title: Signaling Mechanisms in the Nitric Oxide Donor- and Amphetamine-Induced Dopamine Release in Mesencephalic Primary Cultured Neurons.
abstract: Previous research has shown that nitric oxide (NO) synthase inhibitors prevent rodents' sensorimotor gating impairments induced by dopamine releasing drugs, such as amphetamine (Amph) and methylphenidate. The mechanisms of this effect have not been entirely understood. In the present work, we investigated some possible mechanisms by which the NO donor, NOC-12 (3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene), influence spontaneous and Amph-induced dopamine release, using rat mesencephalic primary cultured neurons preparations. Our results showed that NOC-12 increased dopamine release in a concentration-dependent manner and potentiated the Amph-induced one. Dopamine release induced by NOC-12 was disrupted by N-acetyl-L-cystein (NAC-a free radical scavenger) and MK-801, a NMDA (N-methyl-D-aspartate) non-competitive antagonist, and was concentration dependently affected by oxadiazolo[4,3]quinoxalin-1-one, an inhibitor of the soluble guanylate cyclase (sGC). In contrast, dopamine released by Amph was facilitated by NAC and by MK-801 and not affected by nifedipine (a L-type-Ca(+2) channel blocker), which enhanced NOC-12-induced dopamine release. The present work demonstrates that DA release induced by NOC-12 is partially dependent on sGC and on NMDA activation, and is modulated by L-type Ca(+2) channel and the antioxidant NAC. This mechanism differs from the Amph-induced one, which appears not to depend on L-type Ca(+2) channel and seems to be facilitated by NMDA channel blocking and by NAC. These results suggest that Amph and NOC-12 induce dopamine release through complementary pathways, which may explain the potentiation of Amph-induced dopamine release by NOC-12. These findings contribute to understand the involvement of NO in dopamine-related neuropsychiatric and neurodegenerative diseases.
authors.affiliation: ICM, Therapeutique Experimentale de la Neurodegenerescence, Inserm U 975, Centre de Recherche en Neurosciences, Paris, France. cristiane.salum@ufabc.edu.br.|Centro de Matemática, Computação e Cognição, Núcleo de Cognição e Sistemas Complexos, Universidade Federal do ABC, Rua Arcturus, 3 - Jardim Antares, São Bernardo do Campo, SP, CEP: 09606-070, Brazil. cristiane.salum@ufabc.edu.br.
authors.forename: Cristiane
authors.initials: C
authors.lastname: Salum
authors.affiliation: ICM, Therapeutique Experimentale de la Neurodegenerescence, Inserm U 975, Centre de Recherche en Neurosciences, Paris, France.|CNRS-8076BiOCIS-Laboratoire de Pharmacognosie, 92296, Châtenay-Malabry Cedex, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: ICM, Therapeutique Experimentale de la Neurodegenerescence, Inserm U 975, Centre de Recherche en Neurosciences, Paris, France.|UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Sorbonne Université Pierre et Marie Curie-Paris, Paris, France.
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Michel
authors.affiliation: Department of Morphology, Physiology, and Basic Pathology, and Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Ribeirão Preto, SP, 14040-904, Brazil.
authors.forename: Elaine
authors.initials: E
authors.lastname: Del-Bel
authors.affiliation: ICM, Therapeutique Experimentale de la Neurodegenerescence, Inserm U 975, Centre de Recherche en Neurosciences, Paris, France.|UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Sorbonne Université Pierre et Marie Curie-Paris, Paris, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Raisman-Vozari
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004622:Embryo, Mammalian; D005260:Female; D008636:Mesencephalon / Q000166:cytology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D002121:Calcium Channel Blockers; C118603:NOC 12; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D009573:Nitrites; D009603:Nitroso Compounds; D016291:Dizocilpine Maleate; D000661:Amphetamine; D009543:Nifedipine; D004298:Dopamine
keywords: Amphetamine; Cultured mesencephalic neurons; Dopamine release; MK-801; N-acetyl-L-cystein; Nitric oxide