sympathetic pathways are controlled by information descending from the brain to the spinal cord. In humans and rats, erection occurs in different contexts (copulation, reflexive erections, during sleep, as a psychogenic response, in response to drug administration) and it has been suggested that each context could reflect activation of different brain nuclei [19]. In mice, erection occurs during copulation, but not in response to stimulation of the genitals [17], suggesting a difference in the brain control of erection between species. Studies have been conducted to provide a better understanding of the control of erection by the brain. Central dopaminergic pathways play a key role in the control of sexual behavior [12]. The D1/D2 dopaminergic receptor agonist, apomorphine, delivered systemically or centrally, elicits penile erection in rats [2], [11], monkeys [15] and humans [10]. The present study was designed to investigate apomorphine-induced erections in mice. Sublingual apomorphine has been recently proposed for the treatment of erectile dysfunction in humans [14]. Tolerance, i.e. development of resistance to the action of a drug when taken repeatedly, can hamper the development of drugs designed to treat central disorders. Apomorphine, an oral erectogenic drug with a central site of action, has been proposed as a first-line treatment option in patients with erectile dysfunction. In these patients, repeated dosing with sublingual apomorphine enhances efficacy [7]. In contrast, tolerance to the proerectile effects of apomorphine have not been previously evaluated in animal models. We therefore also tested whether tolerance to apomorphine can occur in mice. Our study provides more information about the contexts in which erection occurs in mice. It extends the possibility of using mice, an economic model, for further studies on the effects of compounds on the central neural control of erection.

Section snippets

Material and methods

Adult male BalbC mice were obtained from the animal colony at Institut National de la Recherche Agronomique, Jouy-en-Josas, France. Mice weighed 25–35 g. They were housed 10 per cage in the animal facility under a 12 H:12 H light–dark cycle with lights off at 7:00 p.m. Room temperature was maintained at 20 °C. Mice had ad libitum access to pelleted commercial rodent chow and tap water. During the week before drug injection, mice were habituated to the testing room and test chamber. The chamber

Results

Apomorphine sc elicited three distinct behaviors in BalbC male mice: erection (Fig. 1), erection-like responses and genital grooming. During erection, the erect penis was visible, erection was always accompanied by grooming of the penis, and the mouse held the penis with its forepaws. During erection-like responses, this penile grooming was not observed. In contrast, the mouse groomed the abdomen. During erection and erection-like responses, the animal bent on the extremity of its hindlimbs.

Discussion

There are probably differences in the central neural control of erection between different species of rodents. Male rats display erections in a variety of contexts: during copulation, as a reflex response to genital stimulation, during sleep, in the presence of a receptive female, and in response to drug administration. Because erection occurs in different contexts, it has been suggested that each context reflects the activity of different sets of brain nuclei [19]. Such contexts have not all

Conclusions

The present study provides evidence that mice display drug-induced erections. It also provides reference data for further evaluation of the proerectile properties of other compounds, and opens the way to the use of genetically modified animals. The effects of other compounds on erection can be evaluated by behavioral measures, as in the present study, and by physiological measures, e.g. intracavernous pressure recordings [21]. Models of genetically modified mice are already available, e.g. mice

Acknowledgements

This study was funded by an institutional grant from Institut National de la Recherche Agronomique. The authors gratefully acknowledge Prof. Jean Costentin for helpful comments on the manuscript.

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The use of various dopamine agonists in different animal models for the treatment of SD provides substantial evidence for the involvement of the dopaminergic system in the regulation of sexual function (Koza and Yenisetti, 2020). Apomorphine, a dopamine agonist displayed pro-erectile effects in mice models by activating central dopaminergic D2 receptors (Rampin et al., 2003). Another study using Drosophila model showed that dopamine regulates the male courtship intensity via dopaminergic neurons.
Sexual function which comprises of desire, arousal, orgasm and satisfaction and pain, involves coordinated physiologic responses from multiple different pathways. Sexual dysfunction (SD) occurs when these domains of the sexual response cycle are affected. SD is a common but under-recognized non-motor feature in Parkinson’s disease (PD), a common age-related neurodegenerative disorder. SD significantly affects the quality of life of PD patients and their partners. Advanced age, gender, hormone deficiency, neuropsychiatric and medical comorbidities contribute to SD in PD. Possible potential pathological mechanisms include vasculogenic, endocrinologic, neurogenic and psychogenic factors. Various therapeutic interventions, both pharmacological and non-pharmacological modalities have been suggested to improve SD in PD. However, erectile dysfunction (ED) is the only SD with evidence-based treatment available. Non-pharmacological therapies are also offering promising evidence in the improvement of SD. A multidisciplinary approach in the assessment, investigation, and treatment is needed to address the real life complex issues (gender and comorbidities, neurobiological, vasoactive, hormonal as well as psychosocial aspects). Future clinical studies with validated and standardized methods in assessing SD as well as experimental models will be necessary for better insight into the pathophysiology. This would facilitate appropriate therapy and improve sexual rehabilitation in PD patients.
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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.
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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.
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Early studies proposed that dopamine (DA) facilitated male rat sexual behavior; however, a detailed behavioral analysis indicated that DA has no specific effect upon male sexual behavior but is important for motor functions and general arousal [reviewed in (Paredes and Agmo, 2004)]. On the other hand, treatment with apomorphine (a dopamine agonist) has proerectile effects (Rampin et al., 2003) and facilitates mount and intromission in mice (Sugiura et al., 1997). Dopamine deficient knock-out male mice require dopamine and testosterone to display sexual behavior (Szczypka et al., 1998).
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Dopamine receptors are divided into two main families, D1 and D2-like receptors, which are in turn further subdivided into D1 to D5 receptor subtypes. Apomorphine has a higher affinity for the D2-like receptors [133] that are thought to be the main site for the induction of erections in the PVN [134]. Apomorphine is therefore postulated to increase erectile responses by acting as a conditioner in the PVN, increasing the response to sexual stimuli resulting in enhanced erections induced in the periphery [135].
Pharmacotherapy is the usual initial therapy for most men with erectile dysfunction.
To review the current data relating to the efficacy, tolerability and safety of drugs used in the treatment of men with erectile dysfunction.
A critical review of the literature relating to the use of pharmacotherapeutic agents was undertaken by a committee of eight experts from five countries, building on prior reviews.
Expert opinion and recommendations were based on grading of evidence-based literature, internal committee dialogue, open presentation, and debate.
Almost all currently available evidence relates to sildenafil, tadalafil, and vardenafil. Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for most men with erectile dysfunction who do not have a specific contraindication to their use. There is no evidence of significant differences in efficacy, safety, and tolerability between the PDE5 inhibitors and apomorphine. Intracavernosal injection therapy with alprostadil should be offered to patients as second line therapy for erectile dysfunction. Intraurethral alprostadil is a less effective treatment than intracavernosal alprostadil for the treatment of men with erectile dysfunction.
PDE5 inhibitors are effective, safe, and well-tolerated therapies for the treatment of men with erectile dysfunction. Apomorphine, intracavernosal injection therapy with alprostadil, and intraurethral alprostadil are all effective and well-tolerated treatments for men with erectile dysfunction. We recommend some standardization of the assessment of psychosocial outcomes within clinical trials in the field of erectile dysfunction. Eardley I, Donatucci C, Corbin J, El-Meliegy A, Hatzimouratidis K, McVary K, Munarriz R, and Lee SW. Pharmacotherapy for erectile dysfunction.

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Proerectile effects of apomorphine in mice

Abstract

Introduction

Section snippets

Material and methods

Results

Discussion

Conclusions

Acknowledgements

Journal of Urology

Progress in Neuropsychopharmacology and Biological Psychiatry

Brain Research

Neuroscience and Biobehavioral Reviews

Pharmacology Biochemistry and Behavior

Physiology and Behavior

Pharmacology Biochemistry and Behavior

Neuroscience and Biobehavioral Reviews

General Pharmacology

Cell

Physiology of penile erection

Physiological Reviews