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Menezes F.P.,Laboratorio Of Neuroquimica E Psicofarmacologia | Kist L.W.,Laboratorio Of Biologia Genomica E Molecular | Bogo M.R.,Laboratorio Of Biologia Genomica E Molecular | Bonan C.D.,Laboratorio Of Neuroquimica E Psicofarmacologia | And 3 more authors.
Zebrafish | Year: 2015

Imbalances in glutamatergic signaling have been proposed as the cause of several neurological disturbances. The use of MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, to mimic features of these neurological disorders is effective both in mammals and in fish. However, the variability of the subunits comprising the NMDA receptor during development alters the pharmacokinetic properties of the receptor and leads to different responses to this drug. Here, we evaluated the locomotor response of zebrafish to MK-801 (1, 5, and 20 μM) through the development (30 days postfertilization [dpf] to 2 years postfertilization [ypf]). The NMDA receptor subunit gene expression was also analyzed through the development (7 dpf to 2 ypf). Zebrafish displayed an age-related response to MK-801 with a higher response at 60 and 120 dpf. The magnitude of hyperlocomotion promoted by MK-801 seems to be less powerful for zebrafish in relation to rodents. The verification of expression levels in zebrafish NMDA receptor subunits shows that NR1.1 had a slight reduction throughout the development, while the NR2 subunits, especially NR2A.2 and NR2C.1, vary their expression levels according to the stage of development. The time-specific locomotor response to MK-801 through the development could be a consequence of differential NMDA receptor subunit expression. This result of developmental response to MK-801 is a crucial component in the consolidation of zebrafish as a suitable model to study glutamatergic neurotransmission in early phases. © 2015, Mary Ann Liebert, Inc.


Siebel A.M.,Laboratorio Of Neuroquimica E Psicofarmacologia | Menezes F.P.,Laboratorio Of Neuroquimica E Psicofarmacologia | Capiotti K.M.,Laboratorio Of Neuroquimica E Psicofarmacologia | Kist L.W.,Laboratorio Of Biologia Genomica E Molecular | And 5 more authors.
Zebrafish | Year: 2015

Adenosine is a well-known endogenous modulator of neuronal excitability with anticonvulsant properties. Thus, the modulation exerted by adenosine might be an effective tool to control seizures. In this study, we investigated the effects of drugs that are able to modulate adenosinergic signaling on pentylenetetrazole (PTZ)-induced seizures in adult zebrafish. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) decreased the latency to the onset of the tonic-clonic seizure stage. The adenosine A1 receptor agonist cyclopentyladenosine (CPA) increased the latency to reach the tonic-clonic seizure stage. Both the adenosine A2A receptor agonist and antagonist, CGS 21680 and ZM 241385, respectively, did not promote changes in seizure parameters. Pretreatment with the ecto-5′nucleotidase inhibitor adenosine 5′-(α,β-methylene) diphosphate (AMPCP) decreased the latency to the onset of the tonic-clonic seizure stage. However, when pretreated with the adenosine deaminase (ADA) inhibitor, erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), or with the nucleoside transporter (NT) inhibitors, dipyridamole and S-(4-Nitrobenzyl)-6-thioinosine (NBTI), animals showed longer latency to reach the tonic-clonic seizure status. Finally, our molecular analysis of the c-fos gene expression corroborates these behavioral results. Our findings indicate that the activation of adenosine A1 receptors is an important mechanism to control the development of seizures in zebrafish. Furthermore, the actions of ecto-5′-nucleotidase, ADA, and NTs are directly involved in the control of extracellular adenosine levels and have an important role in the development of seizure episodes in zebrafish. © 2015, Mary Ann Liebert, Inc.


Rosemberg D.B.,Institute Ciencias Basicas da Sau | Rosemberg D.B.,Instituto Nacional em Excitotoxicidade e Neuroprotecao INCT EN | Rico E.P.,Institute Ciencias Basicas da Sau | Rico E.P.,Instituto Nacional em Excitotoxicidade e Neuroprotecao INCT EN | And 10 more authors.
Comparative Biochemistry and Physiology - B Biochemistry and Molecular Biology | Year: 2010

The nucleoside triphosphate diphosphohydrolase (NTPDase) family cleaves tri- and diphosphonucleosides to monophosphonucleosides and is responsible for terminating purinergic transmission. Since the NTPDase family in zebrafish is poorly understood, here we evaluated the nucleotide hydrolysis in three tissues of adult zebrafish (brain, liver, and heart), confirmed the presence of distinct NTPDase members by a phylogenetic analysis and verified their relative gene expression profiles in the respective tissues. A different profile of ATP and ADP hydrolysis in the brain, liver, and heart as a function of time and protein concentration was observed. Sodium azide (20 mM), ARL 67156 (300 μM) and Suramin (300 μM) differently altered the nucleotide hydrolysis in zebrafish tissues, suggesting the contribution of distinct NTPDase activities. Homology-based searches identified the presence of NTPDase1-6 and NTPDase8 orthologs and the phylogeny also grouped three NTPDase2 and two NTPDase5 paralogs. The deduced amino acid sequences share the apyrase conserved regions, conserved cysteine residues, putative N-glycosylation, phosphorylation, N-acetylation sites, and different numbers of transmembrane domains. RT-PCR experiments revealed the existence of a distinct relative entpd1-6 and entpd8 expression profile in brain, liver, and heart. Taken together, these results indicate that several NTPDase members might contribute to a tight regulation of nucleotide hydrolysis in zebrafish tissues. © 2009 Elsevier Inc. All rights reserved.


Rozisky J.R.,Programa de Pos Graduacao em Medicina | Rozisky J.R.,Laboratorio Of Farmacologia | Medeiros L.F.,Laboratorio Of Farmacologia | Adachi L.S.,Programa de Pos Graduacao em Medicina | And 10 more authors.
Brain Research | Year: 2011

Considering the importance of a deeper understanding of the effect throughout life of opioid analgesia at birth, our objective was to determine whether morphine administration in early life, once a day for 7 days in 8-day-old rats, alters the nociceptive response over the short (P16), medium (P30), and long term (P60) and to evaluate which system is involved in the altered nociceptive response. The nociceptive responses were assessed by the formalin test, and the behavior analyzed was the total time spent in biting and flicking of the formalin-injected hindpaw, recorded during the first 5 min (phase I) and from 15-30 min (phase II). The morphine group showed no change in nociceptive response at P16, but at P30 and P60, the nociceptive response was increased in phase I, and in both phases, respectively. At P30 and P60, the animals received a non-steroidal anti-inflammatory drug (indomethacin) or NMDA receptor antagonist (ketamine) 30 min before the formalin test. The increase in the nociceptive response was completely reversed by ketamine, and partially by indomethacin. These results indicate that early morphine exposure causes an increase in the nociceptive response in adult life. It is possible that this lower nociception threshold is due to neuroadaptations in nociceptive circuits, such as the glutamatergic system. Thus, this work demonstrates the importance of evaluating clinical consequences related to early opioid administration and suggests a need for a novel design of agents that may counteract opiate-induced neuroplastic changes. © 2010 Elsevier B.V. All rights reserved.

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