RESUMO
Schizophrenia patients exhibit dysfunctional gamma oscillations in response to simple auditory stimuli or more complex cognitive tasks, a phenomenon explained by reduced NMDA transmission within inhibitory/excitatory cortical networks. Indeed, a simple steady-state auditory click stimulation paradigm at gamma frequency (~40 Hz) has been reproducibly shown to reduce entrainment as measured by electroencephalography (EEG) in patients. However, some investigators have reported increased phase locking factor (PLF) and power in response to 40 Hz auditory stimulus in patients. Interestingly, preclinical literature also reflects this contradiction. We investigated whether a graded deficiency in NMDA transmission can account for such disparate findings by administering subanesthetic ketamine (1-30 mg/kg, i.v.) or vehicle to conscious rats (n=12) and testing their EEG entrainment to 40 Hz click stimuli at various time points (~7-62 min after treatment). In separate cohorts, we examined in vivo NMDA channel occupancy and tissue exposure to contextualize ketamine effects. We report a robust inverse relationship between PLF and NMDA occupancy 7 min after dosing. Moreover, ketamine could produce inhibition or disinhibition of the 40 Hz response in a temporally dynamic manner. These results provide for the first time empirical data to understand how cortical NMDA transmission deficit may lead to opposite modulation of the auditory steady-state response (ASSR). Importantly, our findings posit that 40 Hz ASSR is a pharmacodynamic biomarker for cortical NMDA function that is also robustly translatable. Besides schizophrenia, such a functional biomarker may be of value to neuropsychiatric disorders like bipolar and autism spectrum where 40 Hz ASSR deficits have been documented.
Assuntos
Córtex Cerebral/fisiologia , Potenciais Evocados Auditivos , Ritmo Gama , Receptores de N-Metil-D-Aspartato/fisiologia , Estimulação Acústica , Animais , Biomarcadores , Córtex Cerebral/efeitos dos fármacos , Maleato de Dizocilpina/farmacocinética , Eletroencefalografia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ketamina/administração & dosagem , Masculino , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Processamento de Sinais Assistido por ComputadorRESUMO
BACKGROUND: Previous studies have found that the local anesthetic/sodium channel blocker lidocaine decreased MAC by maximum amounts approximately equal to the decreases produced by dizocilpine (MK-801), a N-methyl-d-aspartate (NMDA) receptor antagonist. Blockade of sodium channels by inhaled anesthetics has been suggested as a possible cause for impairment of transmission through NMDA receptors. We postulated that the net effect of lidocaine and MK-801 on MAC would be the same, albeit by affecting NMDA neurotransmission at different points. METHODS: We measured the effect of various lidocaine infusions on the MAC of cyclopropane, halothane, isoflurane, and o-difluorobenzene in rats. We also measured the effect of concurrent lidocaine-MK-801 infusion on the MAC of isoflurane and o-difluorobenzene. RESULTS: Our data contradicted our predictions. (a) We found no limit to the effect of lidocaine infusion, in some cases finding that lidocaine, alone, produced immobility; (b) lidocaine infusion did not decrease the MAC of o-difluorobenzene differently from the MAC of other inhaled anesthetics; and (c) the addition of MK-801 equally affected the decrease in MAC produced by lidocaine infusion for isoflurane versus o-difluorobenzene. CONCLUSION: Lidocaine does not primarily decrease MAC by decreasing the release of glutamate from nerve terminals.
Assuntos
Maleato de Dizocilpina/farmacocinética , Lidocaína/farmacocinética , Animais , Maleato de Dizocilpina/sangue , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Medicamentosas/fisiologia , Lidocaína/sangue , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
I and coauthor previously reported the memory facilitation effect of morphine. The main purpose of this study was to evaluate the involvement of the N-methyl-D-aspartate (NMDA) receptor in associative tolerance to morphine by a contextual procedure. Antinociceptive response latency was measured by the tail-pinch method during repeated morphine (5 mg/kg, s.c.) injection for four consecutive days with pretreatment by dizocilpine (0.01, 0.05, 0.1 mg/kg, i.p.) at 30 min prior to morphine injection in the training phase and before and after morphine injection in the test phase. The nociceptive response latency was shortened by the single administration of dizocilpine (0.05 to 0.25 mg/kg, i.p.). Pretreatment by dizocilpine at 0.05 or 0.1 mg/kg weakened the antinociception to morphine on Day 1, but decreased the tolerance throughout the training phase. In the test phase, the animals were allocated into the same and different contexts. In the test phase, hyperalgesia before morphine injection in the same context and antinociception after morphine injection in the different context were evident in the saline-pretreated group in the training phase, but they were not observed in those contexts in the dizocilpine-pretreated groups. These results suggest that memory dysfunction with dizocilpine inhibits the recovery of associative tolerance to morphine by contextual change.
Assuntos
Maleato de Dizocilpina/farmacocinética , Memória/efeitos dos fármacos , Morfina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Maleato de Dizocilpina/administração & dosagem , Maleato de Dizocilpina/efeitos adversos , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos/métodos , Tolerância a Medicamentos/fisiologia , Hiperalgesia/fisiopatologia , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Memória/fisiologia , Camundongos , Morfina/administração & dosagem , Morfina/antagonistas & inibidores , Dor/tratamento farmacológico , Dor/fisiopatologia , Limiar da Dor/psicologia , Tempo de Reação/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/administração & dosagem , Cauda/efeitos dos fármacos , Cauda/lesões , Cauda/fisiopatologiaRESUMO
NMDA receptors, an ionotropic subtype of glutamate receptors (GluRs), play an important role in excitatory neurotransmission, synaptic plasticity, and brain development. They are composed of the GluRzeta subunit (NR1) combined with any one of four GluRepsilon subunits (GluRepsilon1-GluRepsilon4; NR2A-NR2D). Although the GluRzeta subunit exists in the majority of the CNS throughout all stages of development, the GluRepsilon subunits are expressed in distinct temporal and spatial patterns. In the present study, we investigated neuronal functions in mice lacking the embryonic GluRepsilon4 subunit. GluRepsilon4 mutant mice exhibited reductions of [(3)H]MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] binding and (45)Ca(2+) uptake through the NMDA receptors. The expression of GluRzeta subunit protein, but not GluRepsilon1 and GluRepsilon2 subunit proteins, was reduced in the frontal cortex and striatum of the mutant mice. A postmortem examination in GluRepsilon4 mutant mice revealed that tissue contents of norepinephrine, dopamine, serotonin, and their metabolites were reduced in the hippocampus and that dopamine, as well as serotonin, metabolism was upregulated in the frontal cortex, striatum, hippocampus, and thalamus. To clarify the phenotypical influences of the alteration in neuronal functions, performances in various behavioral tests were examined. GluRepsilon4 mutant mice showed reduced spontaneous locomotor activity in a novel environment and less sensitivity to stress induced by the elevated plus-maze, light-dark box, and forced swimming tests. These findings suggest that GluRepsilon4 mutant mice have dysfunctional NMDA receptors and altered emotional behavior probably caused by changes in monoaminergic neuronal activities in adulthood.
Assuntos
Monoaminas Biogênicas/metabolismo , Neurônios/metabolismo , Subunidades Proteicas , Receptores de N-Metil-D-Aspartato/metabolismo , Estresse Fisiológico/fisiopatologia , Animais , Comportamento Animal/fisiologia , Radioisótopos de Cálcio/farmacocinética , Corpo Estriado/metabolismo , Maleato de Dizocilpina/metabolismo , Maleato de Dizocilpina/farmacocinética , Emoções/fisiologia , Antagonistas de Aminoácidos Excitatórios/metabolismo , Glicina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Atividade Motora/fisiologia , N-Metilaspartato/farmacologia , Prosencéfalo/química , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismo , Receptores de N-Metil-D-Aspartato/deficiência , Receptores de N-Metil-D-Aspartato/genética , Comportamento Espacial/fisiologia , Estresse Fisiológico/genética , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/metabolismoRESUMO
Linalool is a monoterpene compound reported to be a major component of essential oils of several aromatic species. Several linalool-producing species are used in traditional medical systems for sedative purposes, including the interruption and prevention of seizures. Previous studies in mice revealed that linalool modulates glutamatergic (competitive antagonism of L-[(3)H]glutamate binding, delayed intraperitoneal NMDA-induced convulsions and blockade of intracerebroventricular Quin-induced convulsions) and GABAergic transmission (protection against pentylenetetrazol and picrotoxin-induced convulsions). To further clarify the anticonvulsive mechanisms of linalool, we studied the effects of linalool on binding of [(3)H]MK801 (NMDA antagonist) and [(3)H]muscimol (GABA(A) agonist) to mouse cortical membranes. Linalool showed a dose dependent non-competitive inhibition of [(3)H]MK801 binding (IC(50) = 2.97 mM) but no effect on [(3)H]muscimol binding. The data suggest that the anticonvulsant mode of action of linalool includes a direct interaction with the NMDA receptor complex. The data do not, however, support a direct interaction of linalool with GABA(A) receptors, although changes in GABA-mediated neuronal inhibition or effects on GABA release and uptake cannot be ruled out.
Assuntos
Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Maleato de Dizocilpina/farmacocinética , Agonistas GABAérgicos/farmacocinética , Monoterpenos , Muscimol/farmacocinética , Plantas Medicinais , Receptores de N-Metil-D-Aspartato/agonistas , Terpenos/farmacologia , Monoterpenos Acíclicos , Animais , Masculino , Camundongos , Óleos de Plantas/farmacologia , TrítioRESUMO
In the present study, we have investigated the effects of centrally administered ginsenoside Rc and Rg1 on the modulation of the NMDA receptor and GABA(A)receptor binding in rat brain. The NMDA receptor binding was analysed by quantitative autoradiography using [(3)H]MK-801 binding, and the GABA(A)receptor bindings were analysed by using [(3)H]muscimol and [(3)H]flunitrazepam binding in rat brain slices. Rats were infused with ginsenoside Rc or Rg1 (10 microg/10 microl h(-1), i.c.v.) for 7 days, through pre-implanted cannula using osmotic minipumps (Alzet, model 2ML). The levels of [(3)H]MK-801 binding were highly decreased in part of the parietal layers of the cortex and cingulated by ginsenoside Rc and Rg1. The levels of [(3)H]muscimol binding were strongly elevated in almost all regions of the frontal cortex by the treatment of ginsenoside Rc but decreased by ginsenoside Rg1. However, the [(3)H]flunitrazepam binding was not modulated by ginsenoside Rc or Rg1 infusion. These results suggest that prolonged infusion of ginsenosides could differentially modulate [(3)H]MK-801 and [(3)H]muscimol binding in a region-specific manner.