title: The role of purinergic and dopaminergic systems on MK-801-induced antidepressant effects in zebrafish.
abstract: Depression is a serious disease characterized by low mood, anhedonia, loss of interest in daily activities, appetite and sleep disturbances, reduced concentration, and psychomotor agitation. There is a growing interest in NMDA antagonists as a promising target for the development of new antidepressants. Considering that purinergic and dopaminergic systems are involved in depression and anxiety states, we characterized the role of these signaling pathways on MK-801-induced antidepressant effects in zebrafish. Animals treated with MK-801 at the doses of 5, 10, 15, or 20μM during 15, 30, or 60min spent longer time in the top area of aquariums in comparison to control group, indicating an anxiolytic/antidepressant effect induced by this drug. Animals treated with MK-801 spent longer time period at top area until 2 (5μM MK-801) and 4 (20μM MK-801) hours after treatment, returning to basal levels from 24h to 7days after exposure. Repeated MK-801 treatment did not induce cumulative effects, since animals treated daily during 7days had the same behavioral response pattern observed since the first until the 7th day. In order to investigate the effects of adenosine A1 and A2A receptor antagonist and agonist and the influence of modulation of adenosine levels on MK-801 effects, we treated zebrafish with caffeine, DPCPX, CPA, ZM 241385, CGS 21680, AMPCP, EHNA, dipyridamole, and NBTI during 30min before MK-801 exposure. The non-specific adenosine receptor antagonist caffeine (50mg/kg) and the selective A1 receptor antagonist DPCPX (15mg/kg) prevented the behavioral changes induced by MK-801. The non-specific nucleoside transporter (NT) inhibitor dipyridamole (10mg/kg) exacerbated the behavioral changes induced by MK-801. Dopamine receptor antagonists (sulpiride and SCH 23390) did not change the behavioral alterations induced by MK-801. Our findings demonstrated that antidepressant-like effects of MK-801 in zebrafish are mediated through adenosine A1 receptor activation.
authors.affiliation: PUCRS, Faculdade de Biociências, Programa de Pós-Graduação em Biologia Celular e Molecular, Departamento de Biologia Celular e Molecular, Laboratório de Neuroquímica e Psicofarmacologia, Avenida Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil.
authors.forename: Raquel Bohrer
authors.initials: RB
authors.lastname: da Silva
authors.affiliation: Programa de Pós-Graduação em Ciências Ambientais, Universidade Comunitária da Região de Chapecó, Avenida Senador Atílio Fontana, 591E, 89809-000 Chapecó, SC, Brazil.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Siebel
authors.affiliation: PUCRS, Faculdade de Biociências, Programa de Pós-Graduação em Biologia Celular e Molecular, Departamento de Biologia Celular e Molecular, Laboratório de Neuroquímica e Psicofarmacologia, Avenida Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil. Electronic address: cbonan@pucrs.br.
authors.forename: Carla Denise
authors.initials: CD
authors.lastname: Bonan
mesh_terms: D000241:Adenosine / Q000502:physiology; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D011983:Receptors, Purinergic / Q000187:drug effects / Q000502:physiology; D015027:Zebrafish / Q000502:physiology*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000928:Antidepressive Agents; D018492:Dopamine Antagonists; D011983:Receptors, Purinergic; D016291:Dizocilpine Maleate; D000241:Adenosine
keywords: Adenosine deaminase; Adenosine receptors; Dopamine; Ecto-5’′-nucleotidase; MK-801; Nucleoside transporters