Salvatora Succu

Stimulation of dopamine receptors in the paraventricular nucleus of the hypothalamus of male rats induces penile erection and increases extra-cellular dopamine in the nucleus accumbens: Involvement of central oxytocin.

The effect of a pro-erectile dose of apomorphine, a mixed dopamine receptor agonist, and of PD-168077 (N-[4-(2-cyanophenyl)piperazin-1-ylmethyl]-3-methylbenzamide maleate), a selective dopamine D4 receptor agonist, injected into the paraventricular nucleus of the hypothalamus on the concentration of extra-cellular dopamine and its main metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the dialysate from the nucleus accumbens was studied in male rats. As expected, apomorphine (0.1microg) and PD-168077 (0.1microg) induced penile erection episodes, which occurred concomitantly to an increase in extra-cellular dopamine and DOPAC concentration in the dialysate from the shell of the nucleus accumbens, as measured by intracerebral microdialysis. When induced by apomorphine, these effects were reduced by 80% by raclopride, a selective D2/D3 receptor antagonist (1microg) and only by 40-45% by L-745,870 (1microg), a selective dopamine D4 receptor antagonist. When induced by PD-168077, these effects were reduced by more than 80% by L-745,870 (1microg), but only by 35-40% by raclopride. Irrespective of the dopamine agonist used to induce penile erection, the pro-erectile effect and the concomitant increase in dopamine and DOPAC concentration in the nucleus accumbens dialysate were almost completely abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin(1microg), a potent oxytocin receptor antagonist, given into the lateral ventricles. The present results suggest that stimulation of dopamine receptors (mainly of the D2 to D4 subtype) in the paraventricular nucleus induces the release of oxytocin in brain areas that influence the activity of mesolimbic dopaminergic neurons mediating the appetitive and reinforcing effects of sexual activity. This provides evidence for a role of oxytocin in neural circuits that integrate the activity of neural pathways controlling the consummatory aspects of sexual behaviour (e.g., penile erection) with those controlling sexual motivation and sexual arousal.

Nitric oxide production is increased in the paraventricular nucleus of the hypothalamus of male rats during non‐contact penile erections and copulation

Male rats put in the presence of a receptive female rat that they can see, hear and smell, but cannot touch, show penile erection episodes. These non‐contact erections occur concomitantly with an increase in nitric oxide production in the paraventricular nucleus of the hypothalamus, as detected by the increase in the NO2– and NO3– concentration in the paraventricular dialysate obtained from these males by in vivo microdialysis.

The oxytocin antagonist d(CH2)5Tyr(Me)2-Orn8-vasotocin reduces non-contact penile erections in male rats.

Male rats show four to six penile erection episodes when put for 80 min in the presence of an inaccessible receptive female. These non-contact penile erections were reduced dose-dependently by d(CH2)5Tyr(Me)2-Orn8-vasotocin, a potent and selective oxytocin receptor antagonist, when given into the lateral ventricles (0.1, 0.5 and 1 microg), but not when given into the paraventricular nucleus of the hypothalamus (0.1 and 1 microg). In contrast, non-contact erections were reduced by N(G)-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase, given into the lateral ventricles (50, 100 and 200 microg), or into the paraventricular nucleus (10 and 20 microg). The present results show that central oxytocin is involved in the expression of penile erection induced not only by drugs but also by sexual physiological stimuli.

Morphine injected into the paraventricular nucleus of the hypothalamus prevents noncontact penile erections and impairs copulation: involvement of nitric oxide.

Male rats show four to six penile erection episodes when put in the presence of an inaccessible receptive female for 80u2003min. These noncontact erections occur concomitantly with an increase in nitric oxide production in the paraventricular nucleus of the hypothalamus. This is shown by the increases in the NO2– and NO3– concentrations in the paraventricular dialysate obtained from these males by in vivo microdialysis. The NO2– concentration increased from 0.75u2003±u20030.10u2003μm to 2.89u2003±u20030.39u2003μm and that of NO3– from 4.13u2003±u20030.58u2003μm to 9.5u2003±u20031.2u2003μm. Morphine (0.5, 1 and 5u2003μg), given unilaterally into the paraventricular nucleus 15u2003min before the introduction of the receptive female, prevented the NO2– and NO3– increases, and noncontact erections, dose‐dependently. In contrast, the κ opioid receptor agonist U‐69u2003593 (5u2003μg) was ineffective. The effects of morphine on NO2– and NO3–, and on noncontact erections, were prevented by the opiate receptor antagonist naloxone (10u2003μg) injected into the paraventricular nucleus 15u2003min before morphine. The NO2– and NO3– concentrations were also increased in the paraventricular dialysate of male rats during copulation, i.e. when in copula penile erections occurred. As found with noncontact erections, morphine, but not U‐69u2003593, injected into the paraventricular nucleus prevented the NO2– and NO3– increases and impaired copulatory behaviour, and naloxone prevented these responses when given before morphine. Although some diffusion of the opiate to surrounding brain areas cannot be completely ruled out, the present results suggest that morphine acts through μ receptors in the paraventricular nucleus to impair noncontact erections and copulation. These effects of morphine are apparently mediated by a prevention of the increased nitric oxide production that occurs in the paraventricular nucleus of the hypothalamus of male rats during sexual activity.

Oxytocin injected into the ventral subiculum or the posteromedial cortical nucleus of the amygdala induces penile erection and increases extracellular dopamine levels in the nucleus accumbens of male rats

Oxytocin (20–100u2003ng) was found to be able to induce penile erection when injected unilaterally into the ventral subiculum or the posteromedial cortical nucleus of the amygdala of male rats. The pro‐erectile effect started mostly 30u2003min after treatment and was abolished by the prior injection of d(CH2)5Tyr(Me)2‐Orn8‐vasotocin (1–2u2003μg), an oxytocin receptor antagonist, into the ventral subiculum or posteromedial cortical nucleus. Oxytocin‐induced penile erection occurred 15u2003min after the increase in the concentration of extracellular dopamine and its metabolite 3,4‐dihydroxyphenylacetic acid in the dialysate obtained from the nucleus accumbens, which was also abolished by d(CH2)5Tyr(Me)2‐Orn8‐vasotocin. The pro‐erectile effect of oxytocin was also reduced by cis‐flupentixol (2 and 5u2003μg), a dopamine receptor antagonist, injected into the nucleus accumbens, and by (+)MK‐801 (5u2003μg), a noncompetitive N‐methyl‐d‐aspartate receptor antagonist, injected into the ventral tegmental area, but not into the nucleus accumbens. Together with studies showing that glutamatergic efferents from the ventral subiculum/posteromedial cortical nucleus of the amygdala to other areas of the limbic system modulate the activity of mesolimbic dopaminergic neurons, these findings suggest that oxytocin injected into these areas increases glutamatergic neurotransmission in the ventral tegmental area. This, in turn, activates mesolimbic dopaminergic neurons, leading to penile erection. These results provide evidence that the ventral subiculum and the posteromedial cortical nucleus of the amygdala participate in a neural circuit that controls not only the consummatory aspects of sexual behaviour (e.g. penile erection and copulatory performance), but also its motivational/reward aspects, confirming a key role of oxytocin and dopamine in these processes.

PIP3EA and PD-168077, two selective dopamine D4 receptor agonists, induce penile erection in male rats: site and mechanism of action in the brain

PIP3EA (2‐[4‐(2‐methoxyphenyl)piperazin‐1‐yl‐methyl]imidazo[1,2‐a]pyridine) and PD‐168077 (N‐[4‐2‐cyanophenylpiperazin‐1‐ylmethyl]‐3‐methylbenzamide maleate), two selective dopamine D4 agonists, administered systemically, intracerebroventricularly or into the paraventricular nucleus of the hypothalamus induce penile erection in male Sprague–Dawley rats. A U‐inverted dose–response curve was found with either compound when given subcutaneously (1–100u2003µg/kg) or intracerebroventricularly (0.1–20u2003µg/rat), but not into the paraventricular nucleus (10–200u2003ng/rat). The pro‐erectile effect of PIP3EA and of PD‐168077 occurs concomitantly with an increased nitric oxide (NO) production in the paraventricular nucleus, as measured by the increased concentration of nitrites and nitrates found in the dialysate obtained from the paraventricular nucleus by intracerebral microdialysis. These effects of PIP3EA and PD‐168077 were reduced by L‐745,870 (3‐[4‐(4‐chlorophenyl)piperazin‐1‐ylmethyl]‐1H‐pyrrolo[2,3‐b]pyridine trihydrochloride), a selective dopamine D4 receptors antagonist, by ω‐conotoxin, a blocker of voltage‐dependent Ca2+ channels of the N‐type, by S‐methyl‐thiocitrulline, a neuronal nitric oxide synthase inhibitor, and by d(CH2)5Tyr(Me)2‐Orn8‐vasotocin, an oxytocin receptor antagonist, given into the lateral ventricles, but not into the paraventricular nucleus. Comparison of the dose–response curves of PIP3EA and PD‐168077 revealed that PIP3EA is as potent as PD‐168077 when given into the paraventricular nucleus, but more potent when given systemically. However, both compounds are less efficacious (e.g. induce a lower number of penile erection episodes) than apomorphine, a classical mixed dopamine receptor agonist, irrespective of the route of administration. These results confirm previous findings showing that central D4 receptors mediate penile erection and show that dopamine D4 receptor agonists act in the paraventricular nucleus to facilitate penile erection by increasing central oxytocinergic neurotransmission.

Prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning: involvement of nitric oxide

Abstract The possible involvement of nitric oxide in the prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning was investigated by measuring the concentration of NO2- and NO3- in the dialysate obtained with a vertical microdialysis probe implanted in the paraventricular nucleus of the hypothalamus of male rats. Either apomorphine (80 µg/kgs.c.) or oxytocin (30 ng i.c.v.) increased significantly basal NO2- and NO3- concentration in the paraventricular dialysate, penile erection and yawning. Morphine (1, 5 and 10mg/kg i.p.) prevented dose-dependently either apomorphine or oxytocin responses when given 15min before apomorphine or oxytocin. Prevention by morphine of apomorphine and oxytocin responses was abolished by naloxone (3mg/kg i.p.) given 15min before morphine. Morphine prevented apomorphine and oxytocin responses also when given in the lateral ventricles or directly in the paraventricular nucleus. In contrast, the selective agonist of the kappa opioid receptor subtype U-69,593 was found to be ineffective. The present results confirm previous findings showing that morphine acts through µ receptors in the paraventricular nucleus to prevent apomorphine and oxytocin-induced penile erection and yawning and suggest that this morphine effect is mediated by a decreased activity of nitric oxide in the paraventricular nucleus of the hypothalamus.

Effect of excitatory amino acid, dopamine, and oxytocin receptor antagonists on noncontact penile erections and paraventricular nitric oxide production in male rats

In male rats, noncontact erections occur concomitantly with an increase in NO2- and NO3- in the paraventricular nucleus of the hypothalamus (PVN). In the present study, both responses were reduced by the blockade of PVN excitatory amino acid receptors by dizocilpine, (+)-MK-801(1 and 5 microg), but not by 6-cyano-7-nitro-quinoxaline-2,3-dione (5 microg) or (+)-2-amino-4-phosphono-butanoic acid (5 microg). Also ineffective when injected into the PVN were the dopamine antagonists SCH 23390 (5 microg), S(+)-raclopride (10 microg), and cis-flupenthixol (10 microg), and the oxytocin antagonist d(CH2)5Tyr(Me)2-Om8-vasotocin (1 microg). However, when the last was given into the lateral ventricles, it reduced noncontact erections without modifying NO2- and NO3- increases. These results suggest that excitatory amino acid transmission increases in the PVN during noncontact erections. This may contribute to increased NO production in the PVN, and it may activate oxytocin neurons mediating this sexual response.

Prevention by Morphine of N-Methyl-d-Aspartic Acid-Induced Penile Erection and Yawning: Involvement of Nitric Oxide ☆

The effect of morphine on the increase of NO2- and NO3- concentration in the dialysate obtained with a microdialysis probe implanted in the paraventricular nucleus of the hypothalamus, and penile erection and yawning induced by N-methyl-D-aspartic acid (NMDA) was studied in male rats. NMDA (50 ng) injected in the paraventricular nucleus of the hypothalamus, induced penile erection and yawning and increased NO2- from 1.10 +/- 0.28 microM to 7.30 +/- 1.10 microM and NO3- from 5.05 +/- 0.71 microM to 11.03 +/- 1.61 microM. Morphine (1-10 microg), but not U-69,593 (10 microg), a selective agonist of the kappa opiate receptor subtype, prevented in a dose-dependent manner NMDA-induced increase in NO2- and NO3- concentration when injected in the paraventricular nucleus 15 min before NMDA. Morphine prevention of NMDA-induced NO2- and NO3- increase was related to a concomitant decrease in the number of penile erection and yawning episodes induced by the excitatory amino acid. Morphine effect was not observed in male rats treated with the opiate receptor antagonist naloxone (10 microg) microinjected in the paraventricular nucleus 15 min before morphine. The present results suggest that morphine prevents an NMDA-induced increase in paraventricular NO production, penile erection, and yawning by inhibiting NO synthase activity in the paraventricular nucleus of the hypothalamus through the stimulation of opioid receptors of the micro subtype.

Dopamine D2-like receptor agonists induce penile erection in male rats: differential role of D2, D3 and D4 receptors in the paraventricular nucleus of the hypothalamus

Pramipexole, a dopamine D3/D2 receptor agonist, induces penile erection when administered subcutaneously (s.c.) or into the paraventricular nucleus of the hypothalamus of male rats, like apomorphine, a mixed D1/D2 receptor agonist, and PD 168,077, a D4 receptor agonist. A U-inverted dose-response curve was found with pramipexole and apomorphine, but not with PD 168,077 (0.025-0.5mg/kg s.c.). Pramipexole effect was abolished by L-741,626, a D2 receptor antagonist (2.5 and 5mg/kg s.c.) and raclopride, a D2/D3 receptor antagonist (0.025 and 0.1mg/kg s.c.), but not by SB277011A (2.5 and 10mg/kg s.c.) or FAUC 365 (1 and 2mg/kg s.c.), two D3 receptor antagonists, or L-745,870 (1 and 5mg/kg i.p.), a D4 receptor antagonist. Similar results were found with apomorphine (0.08mg/kg s.c.), although its effect was also partially reduced by L-745,870. In contrast, PD 168,077 effect was abolished by L-745,870, but not L-741,626, SB277011A, FAUC 365 or raclopride. Similar results were found when dopamine agonists (5-200ng/rat) and antagonists (1-5μg/rat) were injected into the paraventricular nucleus. However, no U-inverted dose-response curve was found with any of the three dopamine agonists injected into this nucleus. As pramipexole- and apomorphine-induced penile erection was reduced mainly by D2, but not D3 or D4 antagonists, D2 receptors are those that mediate the pro-erectile effect of these dopamine agonists. Although the selective stimulation of paraventricular D4 receptors induces penile erection, D4 receptors seem to play only a modest role in the pro-erectile effect of the above dopamine agonists.