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

Authors

  • Maria Rosaria Melis,

    1. Bernard B. Brodie Department of Neuroscience, Centre of Excellence for the Neurobiology of Addictions, University of Cagliari, and Institute of Neuroscience, National Research Council, Cagliari Section, S.P. Sestu-Monserrato, KM 0.700, 09042 Monserrato, Italy
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  • Salvatora Succu,

    1. Bernard B. Brodie Department of Neuroscience, Centre of Excellence for the Neurobiology of Addictions, University of Cagliari, and Institute of Neuroscience, National Research Council, Cagliari Section, S.P. Sestu-Monserrato, KM 0.700, 09042 Monserrato, Italy
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  • Fabrizio Sanna,

    1. Bernard B. Brodie Department of Neuroscience, Centre of Excellence for the Neurobiology of Addictions, University of Cagliari, and Institute of Neuroscience, National Research Council, Cagliari Section, S.P. Sestu-Monserrato, KM 0.700, 09042 Monserrato, Italy
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  • Tiziana Melis,

    1. Bernard B. Brodie Department of Neuroscience, Centre of Excellence for the Neurobiology of Addictions, University of Cagliari, and Institute of Neuroscience, National Research Council, Cagliari Section, S.P. Sestu-Monserrato, KM 0.700, 09042 Monserrato, Italy
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  • Maria Stefania Mascia,

    1. Bernard B. Brodie Department of Neuroscience, Centre of Excellence for the Neurobiology of Addictions, University of Cagliari, and Institute of Neuroscience, National Research Council, Cagliari Section, S.P. Sestu-Monserrato, KM 0.700, 09042 Monserrato, Italy
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  • Cécile Enguehard-Gueiffier,

    1. Laboratoire de Chimie Thérapeutique, EA 3857, Faculté de Pharmacie, 31 avenue Monge, Tours, France
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  • Harald Hubner,

    1. Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany
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  • Peter Gmeiner,

    1. Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany
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  • Alain Gueiffier,

    1. Laboratoire de Chimie Thérapeutique, EA 3857, Faculté de Pharmacie, 31 avenue Monge, Tours, France
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  • Antonio Argiolas

    1. Bernard B. Brodie Department of Neuroscience, Centre of Excellence for the Neurobiology of Addictions, University of Cagliari, and Institute of Neuroscience, National Research Council, Cagliari Section, S.P. Sestu-Monserrato, KM 0.700, 09042 Monserrato, Italy
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Professor Maria Rosaria Melis, as above.
E-mail: mrmelis@unica.it

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 µg/kg) or intracerebroventricularly (0.1–20 µg/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 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.

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