RESUMO
Activation of PKCÉ, an abundant and developmentally regulated PKC isoform in the brain, has been implicated in memory throughout life and across species. Yet, direct evidence for a mechanistic role for PKCÉ in memory is still lacking. Hence, we sought to evaluate this in rats, using short-term treatments with two PKCÉ-selective peptides, the inhibitory ÉV1-2 and the activating ψÉRACK, and the novel object recognition task (NORT). Our results show that the PKCÉ-selective activator ψÉRACK, did not have a significant effect on recognition memory. In the short time frames used, however, inhibition of PKCÉ activation with the peptide inhibitor ÉV1-2 significantly impaired recognition memory. Moreover, when we addressed at the molecular level the immediate proximal signalling events of PKCÉ activation in acutely dissected rat hippocampi, we found that ψÉRACK increased in a time-dependent manner phosphorylation of MARCKS and activation of Src, Raf, and finally ERK1/2, whereas ÉV1-2 inhibited all basal activity of this pathway. Taken together, these findings present the first direct evidence that PKCÉ activation is an essential molecular component of recognition memory and point toward the use of systemically administered PKCÉ-regulating peptides as memory study tools and putative therapeutic agents.
Assuntos
Memória/fisiologia , Proteína Quinase C-épsilon/metabolismo , Reconhecimento Psicológico/fisiologia , Animais , Western Blotting , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Produtos do Gene tat/farmacologia , Hipocampo/citologia , Hipocampo/enzimologia , Hipocampo/metabolismo , Técnicas In Vitro , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Neurônios/enzimologia , Fosforilação , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Quinases raf/fisiologia , Quinases da Família src/fisiologiaRESUMO
There are experimental evidences indicating that the non-competitive NMDA receptor antagonist MK-801 impairs cognition and produces a series of schizophrenia-like symptoms in rodents (hypermotility, stereotypies and ataxia). The present study was designed to investigate the efficacy of the selective 5-HT(6) receptor antagonist Ro 04-6790 in counteracting these MK-801-induced behavioural effects in the rat. The effects of Ro 04-6790 in antagonizing MK-801-induced memory deficits were assessed using the object recognition task. The ability of this 5-HT(6) receptor antagonist in counteracting hypermotility, stereotypies and ataxia produced by MK-801 were evaluated in a motor activity cage. Post-training administration of Ro 04-6790 (10 and to some extent also 3mg/kg) antagonized MK-801-induced performance deficits in a recognition memory test. In a subsequent study, Ro 04-6790 (3 and 10 mg/kg) reversed hypermotility and ataxia produced by MK-801. This 5-HT(6) receptor antagonist also alleviated MK-801-induced certain stereotypies. Our findings indicate that Ro 04-6790 attenuates behavioural effects related to the hypofunction of the NMDA receptor suggesting that this compound might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists.
Assuntos
Comportamento Animal/efeitos dos fármacos , Maleato de Dizocilpina , Transtornos Mentais/induzido quimicamente , Transtornos Mentais/tratamento farmacológico , Pirimidinas/uso terapêutico , Antagonistas da Serotonina/uso terapêutico , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Comportamento Exploratório/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Reconhecimento Visual de Modelos/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Crocus sativus L. is a plant cultivated in various parts of the world. Its involvement in learning and memory processes has been proposed. Crocins are water-soluble carotenoids and are among the active components of C. sativus L. The present study was designed to investigate in the rat the effects of crocins on recognition and spatial memory. For this aim, the object recognition task which evaluates non-spatial working memory and a novel version of the radial water maze which assesses spatial reference and spatial working memory were chosen. In a first study, crocins (15 and 30mg/kg) counteracted delay-dependent recognition memory deficits in the normal rat, suggesting that these carotenoids modulate storage and/or retrieval of information. In a subsequent study, treatment with crocins (30mg/kg and to a lesser extent also 15mg/kg) attenuated scopolamine (0.2mg/kg)-induced performance deficits in the radial water maze test. The present results support and extend the enhancing effects of crocins on memory and, then, to our knowledge, for the first time, demonstrate its implication in the mechanisms underlying recognition and spatial memory.
Assuntos
Carotenoides/farmacologia , Crocus/química , Memória de Curto Prazo/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Comportamento Espacial/efeitos dos fármacos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Fatores de TempoRESUMO
There is experimental evidence indicating that the non-competitive NMDA receptor antagonist MK-801 impairs cognition and produces a series of schizophrenia-like symptoms in rodents (hypermotility, stereotypies, and ataxia). The present study was designed to investigate the efficacy of the nitric oxide (NO) donor molsidomine in counteracting these MK-801-induced behavioral effects in the rat. In a first study, post-training administration of molsidomine (at 4 but not 2 mg/kg) successfully antagonized MK-801-induced performance deficits in a recognition memory test. In a subsequent study, molsidomine (2 and 4 mg/kg) was shown to be unable to reverse MK-801-induced hypermotility but attenuated stereotypies (continuous movement whole cage, body sway, and head weaving) produced by MK-801. Moreover, at 4 mg/kg this NO donor counteracted MK-801-induced ataxia. Our findings indicate that molsidomine attenuates behavioral effects related to the hypofunction of the NMDA receptor suggesting that NO might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists.
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Alucinógenos/farmacologia , Molsidomina/farmacologia , Doadores de Óxido Nítrico/farmacologia , Animais , Maleato de Dizocilpina/farmacologia , Masculino , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Functional activation of the 5-HT1A receptor inhibits cognition, although discrepant findings have also been reported. The present study was designed to investigate the role of the 5-HT1A receptor on recognition memory in the rat. For this purpose, the effects induced by the 5-HT1A agonist R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT) and the 5-HT1A antagonist WAY 100635 on memory were evaluated by using the object recognition task. In addition, the possible involvement of the nitrergic system on 5-HT1A receptor's effects was also assessed by using the same behavioral procedure. In the first dose-response study, post-training administration of 8-OH-DPAT (0.1 and 0.3 mg/kg, subcutaneously (s.c.)) dose-dependently impaired animals' performance in this test. WAY 100635 (0.3 and 1 mg/kg, intraperitoneally (i.p.)) successfully antagonized these 8-OH-DPAT-induced performance deficits. The NO donor molsidomine (2 and 4 mg/kg, i.p.) counteracted cognition deficits produced by the highest dose of 8-OH-DPAT (0.3 mg/kg). Our findings indicate (a) that the 5-HT1A receptor is involved in recognition memory, and (b) that a NO component modulates the effects of the 5-HT1A receptor on learning and memory.