Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Int J Neuropsychopharmacol ; 20(5): 403-409, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28031268

RESUMO

Background: Opioid and dopamine systems play crucial roles in reward. Similarities and differences in the neural mechanisms of reward that are mediated by these 2 systems have remained largely unknown. Thus, in the present study, we investigated the differences in reward function in both µ-opioid receptor knockout mice and dopamine transporter knockout mice, important molecules in the opioid and dopamine systems. Methods: Mice were implanted with electrodes into the right lateral hypothalamus (l hour). Mice were then trained to put their muzzle into the hole in the head-dipping chamber for intracranial electrical stimulation, and the influences of gene knockout were assessed. Results: Significant differences are observed between opioid and dopamine systems in reward function. µ-Opioid receptor knockout mice exhibited enhanced intracranial electrical stimulation, which induced dopamine release. They also exhibited greater motility under conditions of "despair" in both the tail suspension test and water wheel test. In contrast, dopamine transporter knockout mice maintained intracranial electrical stimulation responding even when more active efforts were required to obtain the reward. Conclusions: The absence of µ-opioid receptor or dopamine transporter did not lead to the absence of intracranial electrical stimulation responsiveness but rather differentially altered it. The present results in µ-opioid receptor knockout mice are consistent with the suppressive involvement of µ-opioid receptors in both positive incentive motivation associated with intracranial electrical stimulation and negative incentive motivation associated with depressive states. In contrast, the results in dopamine transporter knockout mice are consistent with the involvement of dopamine transporters in positive incentive motivation, especially its persistence. Differences in intracranial electrical stimulation in µ-opioid receptor and dopamine transporter knockout mice underscore the multidimensional nature of reward.


Assuntos
Analgésicos Opioides/metabolismo , Dopamina/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Receptores Opioides mu/deficiência , Animais , Biofísica , Proteínas da Membrana Plasmática de Transporte de Dopamina/deficiência , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Estimulação Elétrica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Motivação , Atividade Motora/efeitos dos fármacos , Receptores Opioides mu/genética , Recompensa , Autoadministração , Fatores de Tempo
2.
J Neurosci ; 28(25): 6459-72, 2008 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-18562617

RESUMO

Long-lasting neuronal plasticity as well as long-term memory (LTM) requires de novo synthesis of proteins through dynamic regulation of gene expression. cAMP-responsive element (CRE)-mediated gene transcription occurs in an activity-dependent manner and plays a pivotal role in neuronal plasticity and LTM in a variety of species. To study the physiological role of inducible cAMP early repressor (ICER), a CRE-mediated gene transcription repressor, in neuronal plasticity and LTM, we generated two types of ICER mutant mice: ICER-overexpressing (OE) mice and ICER-specific knock-out (KO) mice. Both ICER-OE and ICER-KO mice show no apparent abnormalities in their development and reproduction. A comprehensive battery of behavioral tests revealed no robust changes in locomotor activity, sensory and motor functions, and emotional responses in the mutant mice. However, long-term conditioned fear memory was attenuated in ICER-OE mice and enhanced in ICER-KO mice without concurrent changes in short-term fear memory. Furthermore, ICER-OE mice exhibited retardation of kindling development, whereas ICER-KO mice exhibited acceleration of kindling. These results strongly suggest that ICER negatively regulates the neuronal processes required for long-term fear memory and neuronal plasticity underlying kindling epileptogenesis, possibly through suppression of CRE-mediated gene transcription.


Assuntos
Modulador de Elemento de Resposta do AMP Cíclico/fisiologia , Epilepsia/metabolismo , Medo/fisiologia , Excitação Neurológica/metabolismo , Memória/fisiologia , Proteínas Repressoras/fisiologia , Animais , Modulador de Elemento de Resposta do AMP Cíclico/genética , Epilepsia/genética , Feminino , Excitação Neurológica/genética , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Inibição Neural/fisiologia
3.
Brain Res ; 1039(1-2): 130-6, 2005 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-15781054

RESUMO

We examined the effects of acute injections of competitive N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovaleric acid (APV) into the dorsal hippocampus on contextual fear conditioning and classical eyeblink conditioning in C57BL/6 mice. When injected 10 to 40 min before training, APV severely impaired contextual fear conditioning. Thus, APV injection under these conditions was sufficient to suppress hippocampal NMDA receptors. To investigate the role of hippocampal NMDA receptors on eyeblink conditioning, we carried out daily training of mice during 10-40 min after injection of APV. In the delay eyeblink conditioning, in which the unconditioned stimulus (US) is delayed and terminates simultaneously with the conditioned stimulus (CS), APV-injected mice acquired the conditioned responses (CRs) as well as artificial cerebrospinal fluid (aCSF)-injected control mice did. However, in the trace eyeblink conditioning, in which the CS and US were separated by a stimulus-free trace interval of 500 ms, APV-injected mice showed severe impairment in acquisition of the CR. There was no significant difference in pseudo-conditioning between APV- and aCSF-injected mice. These results provide evidence that the NMDA receptor in the dorsal hippocampus is critically involved in acquisition of the CR in long trace eyeblink conditioning.


Assuntos
Condicionamento Clássico/fisiologia , Condicionamento Palpebral/fisiologia , Hipocampo/metabolismo , Memória de Curto Prazo/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Palpebral/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos
4.
Brain Res Mol Brain Res ; 98(1-2): 102-10, 2002 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-11834300

RESUMO

Fyn tyrosine kinase deficient mice are known to show increased fearfulness. We investigated the fear response of these mice using the light-potentiation of the acoustic startle response (ASR) and examined its neurochemical correlates using in vivo microdialysis. Female homozygous Fyn-deficient mice showed an enhancement of the startle amplitude under a bright light while heterozygotes and wild-types did not show such a change. Along with these behavioral findings, the homozygous Fyn-deficient mice showed an increase in extracellular serotonin (5-HT) and dopamine (DA) in the prefrontal cortex and 5-HT in the hippocampus when they were exposed to bright light, while heterozygous and wild-type mice did not show such changes. These results suggest that the increased fearfulness of Fyn-deficient mice is related to enhanced serotonergic and dopaminergic activity in the prefrontal cortex and limbic system.


Assuntos
Corpo Estriado/fisiologia , Dopamina/metabolismo , Medo/fisiologia , Hipocampo/fisiologia , Luz , Sistema Límbico/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Reflexo de Sobressalto/efeitos da radiação , Serotonina/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Corpo Estriado/enzimologia , Cruzamentos Genéticos , Escuridão , Feminino , Genótipo , Hipocampo/enzimologia , Sistema Límbico/enzimologia , Camundongos , Camundongos Knockout , Microdiálise , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal/enzimologia , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-fyn
5.
Brain Res Mol Brain Res ; 102(1-2): 113-7, 2002 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-12191501

RESUMO

It has been shown that the N-methyl-D-asparate (NMDA) receptor in the inferior colliculus is involved in the induction of audiogenic seizures (AGS). In the present study we examined audiogenic-like seizure susceptibility in GluR epsilon 1 null KO adult mice (n=32) and wild-type adult mice (n=28) by electrically stimulating the inferior colliculus (IC). Threshold current intensities of the GluR epsilon 1 KO mice for wild running, clonic and tonic seizures were higher than those of wild-type mice. In addition, the incidence rates of each seizure syndrome in GluR epsilon 1 KO mice were lower than in wild-type mice at each current intensity. These results show that GluR epsilon 1 KO mice were more resistant to audiogenic-like seizures induced by stimulating the IC. Thus, our findings suggest that the GluR epsilon 1 subunit plays an important role in regulating AGS.


Assuntos
Epilepsia Reflexa/genética , Epilepsia Reflexa/metabolismo , Colículos Inferiores/metabolismo , Mutação/genética , Receptores de N-Metil-D-Aspartato/deficiência , Convulsões/genética , Convulsões/metabolismo , Animais , Células Cultivadas , Estimulação Elétrica , Epilepsia Reflexa/fisiopatologia , Feminino , Colículos Inferiores/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Receptores de N-Metil-D-Aspartato/genética , Convulsões/fisiopatologia , Transmissão Sináptica/genética
6.
Ann N Y Acad Sci ; 1025: 140-5, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15542711

RESUMO

Dopamine (DA) plays roles in circuits that are important for brain reward and in striatal brain regions that are important for certain types of habit learning. These processes in wildtype, heterozygous, and homozygous dopamine transporter knockout (DAT-KO) mice, which were mildly food deprived and allowed to make nose-poke responses for food reinforcement, were studied. The mice were given 20-min sessions of daily (a) baseline exposure to the operant chambers, (b) acquisition of nose-poke responses in which responses were reinforced under a fixed ratio (FR5) schedule, (c) a progressive ratio schedule in which the number of responses required to obtain food was gradually increased, and (d) extinction of responses in which nose pokes were not followed by food. Neither heterozygous nor homozygous DAT-KO mice differed from their wildtype litter mates in the number of nose pokes displayed during baseline exposures to the chambers, the number of sessions required for acquisition, the number of responses under the FR5 schedule, or the number of responses under the progressive ratio schedule. Interestingly, however, in the five extinction sessions in which food was no longer delivered by nose poking, homozygous DAT-KO mice exerted significantly more responses than mice of either of the other two genotypes. These lines of evidence suggest a greater resistance of DAT-KO mice to the elimination of the response and support roles of dopaminergic systems in habit memory.


Assuntos
Condicionamento Operante/fisiologia , Ingestão de Alimentos/fisiologia , Extinção Psicológica/fisiologia , Glicoproteínas de Membrana/deficiência , Proteínas de Membrana Transportadoras/deficiência , Proteínas do Tecido Nervoso/deficiência , Esquema de Reforço , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/biossíntese , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética
7.
Neurosci Res ; 44(3): 305-13, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12413659

RESUMO

Mice become highly susceptible to audiogenic seizures (AGS) after being exposed to intense, high-frequency noise during a critical period of early life (priming). To determine the critical site for AGS priming in the auditory brainstem, animals in the experimental group were primed at 21 days, and the tone-induced Fos immunoreactivity was examined 1, 7, and 14 days after priming as an index of excitability of neurons. Enhanced Fos immunoreactivity was observed in the inferior colliculus (IC) of the primed mice 7 and 14 days after priming as compared to that of non-primed mice and attenuated Fos expression was observed 1 day after priming. No significant elevation of Fos expression was observed in the cochlear nucleus and the deep layer of the superior colliculus of either type of mice. These results strongly suggest that the IC is the target site of AGS priming.


Assuntos
Regulação da Expressão Gênica/fisiologia , Genes fos/genética , Colículos Inferiores/metabolismo , Colículos Inferiores/fisiologia , Ruído/efeitos adversos , Estimulação Acústica , Animais , Núcleo Coclear/metabolismo , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Convulsões/genética , Convulsões/fisiopatologia
8.
Neurosci Res ; 44(2): 121-131, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12354627

RESUMO

Opioids and ethanol have been used since ancient times for pain relief. Opioid signaling is mediated by various effectors, including G protein-activated inwardly rectifying potassium (GIRK) channels, adenylyl cyclases, voltage-dependent calcium channels, phospholipase Cbeta(PLCbeta), and mitogen-activated protein kinases, although it has been unclear which effector mediates the analgesic effects of opioids. Ethanol induces a variety of physiological phenomena via various proteins, including GIRK channels rather than via membrane lipids. GIRK channel activation by either G proteins or ethanol is impaired in weaver mutant mice. The mutant mice may therefore serve as a useful animal model for studying the role of GIRK channels in vivo. Reduced analgesia by using either opioids or ethanol in weaver mutant mice suggests that GIRK channels are important effectors in both opioid- and ethanol-induced analgesia. This hypothesis is supported by similar findings in GIRK2 knockout mice. Among the various effectors coupled with opioid receptors and various targets of ethanol, GIRK channels are the only molecules whose involvement in opioid- and ethanol-induced analgesia has been demonstrated in vivo. The GIRK channel is potentially one of the key molecules in furthering the understanding of the pain control system and in developing advanced analgesics with fewer adverse effects.


Assuntos
Analgésicos Opioides/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Etanol/farmacologia , Dor/tratamento farmacológico , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/deficiência , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Sistema Nervoso Central/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G , Proteínas de Ligação ao GTP/metabolismo , Humanos , Camundongos , Modelos Animais , Dor/metabolismo , Dor/fisiopatologia , Canais de Potássio/genética , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/metabolismo
9.
Synapse ; 46(2): 100-7, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12211088

RESUMO

Given the evidence that the inferior colliculus (IC) and superior colliculus (SC) seem to play key roles in connecting auditory pathways and seizure output pathways in the neuronal network for audiogenic seizures (AS) in rats, we examined Fos activation in GABAergic cells and cells immunopositive for glutamate N-methyl-D-aspartate (NMDA) receptors in the IC and SC following AS using the double-labeling procedure. Generalized tonic-clonic seizures (GTCS), which developed as an advanced form of AS in some of the susceptible rats, induced an increase in Fos expression in three IC substructures-the dorsal cortex of IC (DCIC), central nucleus of IC (CIC), and external cortex of IC (ECIC)-and in one SC substructure, the deep gray layer of SC (DpG). Compared with the rats showing GTCS, rats exhibiting wild running (WR) without proceeding to GTCS showed a different pattern of AS-induced Fos expression. The DpG in the WR animals showed no significant increase in the levels of Fos-like immunoreactivity. The degrees of Fos activation that occurred in GABAergic cells and cells immunopositive for NMDA receptors were similar in the DCIC, CIC, ECIC, and DpG following AS. These results suggest that Fos activation in the DpG is involved in the development from WR to GTCS in AS-susceptible rats. They also provide some evidence that some GABAergic neurons in the IC and SC and glutamatergic afferents (via NMDA receptors) to these structures are activated by AS.


Assuntos
Epilepsia Reflexa/metabolismo , Colículos Inferiores/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Colículos Superiores/metabolismo , Estimulação Acústica/efeitos adversos , Animais , Epilepsia Reflexa/etiologia , Epilepsia Reflexa/genética , Feminino , Imuno-Histoquímica , Masculino , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Wistar , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
10.
Eur J Neurosci ; 17(5): 929-36, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12653969

RESUMO

NB-2, a member of the contactin subgroup in the immunoglobulin superfamily, is expressed specifically in the postnatal nervous system, reaching a maximum level at 3 weeks postnatal. NB-2 displays neurite outgrowth-promoting activity in vitro. To assess its function in the nervous system, we generated mutant mice in which a part of the NB-2 gene was ablated and replaced with the tau-LacZ gene. The general appearance of NB-2-deficient mice and their gross anatomical features were normal. The LacZ expression patterns in heterozygous mice revealed that NB-2 is preferentially expressed in the central auditory pathways. In the audiogenic seizure test, NB-2-deficient mice exhibited a lower incidence of wild running, but a higher mortality rate than the wild-type littermates. c-Fos immunohistochemistry demonstrated that neural excitability induced by the audiogenic seizure test in the NB-2-deficient mice was prominently attenuated in both the dorsal and external cortices of the inferior colliculus, where enhanced neural excitability was observed in the wild-type mice. In response to pure-tone stimulation after priming, NB-2-deficient mice exhibited a diffuse and low level of c-Fos expression in the central nucleus of the inferior colliculus, which was distinctly different from the band-like c-Fos expression corresponding to the tonotopic map in the wild-type littermates. Taken together, these results suggest that a lack of NB-2 causes impairment of the neuronal activity in the auditory system.


Assuntos
Vias Auditivas/fisiopatologia , Moléculas de Adesão Celular Neuronais/deficiência , Convulsões/fisiopatologia , Estimulação Acústica , Animais , Vias Auditivas/metabolismo , Encéfalo/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Contactinas , Genes Reporter , Genes fos/fisiologia , Imuno-Histoquímica , Óperon Lac/genética , Camundongos , Camundongos Mutantes , Convulsões/genética
11.
Hum Mol Genet ; 11(11): 1251-62, 2002 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-12019206

RESUMO

Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause Lafora disease (LD), a progressive and invariably fatal epilepsy with periodic acid-Schiff-positive (PAS+) cytoplasmic inclusions (Lafora bodies) in the central nervous system. To study the pathology of LD and the functions of laforin, we disrupted the Epm2a gene in mice. At two months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibit swelling in the endoplasmic reticulum, Golgi networks and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies become more prominent at 4-12 months, organelles and nuclei are disrupted. The Lafora bodies, present both in neuronal and non-neural tissues, are positive for ubiquitin and advanced glycation end-products only in neurons, suggesting different pathological consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predate the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures and EEG epileptiform activity. Our results suggest that LD is a primary neurodegenerative disorder that may utilize a non-apoptotic mechanism of cell death.


Assuntos
Doença de Lafora/genética , Proteínas Tirosina Fosfatases/genética , Animais , Ataxia/fisiopatologia , Comportamento Animal , Morte Celular , Fosfatases de Especificidade Dupla , Eletroencefalografia , Epilepsias Mioclônicas/fisiopatologia , Feminino , Corpos de Inclusão/metabolismo , Doença de Lafora/patologia , Doença de Lafora/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutagênese Sítio-Dirigida , Neurônios/metabolismo , Neurônios/ultraestrutura , Proteínas Tirosina Fosfatases/deficiência , Proteínas Tirosina Fosfatases/fisiologia , Proteínas Tirosina Fosfatases não Receptoras , Ubiquitina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA