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

Abstract

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 (1-100 microg/kg) or intracerebroventricularly (0.1-20 microg/rat), but not into the paraventricular nucleus (10-200 ng/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 omega-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.

Proerectile Effects of Dopamine D2-Like Agonists Are Mediated by the D3 Receptor in Rats and Mice

“…In agreement with this notion but contrary to previous findings Melis et al, 2005;EnguehardGueiffier et al, 2006), all of the highly selective D 4 agonists failed to induce PE. It should be noted, however, that the maximal PE responses for apomorphine, quinpirole, and pramipexole were lower than some previous reports (e.g., Melis et al, 2006), suggesting procedural differences may have affected the PE response. Nevertheless, the percentage incidences of PE for apomorphine and the D 3 -preferring agonists were similar to previous reports (e.g., Hsieh et al, 2004), suggesting that any procedural differences only affected the maximal number of PEs observed, not the absolute capacity of the agonists to induce PE.…”

“…Although Ro 61-6270 has not been characterized extensively (Clifford and Waddington, 2000), L-745,870 has been shown to possess favorable pharmacokinetics (0.3 mg/kg p.o. is thought to be sufficient to occupy ϳ90% of D 4 receptors; Patel et al, 1997) and has been shown to inhibit PD-168,077-and PIP3EA-induced PE at a dose of 1.0 mg/kg Melis et al, 2006), suggesting that the doses used in the current studies were sufficient to block D 4 receptors. Together with previous reports that L-745,870 was unable to alter apomorphine-induced PE , the current studies suggest that the proerectile effects of D 2 -like agonists (e.g., apomorphine and pramipexole) are mediated by activation of the D 3 , but not the D 4 , receptor.…”

The dopamine D4 receptor: biochemical and signalling properties

“…In vivo administration to rats to test potential treatment of erectile dysfunction [184,185] WAY 100635 16.4 D4 receptor agonist and 5HT1A antagonist; produces discriminative stimulus effects in rats [186,187] PD 168077 8.7 Selective D4 agonist, proerectile effect in rats [188]; tested in mice for memory consolidation studies [189] PNU 96415E 3 Tested for antipsychotic potential [190] Ro 10-5824 5.2 Selective D4 agonist, increases novel exploration in mice [191] NGD 94-1 3…”

Effects of acute and chronic apomorphine on sex behavior and copulation-induced neural activation in the male rat

“…Adding to the complexity, apomorphine, as a non-selective dopaminergic receptor agonist, affects several types of dopaminergic receptors among them D 1 , D 2 and D 4 (Brioni and Moreland, 2006;Brioni et al, 2004;Melis et al, 2005Melis et al, , 2006Schechter and Greer, 1987), whereas chronic treatment with apomorphine may change the balance between dopamine D 1 and D 2 receptors, favoring the D 1 type (Acerbo et al, 2005).…”

“…Dopamine is one of the main neurotransmitters involved in the central control of erectile functions, genital reflexes and male sexual behavior (Andersen et al, 2003;Argiolas and Melis, 2005;Giuliano and Rampin, 2000a,b;Giuliano and Allard, 2001;Heaton, 2000;Hull et al, 1986;Martino et al, 2005;Melis and Argiolas, 1995;Melis et al, 2006;Moses et al, 1995;Paredes and Agmo, 2004;Pehek et al, 1989;Succu et al, 2007). Apparently, the paraventricular hypothalamic nucleus, especially its oxytocinergic neurons, play an eminent role in the control of erectile function Melis, 2004, 2005;Martino et al, 2005;Succu et al, 2007).…”