Maria Rosaria Melis

Dopamine and sexual behavior

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.

Stress-induced increase in 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the cerebral cortex and in n. accumbens: reversal by diazepam.

Abstract The effect of electrical foot shock stress on dopamine and DOPAC levels was examined in the frontal cortex, nucleus accumbens, striatum, substantia nigra and medial basal hypothalamus of rats. DA content did not change after stress in any of the structures analyzed except in the substantia nigra in which DA level decreased by about 35% following 20, 60 or 180 min of stress. DOPAC level did not change in the striatum, medial basal hypothalamus and substantia nigra, but increased in the frontal cortex and in n. accumbens by about 75% and 40%, respectively. Pretreatment with diazepam, but not with pentobarbital, prevented stress-induced increased in DOPAC levels.

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

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

The neuropharmacology of yawning

Yawning is a phylogenetically old, stereotyped event that occurs alone or associated with stretching and/or penile erection in humans and in animals from reptiles to birds and mammals under different conditions. Although its physiological function is still unknown, yawning is under the control of several neurotransmitters and neuropeptides at the central level as this short overview of the literature on the neurochemistry of yawning shows. Among these substances, the best known are dopamine, excitatory amino acids, acetylcholine, serotonin, nitric oxide, adrenocorticotropic hormone-related peptides and oxytocin, that facilitate yawning and opioid peptides that inhibit this behavioral response. Some of the above compounds interact in the paraventricular nucleus of the hypothalamus to control yawning. This hypothalamic nucleus contains the cell bodies of oxytocinergic neurons projecting to extra-hypothalamic brain areas that play a key role in the expression of this behavioral event. When activated by dopamine, excitatory amino acids and oxytocin itself, these neurons facilitate yawning by releasing oxytocin at sites distant form the paraventricular nucleus, i.e. the hippocampus, the pons and/or the medulla oblongata. Conversely, activation of these neurons by dopamine, oxytocin or excitatory amino acids, is antagonized by opioid peptides, that, in turn, prevent the yawning response. The activation and inhibition, respectively of these oxytocinergic neurons is related to a concomitant increase and decrease, respectively, of paraventricular nitric oxide synthase activity. However, other neuronal systems in addition to the central paraventricular oxytocinergic neurons are involved in the control of yawning, since they do not seem to be involved in the expression of yawning induced by the stimulation of acetylcholine or serotoninergic receptors, nor by adrenocorticotropic hormone (ACTH) and related peptides. Nitric oxide is also involved in the induction of yawning by the latter compounds and neuronal links, for instance between dopamine and acetylcholine and dopamine and serotonin, seem to be involved in the yawning response. Finally, other neurotransmitters, i.e. gamma-aminobutyric acid (GABA) and noradrenaline, and neuropeptides, i.e. neurotensin and luteinizing hormone-releasing hormone (LH-RH), influence this behavioral response. In conclusion, in spite of some recent progress, little is known of, and more has to be done to identify, the neurochemical mechanisms underlying yawning at the central level.

NEUROMODULATION OF PENILE ERECTION: AN OVERVIEW OF THE ROLE OF NEUROTRANSMITTERS AND NEUROPEPTIDES

erection is regulated by several neurotransmitters and neuropeptides at penile tissue and central nervous system levels. At penile level, the key event is the relaxation of corpora cavernosa smooth muscles. Here, three kinds of neural autonomic control have been characterized in detail. one adrenergic stimulatory, that under normal conditions maintains the corpora cavernosa contracted (that is a flaccid penis), a second cholinergic inhibitory that is believed to cooperate with a third, nonadrenergic-noncholinergic control also inhibitory, possibly mediated by nitric oxide (NO), to reduce the adrenergic tone favouring the relaxation of corpora cavernosa, as during a sexual stimulus. However, the complex interactions between these neurotransmitters that determine the final condition of the corpora cavernosa, e.g. the presence or the absence of penile erection, are still a matter of controversy. This is further complicated by the presence of several neuropeptides in nervous penile vascular and smooth muscle tissues such as vasoactive intestinal polypeptide, peptide histidine- isoleucine, peptide histidine-methionine, neuropeptide Y and endothelins,that often exert very potent (relaxant or contractant) effects in penile tissues. Also at the central level, several neurotransmitters and neuropeptides that influence penile erection have been identified. Among neurotransmitters, the most studied are dopamine (DA), serotonin (SHT), acetylcholine (ACh), glutamic acid and NO. DA, ACh. glutamic acid and NO seem to have a facilitatory role, while 5HT may be either facilitatory or inhibitory, depending on the receptor subtype involved. Among neuropeptides, the best known are oxytocin, adrenocorticotropin (ACTH)-cc-melanocyte stimulating hormone (r-MSH)-related peptides and opioid peptides. Interestingly DA, glutamic acid and NO seem to facilitate while opioid peptides inhibit penile erection by increasing and decreasing, respectively, central oxytocinergic transmission by acting in the paraventricular nucleus of the hypothalamus. ACTH-MSH peptides also facilitate penile erection, although with a mechanism(s) different from those recalled above. Despite some recent progress, more has still to be done to clarify the role played by neurotransmitters and neuropeptides at peripheral and central levels in the control of this primary sexual function.

Oxytocin injected into the ventral tegmental area induces penile erection and increases extracellular dopamine in the nucleus accumbens and paraventricular nucleus of the hypothalamus of male rats.

The neuropeptide oxytocin (20–100 ng), induces penile erection when injected unilaterally into the caudal but not rostral mesencephalic ventral tegmental area (VTA) of male Sprague–Dawley rats. Such pro‐erectile effect started 30 min after treatment and was abolished by the prior injection of d(CH2)5Tyr(Me)2‐Orn8‐vasotocin (1 µg), an oxytocin receptor antagonist injected into the same caudal ventral tegmental area or of haloperidol (1 µg), a dopamine receptor antagonist, injected either into the nucleus accumbens shell (NAs) or into the paraventricular nucleus of the hypothalamus (PVN) ipsilateral to the injected ventral tegmental area. Penile erection was seen 15 min after the occurrence of, or concomitantly to, an increase in extracellular dopamine and its metabolite 3,4‐dihydroxyphenylacetic acid (DOPAC) in the dialysate obtained from the nucleus accumbens or the paraventricular nucleus, which was also abolished by d(CH2)5Tyr(Me)2‐Orn8‐vasotocin (1 µg), injected into the ventral tegmental area before oxytocin. In the caudal ventral tegmental area oxytocin‐containing axons/fibres (originating from the paraventricular nucleus) appeared to closely contact cell bodies of mesolimbic dopaminergic neurons retrogradely labelled with Fluorogold injected into the nucleus accumbens shell, suggesting that oxytocin effects are mediated by the activation of mesolimbic dopaminergic neurons, followed in turn by that of incerto‐hypothalamic dopaminergic neurons impinging on oxytocinergic neurons mediating penile erection. As the stimulation of paraventricular dopamine receptors not only induces penile erection, but also increases mesolimbic dopamine neurotransmission by activating oxytocinergic neurons, these results provide further support for the existence of a neural circuit in which dopamine and oxytocin influence both the consummatory and motivational/rewarding aspects of sexual behaviour.

The role of oxytocin and the paraventricular nucleus in the sexual behaviour of male mammals

The paraventricular nucleus of the hypothalamus contains the cell bodies of a group of oxytocinergic neurons projecting to extrahypothalamic brain areas and to the spinal cord, which are involved in the control of erectile function and copulation. In male rats, these neurons can be activated by dopamine, excitatory amino acids, nitric oxide (NO), hexarelin analogue peptides and oxytocin itself to induce penile erection and facilitate copulation, while their inhibition by gamma-aminobutyric acid (GABA) and GABA agonists and by opioid peptides and opiate-like drugs inhibits sexual responses. The activation of paraventricular oxytocinergic neurons by dopamine, oxytocin, excitatory amino acids and hexarelin analogue peptides is apparently mediated by the activation of nitric oxide (NO) synthase. NO in turn activates, by a mechanism that is as yet unidentified, the release of oxytocin from oxytocinergic neurons in extrahypothalamic brain areas. Paraventricular oxytocinergic neurons and mechanisms similar to those reported above are also involved in the expression of penile erection in physiological contexts, namely, when penile erection is induced in the male by the presence of an inaccessible receptive female, which is considered a model for psychogenic impotence in man, as well as during copulation. These findings show that paraventricular oxytocinergic neurons projecting to extrahypothalamic brain areas and to the spinal cord and the paraventricular nucleus play an important role in the control of erectile function and male sexual behaviour in mammals.

Dopamine agonists increase nitric oxide production in the paraventricular nucleus of the hypothalamus: correlation with penile erection and yawning

A low dose of apomorphine (80 μg/kg s.c.), a mixed D1/D2 agonist that induces penile erection and yawning, increased the concentration of NO2− from 1.12 ± 0.45 μM to 3.8 ± 0.75 μM and NO3− from 5.53 ± 0.82 to 11.25 ± 2.30 μM in the dialysate collected from the paraventricular nucleus of the hypothalamus of male rats by in vivo microdialysis. The NO2− concentration was also increased by LY 171555 (50 μg/kg s.c.), a D2 agonist that induces penile erection and yawning, but not by SKF 38393 (5 mg/kg s.c.), a D1 agonist with no effect on these responses. Conversely, apomorphines effect on NO2− was prevented by haloperidol (0.5 mg/kg i.p.), a mixed D1/D2 antagonist and L‐sulpiride (25 mg/kg i.p.), a D2 antagonist, but not by the D1 agonist SCH 23390 (50 μg/kg s.c.), although all three compounds prevented penile erection and yawning. The apomorphine effect on NO2−, penile erection and yawning was also prevented by the nitric oxide synthase inhibitor NG‐nitro‐L‐arginine methyl ester (200 μg l.c.v.). The nitric oxide scavenger haemoglobin (200 μg l.c.v.) also prevented the NO2− increase, but was ineffective against penile erection and yawning. In contrast, the oxytocin antagonist d(CH2)5Tyr(Me)‐Orn8‐vasotocin (1 μg i.c.v.) and the guanylate cyclase inhibitor methylene blue (300 μg l.c.v.) had no effect on the NO2− increase, but did prevent the behavioural responses. We infer from this that dopamine agonists induce penile erection and yawning by acting on D2 receptors that increase nitric oxide synthase activity in the cell bodies of paraventricular oxytocinergic neurons projecting to extra‐hypothalamic brain areas.

The oxytocin antagonist d(CH2)5Tyr(Me)-Orn8-vasotocin inhibits male copulatory behaviour in rats

The effect of an intracerebroventricular (i.c.v.) injection of the oxytocin antagonist, d(CH2)5Tyr(Me)-Orn8-vasotocin, on the copulatory behaviour of vigorous male rats in the presence of females in estrus was studied. The peptide (2.5, 25 and 50 ng, 15 min before mating tests) decreased the number of mounts and intromissions, and abolished ejaculation almost completely at all doses tested. The peptide failed to significantly influence motor activity at the doses used. The results support the hypothesis that central oxytocin plays a physiological role in the expression of copulatory behaviour.

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

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