RESUMO
In the 1960s and 70s, biochemical and pharmacological evidence was pointing toward glutamate as a synaptic transmitter at a number of distinct receptor classes, known as NMDA and non-NMDA receptors. The field, however, lacked a potent and highly selective antagonist to block these putative postsynaptic receptors. So, the discoveries in the early 1980s of D-AP5 as a selective NMDA receptor antagonist and of its ability to block synaptic events and plasticity were a major breakthrough leading to an explosion of knowledge about this receptor subtype. During the next 10 years, the role of NMDA receptors was established in synaptic transmission, long-term potentiation, learning and memory, epilepsy, pain, among others. Hints at pharmacological heterogeneity among NMDA receptors were followed by the cloning of separate subunits. The purpose of this review is to recognize the important contributions made in the 1980s by Graham L. Collingridge and other key scientists to the advances in our understanding of the functions of NMDA receptors throughout the central nervous system.
Assuntos
Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Transmissão Sináptica/fisiologia , Animais , Ácido Glutâmico/metabolismo , História do Século XX , História do Século XXI , Humanos , Aprendizagem/fisiologia , Memória/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Different types of memory are thought to rely on different types of synaptic plasticity, many of which depend on the activation of the N-Methyl-D Aspartate (NMDA) subtype of glutamate receptors. Accordingly, there is considerable interest in the possibility of using positive allosteric modulators (PAMs) of NMDA receptors (NMDARs) as cognitive enhancers. Here we firstly review the evidence that NMDA receptor-dependent forms of synaptic plasticity: short-term potentiation (STP), long-term potentiation (LTP) and long-term depression (LTD) can be pharmacologically differentiated by using NMDAR ligands. These observations suggest that PAMs of NMDAR function, depending on their subtype selectivity, might differentially regulate STP, LTP and LTD. To test this hypothesis, we secondly performed experiments in rodent hippocampal slices with UBP714 (a GluN2A/2B preferring PAM), CIQ (a GluN2C/D selective PAM) and UBP709 (a pan-PAM that potentiates all GluN2 subunits). We report here, for the first time, that: (i) UBP714 potentiates sub-maximal LTP and reduces LTD; (ii) CIQ potentiates STP without affecting LTP; (iii) UBP709 enhances LTD and decreases LTP. We conclude that PAMs can differentially regulate distinct forms of NMDAR-dependent synaptic plasticity due to their subtype selectivity.
Assuntos
Potenciação de Longa Duração/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Regulação Alostérica , Animais , Benzimidazóis/farmacologia , Hipocampo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos WistarRESUMO
The mechanisms involved in mossy fiber LTP in the hippocampus are not well established. In the present study, we show that the kainate receptor antagonist LY382884 (10 microM) is selective for presynaptic kainate receptors in the CA3 region of the hippocampus. At a concentration at which it blocks mossy fiber LTP, LY382884 selectively blocks the synaptic activation of a presynaptic kainate receptor that facilitates AMPA receptor-mediated synaptic transmission. Following the induction of mossy fiber LTP, there is a complete loss of the presynaptic kainate receptor-mediated facilitation of synaptic transmission. These results identify a central role for the presynaptic kainate receptor in the induction of mossy fiber LTP. In addition, these results suggest that the pathway by which kainate receptors facilitate glutamate release is utilized for the expression of mossy fiber LTP.
Assuntos
Potenciação de Longa Duração/fisiologia , Fibras Musgosas Hipocampais/fisiologia , Receptores de Ácido Caínico/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Benzodiazepinas/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Técnicas In Vitro , Isoquinolinas/farmacologia , Ratos , Receptores de Ácido Caínico/antagonistas & inibidores , Receptores Pré-Sinápticos/antagonistas & inibidores , Receptores Pré-Sinápticos/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
We investigated the role of PDZ proteins (GRIP, ABP, and PICK1) interacting with the C-terminal GluR2 by infusing a ct-GluR2 peptide ("pep2-SVKI") into CA1 pyramidal neurons in hippocampal slices using whole-cell recordings. Pep2-SVKI, but not a control or PICK1 selective peptide, caused AMPAR-mediated EPSC amplitude to increase in approximately one-third of control neurons and in most neurons following the prior induction of LTD. Pep2-SVKI also blocked LTD; however, this occurred in all neurons. A PKC inhibitor prevented these effects of pep2-SVKI on synaptic transmission and LTD. We propose a model in which the maintenance of LTD involves the binding of AMPARs to PDZ proteins to prevent their reinsertion. We also present evidence that PKC regulates AMPAR reinsertion during dedepression.
Assuntos
Hipocampo/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteína Quinase C/metabolismo , Receptores de AMPA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Motivos de Aminoácidos , Peptídeos beta-Amiloides/metabolismo , Animais , Proteínas de Transporte/metabolismo , Células Cultivadas , Proteínas do Citoesqueleto , Inibidores Enzimáticos/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/citologia , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intracelular , Modelos Neurológicos , Proteínas do Tecido Nervoso/metabolismo , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Proteínas Nucleares/metabolismo , Técnicas de Patch-Clamp , Fragmentos de Peptídeos/genética , Proteína Quinase C/antagonistas & inibidores , Estrutura Terciária de Proteína/genética , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ratos , Receptores de AMPA/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia , Transmissão Sináptica/efeitos dos fármacosRESUMO
Glycogen synthase kinase-3 (GSK-3), an important component of the glycogen metabolism pathway, is highly expressed in the CNS. It has been implicated in major neurological disorders including Alzheimer's disease, schizophrenia and bipolar disorders. Despite its central role in these conditions it was not known until recently whether GSK-3 has neuronal-specific functions under normal conditions. However recent work has shown that GSK-3 is involved in the regulation of, and cross-talk between, two major forms of synaptic plasticity, N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and NMDAR-dependent long-term depression (LTD). The present article summarizes this recent work and discusses its potential relevance to the treatment of neurological disorders.
Assuntos
Quinase 3 da Glicogênio Sintase/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Animais , Quinase 3 da Glicogênio Sintase/efeitos dos fármacos , Humanos , Plasticidade Neuronal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Sinapses/efeitos dos fármacosRESUMO
Metabotropic L-glutamate receptors are involved in various forms of synaptic plasticity in the hippocampus. The use of a new antagonist (LY341495) that blocks all known metabotropic L-glutamate receptors in the brain, together with subtype-selective antagonists, has identified multiple roles both for cloned and novel metabotropic L-glutamate receptors in hippocampal long-term potentiation and long-term depression.
Assuntos
Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Química Encefálica/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
We investigated the involvement of protein synthesis in the stimulatory action of thyroid hormones on amino acid accumulation and characterized K(+) currents involved in the hyperpolarizing effect of thyroxine (T(4)) on Sertoli cells. Immature rat testes were incubated in Krebs Ringer-bicarbonate buffer (KRb) in the presence of [(14)C]methylaminoisobutyric acid with and without T(4), 3,5,3'-l-triiodothyronine (T(3)) and/or cycloheximide. Sertoli cells were monitored by intracellular recording in a chamber perfused with KRb with and without T(4), T(3) and/or blockers, and the membrane potential was monitored. T(4) and T(3) stimulated amino acid accumulation and protein synthesis. Treatment with cycloheximide diminished T(3) stimulatory actions on amino acid accumulation but had no effect on T(4) action. Both hormones elicited a hyperpolarization of the Sertoli cell membrane potential which involved K(+) channels, since TEA and apamin abolished this effect. These findings on rapid membrane actions of thyroid hormone in the testis suggest that some effects of T(4) are modulated by non-genomic mechanisms.
Assuntos
Proteínas/metabolismo , Transdução de Sinais/fisiologia , Testículo/efeitos dos fármacos , Testículo/fisiologia , Tiroxina/farmacologia , Animais , Cicloeximida/farmacologia , Eletrofisiologia , Masculino , Ratos , Ratos Wistar , Células de Sertoli/fisiologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Tri-Iodotironina/farmacologiaRESUMO
Glucocorticoids (GC) released during stress response exert feedforward effects in the whole brain, but particularly in the limbic circuits that modulates cognition, emotion and behavior. GC are the most commonly prescribed anti-inflammatory and immunosuppressant medication worldwide and pharmacological GC treatment has been paralleled by the high incidence of acute and chronic neuropsychiatric side effects, which reinforces the brain sensitivity for GC. Synapses can be bi-directionally modifiable via potentiation (long-term potentiation, LTP) or depotentiation (long-term depression, LTD) of synaptic transmission efficacy, and the phosphorylation state of Ser831 and Ser845 sites, in the GluA1 subunit of the glutamate AMPA receptors, are a critical event for these synaptic neuroplasticity events. Through a quasi-randomized controlled study, we show that a single high dexamethasone dose significantly reduces in a dose-dependent manner the levels of GluA1-Ser831 phosphorylation in the amygdala resected during surgery for temporal lobe epilepsy. This is the first report demonstrating GC effects on key markers of synaptic neuroplasticity in the human limbic system. The results contribute to understanding how GC affects the human brain under physiologic and pharmacologic conditions.
Assuntos
Dexametasona/farmacologia , Sistema Límbico/efeitos dos fármacos , Receptores de AMPA/metabolismo , Adulto , Tonsila do Cerebelo/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Epilepsia do Lobo Temporal/cirurgia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/cirurgia , Humanos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/cirurgiaRESUMO
Seizures induced by pilocarpine (PILO) have proven to be a useful procedure for investigating the basic mechanisms essential for generation, spread and motor expression of seizures in rodents. Here we report the long-term effects of PILO in rats. Following PILO (380 mg/kg, IP), 3 distinct phases were observed: 1) an acute period which lasted 1-2 days which corresponds to the pattern of repetitive seizures and status epilepticus; 2) a silent period (4-44 days) characterized by a progressive return to normal EEG and behavior; and 3) a period of recurrent seizures which started 5-45 days after PILO and lasted up to 120 days. These seizures lasted up to 50-60 sec, recurred 2-3 times per week and were more frequent during the light period of the light-dark cycle. These serial events offer a new method to induce spontaneous recurrent seizures in rats.
Assuntos
Convulsões/fisiopatologia , Agressão/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/fisiologia , Modelos Animais de Doenças , Eletroencefalografia , Hipocampo/fisiologia , Humanos , Sistema Límbico/fisiologia , N-Metilescopolamina , Parassimpatolíticos/farmacologia , Pilocarpina/farmacologia , Ratos , Ratos Endogâmicos , Recidiva , Derivados da Escopolamina/farmacologia , Convulsões/induzido quimicamenteRESUMO
The transient activation of the N-methyl-D-aspartate (NMDA) receptor system by high frequency (tetanic) stimulation results in a rapidly developing and long-lasting potentiation of synaptic transmission in the CA1 region of the hippocampus. This potentiation can be divided into an early decremental component, known as short-term potentiation (STP), and a more slowly developing persistent phase, termed long-term potentiation (LTP). Here we describe how activation of metabotropic glutamate receptors (mGluRs), by aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD), can induce the same stable form of LTP, but without the STP component. 1S,3R-ACPD-induced LTP does not require electrical stimulation during its induction, but is dependent on an intact connection between the CA3 and CA1 regions of the hippocampus. 1S,3R-ACPD-induced LTP circumvents the need for the activation of NMDA receptors and is likely to involve both the stimulation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores.
Assuntos
Hipocampo/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Receptores de Glutamato/efeitos dos fármacos , Alcaloides/farmacologia , Animais , ATPases Transportadoras de Cálcio/antagonistas & inibidores , Cicloleucina/análogos & derivados , Cicloleucina/farmacologia , Estimulação Elétrica , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Fosfatidilinositóis/fisiologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/fisiologia , Transdução de Sinais/fisiologia , Estaurosporina , Estereoisomerismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Terpenos/farmacologia , TapsigarginaRESUMO
We have reported previously that transient application of a specific metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD) can induce a slow-onset form of long-term potentiation (LTP) of synaptic transmission in the CA1 region of rat hippocampal slices [Bortolotto Z. A. and Collingridge G. L. (1993) Neuropharmacology 32, 1-9]. Here we have investigated further the mechanisms involved in the induction and expression of ACPD-induced LTP. Unless otherwise stated, field excitatory postsynaptic potentials (EPSPs) were recorded in stratum radiatum in response to low frequency (0.033 Hz stimulation) of the Schaffer collateral-commissural pathway and 10 microM ACPD was added for 20 min to the perfusate. ACPD-induced LTP was still observed following blockade of GABAA receptor-mediated synaptic inhibition using picrotoxin (50 microM) and was not the result of a change in the presynaptic fibre volley. Intracellular recording from area CA1 revealed an increase in the size of the EPSP but no associated change in membrane potential or input resistance. However, ACPD-induced potentiation was never seen when intracellular electrodes contained the Ca(2+)-chelating agent 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA; 0.5 M). In area CA3, ACPD elicited a slow-onset LTP of the intracellularly recorded EPSP, evoked by stimulation of associational fibres. In contrast to area CA1, 10 microM ACPD depolarized CA3 neurones. Unlike certain other forms of tetanus- and chemically-induced potentiation, ACPD-induced LTP was not affected by the L-type Ca2+ channel antagonist nimodipine (50 microM). It was, however, prevented by delivering low frequency stimulation (900 shocks at 1 Hz) immediately following termination of the application of ACPD; an effect which was inhibited by the specific N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate (AP5; 50 microM). ACPD failed to induce LTP of pharmacologically-isolated NMDA receptor-mediated EPSPs. The induction of ACPD-induced LTP was blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), in a reversible manner. In slices in which area CA3 had been removed ACPD failed to induce LTP when applied alone or together with AMPA. However, a slow-onset form of LTP was induced, in slices lacking area CA3, when a tetanus (100 Hz, 1 sec) was delivered in the presence of ACPD and 50 microM AP5 (the latter applied to prevent conventional tetanus-induced LTP). ACPD-induced LTP was associated with a parallel increase in the sensitivity of CA1 neurones to AMPA. Considered together, these data suggest that ACPD-induced LTP is due to a direct increase in the AMPA receptor-mediated synaptic conductance and involves postsynaptic induction and expression mechanisms.
Assuntos
Cicloleucina/análogos & derivados , Agonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Cicloleucina/farmacologia , Potenciais Evocados/efeitos dos fármacos , Feminino , Técnicas In Vitro , Nimodipina/farmacologia , Ratos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores Pré-Sinápticos/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologiaRESUMO
Long-term potentiation (LTP) is the form of synaptic plasticity most commonly associated with learning and memory. Studies using protein kinase inhibitors have suggested functional roles for several kinases in the induction of LTP in the CA1 region of the hippocampus, though the precise role of any given kinase has yet to be fully established. Here we report that the selective calcium/calmodulin-dependent protein kinase (CaMK) inhibitor KN-62 has two distinct actions on LTP. As reported previously, KN-62 (3 microM) prevented the induction of LTP. Here we show that KN-62 also prevents the setting of a molecular switch, initiated by the synaptic activation of (S)-alpha-methyl-4-carboxyphenylglycine (MCPG)-sensitive metabotropic glutamate (mGlu) receptors. There are two aspects of this work which might be considered surprising. First, the setting of the molecular switch was prevented by a concentration of KN-62 (1 microM) subthreshold for the inhibition of the induction of LTP per se. Second, the setting of the molecular switch, by the delivery of a tetanus (100 Hz, 1 s) in the presence of a specific NMDA receptor antagonist (R)-2-amino-5-phosphonopentanoate (AP5), reduced the sensitivity of LTP to KN-62, such that at a concentration of 3 microM it no longer blocked induction (though at 10 microM it did). This conditioning effect of a tetanus, delivered in the presence of AP5, was prevented by MCPG (200 microM). These data reveal unexpected complexities in the involvement of KN-62-sensitive processes (presumably CaMKII) in the induction of LTP. They suggest that activation of KN-62-sensitive processes leads to (at least) two phosphorylation steps with fundamentally different roles in synaptic plasticity within a single synapse. They also raise the possibility that CaMKII is an integral part of the MCPG-sensitive molecular switch mechanism.
Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/fisiologia , Hipocampo/enzimologia , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Benzoatos/farmacologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos , Antagonistas de Aminoácidos Excitatórios , Glicina/análogos & derivados , Glicina/farmacologia , Hipocampo/citologia , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Perfusão , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sinapses/fisiologiaRESUMO
The development of GluR5-selective kainate receptor ligands is helping to elucidate the functions of kainate receptors in the CNS. Here we have further characterised the actions of a GluR5 selective agonist, ATPA, and a GluR5 selective antagonist, LY382884, in the CA3 region of rat hippocampal slices. In addition, we have used LY382884 to study a novel synaptic mechanism. This antagonist substantially reduces frequency facilitation of mossy fibre synaptic transmission, monitored as either AMPA or NMDA receptor-mediated EPSCs. This suggests that GluR5-containing kainate receptors on mossy fibres function as autoreceptors to facilitate the synaptic release of L-glutamate, in a frequency-dependent manner.
Assuntos
Fibras Musgosas Hipocampais/fisiologia , Receptores de AMPA/fisiologia , Receptores de Ácido Caínico/fisiologia , Receptores Pré-Sinápticos/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Agonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Técnicas In Vitro , Isoxazóis/farmacologia , Fibras Musgosas Hipocampais/efeitos dos fármacos , Propionatos/farmacologia , Ratos , Receptores de Ácido Caínico/agonistas , Receptores de Ácido Caínico/antagonistas & inibidores , Receptores Pré-Sinápticos/agonistas , Receptores Pré-Sinápticos/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacosRESUMO
Understanding the roles of metabotropic glutamate (mGlu) receptors has been severely hampered by the lack of potent antagonists. LY341495 (2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-y l)propanoic acid) has been shown to block group II mGlu receptors in low nanomolar concentrations (Kingston, A.E., Ornstein, P.L., Wright, R.A., Johnson, B.G., Mayne, N.G., Burnett, J.P., Belagaje, R., Wu, S., Schoepp, D.D., 1998. LY341495 is a nanomolar potent and selective antagonist at group II metabotropic glutamate receptors. Neuropharmacology 37, 1-12) but can be used in higher concentrations to block all hippocampal mGlu receptors, identified so far by molecular cloning (mGlu1-5,7,8). Here we have further characterised the mGlu receptor antagonist activity of LY341495 and have used this compound to investigate roles of mGlu receptors in hippocampal long-term potentiation (LTP) and long-term depression (LTD). LY341495 competitively antagonised DHPG-stimulated PI hydrolysis in AV12-664 cells expressing either human mGlu1 or mGlu5 receptors with Ki-values of 7.0 and 7.6 microM, respectively. When tested against 10 microM L-glutamate-stimulated Ca2+ mobilisation in rat mGlu5 expressing CHO cells, it produced substantial or complete block at a concentration of 100 microM. In rat hippocampal slices, LY341495 eliminated 30 microM DHPG-stimulated PI hydrolysis and 100 microM (1S,3R)-ACPD-inhibition of forskolin-stimulated cAMP formation at concentrations of 100 and 0.03 microM, respectively. In area CA1, it antagonised DHPG-mediated potentiation of NMDA-induced depolarisations and DHPG-induced long-lasting depression of AMPA receptor-mediated synaptic transmission. LY341495 also blocked NMDA receptor-independent depotentiation and setting of a molecular switch involved in the induction of LTP; effects which have previously been shown to be blocked by the mGlu receptor antagonist (S)-MCPG. These effects may therefore be due to activation of cloned mGlu receptors. In contrast, LY341495 did not affect NMDA receptor-dependent homosynaptic LTD; an effect which may therefore be independent of cloned mGlu receptors. Finally, LY341495 failed to antagonise NMDA receptor-dependent LTP and, in area CA3, NMDA receptor-independent, mossy fibre LTP. Since in the same inputs these forms of LTP were blocked by (S)-MCPG, a novel type of mGlu receptor may be involved in their induction.
Assuntos
Aminoácidos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Xantenos/farmacologia , Envelhecimento , Animais , Ligação Competitiva , Células CHO , Linhagem Celular , Clonagem Molecular , Cricetinae , Cicloleucina/análogos & derivados , Cicloleucina/farmacologia , Ácido Glutâmico/farmacologia , Ácido Glutâmico/fisiologia , Glicina/análogos & derivados , Glicina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Humanos , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/genética , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Resorcinóis/farmacologia , TransfecçãoRESUMO
Morphine hydrochloride (25-200 nmol), [D-Ala2, D-Leu5]enkephalin (10-200 nmol) and naloxone hydrochloride (100-1000 nmol) were injected unilaterally into the rat amygdala and the following electrographic, behavioural and neuropathological responses were studied. Microinjections of low doses of morphine (25-50 nmol) resulted in behavioural alterations characterized by staring, gustatory automatisms and wet shakes, whereas higher doses additionally produced motor limbic seizures and status epilepticus. The first changes in the electroencephalogram appeared in the amygdala immediately after the administration of morphine and rapidly spread to hippocampal and cortical areas. Electrographic alterations consisted of high voltage fast activity, spiking, bursts of polyspiking, electrographic seizures and periods of postictal depression. Neuropathological analysis of frontal forebrain sections by means of light microscopy revealed widespread, seizure-related damage confined to amygdala, olfactory cortex, thalamus, hippocampal formation, neocortex and substantia nigra. Pretreatment of animals with naloxone, 2-20 mg/kg s.c., as well as simultaneous microinjection of the non-convulsant dose of naloxone, 100 nmol, with morphine, 100 nmol, into the amygdala failed to block the development of convulsant activity and seizure-related brain damage produced by the opiate. In contrast, diazepam, 10 mg/kg i.p., when administered prior to the microinjection of morphine into the amygdala, abolished the epileptogenic effects of the drug. [D-Ala2, D-Leu5]Enkephalin, 10-200 nmol, elicited electrographic and behavioural responses similar to those seen after low doses of morphine, when administered into the amygdala. High voltage fast activity, single spikes, bursts of polyspiking, electrographic seizures and periods of postictal depression were seen in the electroencephalogram, but no behavioural signs of motor limbic seizures could be detected. The only behavioural correlates of epileptiform electrographic activity were wet shakes, myoclonic head twiches and gustatory automatisms. The examination of frontal forebrain sections from rats receiving [D-Ala2, D-Leu5]enkephalin revealed no morphological changes. Pretreatment of rats with either naloxone, 2 mg/kg, or diazepam, 10 mg/kg, blocked the development of behavioural and electrographic sequelae of the peptide. Naloxone, 100-1000 nmol, when microinjected into the amygdala, produced electrographic, behavioural and morphological alterations resembling those seen after high doses of morphine.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Convulsivantes , Encefalina Leucina/análogos & derivados , Morfina/farmacologia , Naloxona/farmacologia , Animais , Encéfalo/patologia , Diazepam/farmacologia , Interações Medicamentosas , Eletroencefalografia , Encefalina Leucina/farmacologia , Leucina Encefalina-2-Alanina , Masculino , Microinjeções , Ratos , Ratos EndogâmicosRESUMO
The perirhinal cortex is crucially involved in various forms of learning and memory. Decrements in neuronal responsiveness occur in the perirhinal cortex with stimulus repetition during visual recognition performance. However, very little is known concerning the underlying mechanisms of synaptic transmission and plasticity in this cortical region. In this study, we provide evidence demonstrating the presence of functional group I, II and III metabotropic glutamate receptors in the rat perirhinal cortex in vitro. Furthermore, the results demonstrate long-lasting synaptic depression in the perirhinal cortex. Extracellular synaptic responses were recorded from superficial layers of the perirhinal cortex directly below the rhinal sulcus, in response to electrical stimuli delivered in the superficial or intermediate layers to the entorhinal or temporal cortex sides of the rhinal sulcus. Evoked synaptic potentials were depressed during bath perfusion of each of the following: the broad-spectrum metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, the selective group I agonist (R,S)-3,5-dihydroxyphenylglycine, the group II agonist (2S,1'R,2'R,3'R)-(2',3'-dicarboxycyclopropyl)glycine and the group III agonist (S)-2-amino-4-phosphonobutanoate. Furthermore, there was a long-lasting depression of synaptic transmission following washout of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, (R,S)-3,5-dihydroxyphenylglycine or (2S,1'R,2'R,3'R)-(2',3'-dicarboxy-cyclopropyl)glycine. Activation of group III metabotropic glutamate receptors by (S)-2-amino-4-phosphonobutanoate did not result in long-lasting changes in synaptic transmission. Thus, the pharmacological activation of metabotropic glutamate receptors can produce short- or long-term changes in synaptic transmission in the perirhinal cortex. It is possible therefore, that metabotropic glutamate receptors are involved in the decrement in neuronal responsiveness associated with visual recognition in the perirhinal cortex.
Assuntos
Agonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/fisiologia , Hipocampo/efeitos dos fármacos , Neocórtex/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Cicloleucina/análogos & derivados , Cicloleucina/farmacologia , Ciclopropanos/farmacologia , Estimulação Elétrica , Córtex Entorrinal/fisiologia , Agonistas de Aminoácidos Excitatórios/classificação , Feminino , Glicina/análogos & derivados , Glicina/farmacologia , Hipocampo/fisiologia , Masculino , Neocórtex/fisiologia , Plasticidade Neuronal , Técnicas de Cultura de Órgãos , Propionatos/farmacologia , Ratos , Ratos Endogâmicos , Ratos Wistar , Receptores de Glutamato Metabotrópico/fisiologia , Resorcinóis/farmacologia , Lobo Temporal/fisiologiaRESUMO
1. We have investigated the pharmacological properties of LY344545, a structurally related epimer of the broad spectrum competitive metabotropic glutamate receptor antagonist, LY341495. We have found that LY344545 also antagonizes competitively nearly all mGlu receptor subtypes, but with a wide spectrum of activity. The order of potency for the human receptor isoforms was mGlu(5a) (IC(50) of 5. 5+/-0.6 microM)>mGlu(2)=mGlu(3)>mGlu(1alpha)=mG lu(7)>mGlu(6)=mGlu(8). No significant mGlu(4) receptor antagonist activity was detected at the highest concentration used (100 microM). 100 microM LY344545 displaced 50+/-5% of [(3)H]-CGP39653 binding, but less than 30% of [(3)H]-kainate or [(3)H]-AMPA in radioligand binding assays. 2. LY344545 antagonized L-glutamate stimulated Ca(2+) release in CHO cells transfected with mGlu receptors in a concentration dependent manner with a 10 fold higher affinity for the rat mGlu(5a) receptor (K:(i)=2.1+/-0.6 microM) compared to the rat mGlu(1alpha) receptor (K:(i)=20.5+/-2.1 microM). 50 microM (1S, 3R)-ACPD-induced Ca(2+) rises in hippocampal CA1 neurones were also antagonized (IC(50)=6. 8+/-0.7 microM). 3. LY344545 antagonized 10 microM (S)-3,5-DHPG-induced potentiation of NMDA depolarizations in CA1 neurones (EC(50)=10. 6+/-1.0 microM). At higher concentrations (> or =100 microM), LY344545 was an NMDA receptor antagonist. 4. LY344545 also blocked the induction, but not the expression, of LTP at CA3 to CA1 synapses with an IC(50)>300 microM. This effect is consistent with its weak activity at NMDA receptors. 5. These results demonstrate that the binding of ligands to mGlu receptor subtypes is critically dependent on the spatial orientation of the same molecular substituents within a given chemical pharmacophore. The identification of LY344545 as the first competitive antagonist to show selectivity towards mGlu(5) receptors supports the potential to design more selective and potent competitive antagonists of this receptor. 6. These results further indicate that mGlu receptor-mediated potentiation of NMDA responses is not essential for the induction of LTP.
Assuntos
Aminoácidos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/farmacologia , N-Metilaspartato/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Xantenos/farmacologia , Animais , Linhagem Celular , Sinergismo Farmacológico , Agonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/metabolismo , Humanos , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Metoxi-Hidroxifenilglicol/antagonistas & inibidores , N-Metilaspartato/antagonistas & inibidores , Ratos , Receptor de Glutamato Metabotrópico 5RESUMO
There has been considerable interest recently in trying to elucidate the roles of metabotropic glutamate receptors (mGluRs) in the induction of long-term potentiation (LTP) in area CA1 of rat hippocampal slices. This has come about principally because of the development of specific mGluR agonists and antagonists. Recently we reported that the competitive mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) blocks the induction of LTP but not short-term potentiation (STP). We describe here the dose-dependency of the MCPG block; there is no effect at 100 microM while at 200 microM the block of LTP is normally complete but STP is spared. A higher concentration of MCPG (500 microM) has the same effect as 200 microM. We have also reported recently that high-frequency (tetanic) stimulation conditions a pathway such that MCPG fails to block the induction of subsequent LTP. We illustrate here that the conditioning effect of a tetanus lasts at least 6 h. We show how the pathway can be conditioned, without any persistent change in the synaptic response, by delivering tetanic stimulation in the presence of the specific NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (AP5). The pathway can subsequently be deconditioned by delivering low-frequency stimulation (900 shocks at 2 Hz) so that MCPG blocks the induction of subsequent LTP. We also have reported that the specific mGluR agonist 1-aminocyclopentane-(1S,3R)-dicarboxylate (ACPD) can induce LTP without the need for STP.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Eletrofisiologia/métodos , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Relação Dose-Resposta a Droga , Feminino , Ácido Glutâmico/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de TempoRESUMO
We used amygdala-kindled seizures in rats to study the function of striatal gamma-aminobutyrate (GABA) in the regulation of the seizure threshold of the limbic forebrain. Microinjections of the GABAA antagonist, bicuculline methiodide, 1 pmol, into the caudate-putamen protected rats against amygdala-kindled seizures. This result shows that striatal GABA differentially modulates the threshold for limbic seizures.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Bicuculina/análogos & derivados , Núcleo Caudado/efeitos dos fármacos , Excitação Neurológica/efeitos dos fármacos , Putamen/efeitos dos fármacos , Animais , Bicuculina/farmacologia , Estimulação Elétrica , Eletroencefalografia , Masculino , Microinjeções , Ratos , Ratos Endogâmicos , Ácido gama-Aminobutírico/fisiologiaRESUMO
Bilateral clamping of the carotid arteries (BCCA) for 24 min protects animals against convulsive effects of intraperitoneal injection of 300 mg/kg of pilocarpine when administered 14 days after surgery. Electrographic recordings from hippocampus, frontal cortex, striatum and substantia nigra demonstrate that (1) no spontaneous spiking activity is caused by the BCCA when observed for up to 10 days after surgery, (2) spiking activity can only be recorded in limbic structures but not in the frontal cortex after systemic administration of pilocarpine. These observations suggest that the propagation of seizure activity from subcortical limbic structures to the neocortex is affected by BCCA.