Central control of penile erection: Role of the paraventricular nucleus of the hypothalamus

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Abstract

The paraventricular nucleus of the hypothalamus is an integration centre between the central and peripheral autonomic nervous systems. It is involved in numerous functions from feeding, metabolic balance, blood pressure and heart rate, to erectile function and sexual behaviour. In particular, a group of oxytocinergic neurons originating in this nucleus and projecting to extra-hypothalamic brain areas (e.g., hippocampus, medulla oblongata and spinal cord) control penile erection in male rats. Activation of these neurons by dopamine and its agonists, excitatory amino acids (N-methyl-d-aspartic acid) or oxytocin itself, or by electrical stimulation leads to penile erection, while their inhibition by γ-amino-butyric acid (GABA) and its agonists or by opioid peptides and opiate-like drugs inhibits this sexual response. The activation of these neurons is secondary to the activation of nitric oxide synthase, which produces nitric oxide. Nitric oxide in turn causes, by a mechanism that is as yet unidentified, the release of oxytocin in extra-hypothalamic brain areas. Other compounds recently identified that facilitate penile erection by activating central oxytocinergic neurons are peptide analogues of hexarelin, a growth hormone releasing peptide, pro-VGF-derived peptides, endogenous peptides that may be released by neuronal nerve endings impinging on oxytocinergic cell bodies, SR 141716A, a cannabinoid CB1 receptor antagonist, and, less convincingly, adrenocorticotropin-melanocyte-stimulating hormone (ACTH-MSH)-related peptides. Paraventricular oxytocinergic neurons and similar mechanisms are also involved in penile erection occurring in physiological contexts, namely noncontact erections that occur in male rats in the presence of an inaccessible receptive female, and during copulation. These findings show that the paraventricular nucleus of the hypothalamus plays an important role in the control of erectile function and sexual activity. As the male rat is a model of sexual behaviour and penile physiology, which has largely increased in the last years our knowledge of peripheral and central mechanisms controlling erectile function (drugs that induce penile erection in male rats usually do so also in man), the above results may have great significance in terms of a human perspective for the treatment of erectile dysfunction.

Introduction

Penile erection is the result of a complex neural central and peripheral interaction that induces muscle and vascular changes at the level of the erectile tissues of the male genital apparatus (corpora cavernosa, corpus spongiosum, and other perineal muscles, such as the elevator ani muscle when present). This is further complicated by humoral and endocrine influences, exerted mainly by testosterone and its metabolites, both at central and peripheral levels (see Sachs and Meisel, 1988, Meisel and Sachs, 1994, Hull et al., 2002; and references therein). Although the achievement of penile erection is essential for the success of reproduction, this sexual response can occur not only during sexual activity but also in other contexts, such as after simple manipulation of the genitalia, or during sleep or erotic fantasies in humans, or in male rats in the presence of an inaccessible receptive female, or after treatment with several classes of drugs acting in the central nervous system or peripherally (i.e., dopamine agonists, serotonin agonists, adrenocorticotropin (ACTH)-melanonocyte stimulating hormone (α-MSH)-related peptides, oxytocin, hexarelin analogues, nitric oxide donors, phosphodiesterase inhibitors, soluble guanylate cyclase activators, RhoA-Rho kinase inhibitors, etc.) (see Andersson and Wagner, 1995, Argiolas and Melis, 1995, Argiolas and Melis, 2004, McKenna, 1998, McKenna, 2000, Argiolas, 1999, Sachs, 2000, Giuliano and Rampin, 2000, Giuliano and Rampin, 2004, Heaton, 2000, Andersson, 2001, Chitaley et al., 2001, Giuliano and Allard, 2001, Melis and Argiolas, 2003). Depending on the context in which penile erection occurs, it is generally accepted that different central and peripheral neural and/or humoral endocrine mechanisms may participate in the regulation of this sexual response, often in a very complex fashion (see Fig. 1 for a schematic representation of central and peripheral neural pathways controlling penile erection). Conversely, dysfunctions of the central or peripheral autonomic nervous system, or both may impair the achievement of penile erection, even when the key effector organs (e.g., vasculature and corpora cavernosa smooth muscles) are intact. Of the central and peripheral mechanisms regulating penile erection that have been identified so far, the best known are those that control penile erection locally at the level of penile tissue, in particular those involved in the relaxation of the corpora cavernosa, the key event for the achievement of penile erection (see Andersson and Wagner, 1995, Argiolas and Melis, 1995, Andersson, 2001; and references therein) (Table 1). This has produced in the last 10 years considerable progress in the pharmacological treatment of organic erectile dysfunction, providing drugs capable of interacting, often selectively, with the neurotransmitters and/or modulators that control the relaxation of corpora cavernosa (see Garcia-Reboll et al., 1997, Moreland et al., 2001, Lue et al., 2004). In contrast, much less is known of the mechanisms through which the central nervous system controls penile erection, although some progress in this field has also been achieved recently. Indeed, at the central level several neurotransmitters and neuropeptides, which control erectile function, have also been identified (Table 2). These compounds act in several brain areas conveying information to the lower genital apparatus through the spinal cord. Among these areas, the most studied are the medial preoptic area (Hull et al., 1986, Hull et al., 1989, Hull et al., 1995, Sato et al., 1995, Sato et al., 2001, Sato and Christ, 2000, Giuliano et al., 1996, Liu et al., 1997a, Matuszewich et al., 2000), the paraventricular nucleus of the hypothalamus (Melis et al., 1986, Melis et al., 1987, Melis et al., 1998, Melis et al., 1999b, Melis et al., 2002, Eaton et al., 1991, Liu et al., 1997b), the amygdala (Kondo et al., 1998, Dominguez et al., 2001), the nucleus paragigantocellularis of the ventral reticular formation (Marson and McKenna, 1990, Marson and McKenna, 1992, Marson and McKenna, 1994, Marson et al., 1992, Marson et al., 1993) and the spinal cord (Wagner and Clemens, 1991, Wagner and Clemens, 1993, Marson and McKenna, 1996, Rampin et al., 1997, Tang et al., 1998, Bancila et al., 1999, Veronneau-Longueville et al., 1999, Giuliano et al., 2001a, Giuliano et al., 2001c, Giuliano et al., 2002, Giuliano and Allard, 2001). The aim of this short review is to summarize the results obtained independently by several groups of researchers with different experimental (pharmacological, electrophysiological and neuroanatomical) approaches that show an important role of the paraventricular nucleus of the hypothalamus in the control of erectile function. Two examples are (1) electrical or chemical stimulation of this hypothalamic nucleus induces penile erection as revealed either by visual inspection or by telemetry monitoring of the intracavernosal pressure in awake or anesthetized male rats (Roeling et al., 1991, Melis et al., 1994a, Chen et al., 1997, Zahran et al., 2000, Chen and Chang, 2003), and (2) its bilateral lesions reduce dramatically the proerectile effect of several compounds (Argiolas et al., 1987a, Liu et al., 1997b), as well as erections that occur in physiological contexts, for example, noncontact erections seen in male rats in the presence of an inaccessible receptive female (Liu et al., 1997b), which are induced mainly by physiological olfactory sexual stimuli (Sachs et al., 1994, Sachs, 1997, Edwards and Davis, 1997), or erections during copulation (Liu et al., 1997b). Together these studies show that a group of oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus and projecting to several extra-hypothalamic brain areas (e.g., hippocampus, pons, medulla oblongata and spinal cord) control penile erection in male rats. As shown in detail below, activation of these neurons by several endogenous (e.g., classical neurotransmitters and/or neuropeptides) and exogenous substances induces penile erection, while their inhibition reduces this sexual response (Fig. 2). As the literature on these studies has already been reviewed in detail (Andersson and Wagner, 1995, Argiolas and Melis, 1995, McKenna, 1998, Argiolas, 1999, Andersson, 2001, Melis and Argiolas, 2003, Argiolas and Melis, 2004), particular attention is dedicated to the most recent findings confirming such a role. As the male rat is a well recognized model in the field of sexual behaviour and penile physiology, which has largely contributed in the last 15 years to our knowledge of the peripheral and central mechanisms controlling erectile function and sexual behaviour (drugs that induce penile erection in male rats usually do so also in man), the reviewed studies have great significance in a human perspective for the treatment of erectile dysfunction.

Section snippets

Paraventricular oxytocinergic neurons projecting to extra-hypothalamic brain areas and to the spinal cord control penile erection

The paraventricular nucleus of the hypothalamus is considered a sort of integration centre between the central and peripheral autonomic nervous systems. In line with this role, it is characterized by a very complex architecture and is involved in numerous functions, from stress to the control of feeding, body energy balance, blood pressure, heart rate and sexual activity, including penile erection (see Swanson and Sawchensko, 1983). It also contains the cell bodies of oxytocin and vasopressin

Neurotransmitters and neuropeptides that activate paraventricular oxytocinergic neurons facilitate penile erection

As reviewed in detail in the following sections, the endogenous neurotransmitters and neuropeptides that activate oxytocinergic neurons at the paraventricular level and induce penile erection identified so far are dopamine, excitatory amino acids, nitric oxide and oxytocin itself (see also Melis and Argiolas, 2003; and references therein). With the exception of nitric oxide, which is likely to act as an intracellular messenger inside the cell bodies of oxytocinergic neurons (see below), in

Neurotransmitters and/or neuropeptides that inhibit paraventricular oxytocinergic neurons impair penile erection

The endogenous neurotransmitters and/or neuropeptides that inhibit oxytocinergic neurons at the paraventricular level and reduce penile erection identified so far are γ-amino-butyric acid (GABA), the main inhibitory neurotransmitter present in the brain, and opioid peptides. Both neuromediators apparently act by stimulating specific receptors located on the cell bodies of oxytocinergic neurons, although indirect effects cannot be ruled out. This, in turn, causes a decrease in the release of

Conclusions

The results of the studies reviewed above support a physiological role of the paraventricular nucleus of the hypothalamus in the control of erectile function mainly in the male rat. In particular, these studies provide evidence that a group of oxytocinergic neurons originating in this hypothalamic nucleus and projecting to extra-hypothalamic brain areas and to the spinal cord, including the spinal nuclei from which peripheral and autonomic nervous pathways originate to reach the penile erectile

Acknowledgement

This work was partially supported by FIRB Grant RBNE01JKLF_007 of the Italian Ministry of University and Research to AA.

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