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1.
Neuropharmacology ; 119: 141-156, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28400257

RESUMEN

In vivo, theta (4-7 Hz) and gamma (30-80 Hz) neuronal network oscillations are known to coexist and display phase-amplitude coupling (PAC). However, in vitro, these oscillations have for many years been studied in isolation. Using an improved brain slice preparation technique we have, using co-application of carbachol (10 µM) and kainic acid (150 nM), elicited simultaneous theta (6.6 ± 0.1 Hz) and gamma (36.6 ± 0.4 Hz) oscillations in rodent primary motor cortex (M1). Each oscillation showed greatest power in layer V. Using a variety of time series analyses we detected significant cross-frequency coupling in 74% of slice preparations. Differences were observed in the pharmacological profile of each oscillation. Thus, gamma oscillations were reduced by the GABAA receptor antagonists, gabazine (250 nM and 2 µM), and picrotoxin (50 µM) and augmented by AMPA receptor antagonism with SYM2206 (20 µM). In contrast, theta oscillatory power was increased by gabazine, picrotoxin and SYM2206. GABAB receptor blockade with CGP55845 (5 µM) increased both theta and gamma power, and similar effects were seen with diazepam, zolpidem, MK801 and a series of metabotropic glutamate receptor antagonists. Oscillatory activity at both frequencies was reduced by the gap junction blocker carbenoxolone (200 µM) and by atropine (5 µM). These data show theta and gamma oscillations in layer V of rat M1 in vitro are cross-frequency coupled, and are mechanistically distinct. The development of an in vitro model of phase-amplitude coupled oscillations will facilitate further mechanistic investigation of the generation and modulation of coupled activity in mammalian cortex.


Asunto(s)
Ritmo Gamma/fisiología , Corteza Motora/fisiología , Ritmo Teta/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Animales Recién Nacidos , Carbacol/farmacología , Agonistas Colinérgicos/farmacología , Relación Dosis-Respuesta a Droga , Agonistas de Aminoácidos Excitadores , Ritmo Gamma/efectos de los fármacos , Técnicas In Vitro , Ácido Kaínico/farmacología , Masculino , Corteza Motora/efectos de los fármacos , Neurotransmisores/farmacología , Ratas , Ratas Wistar , Receptores de GABA/metabolismo , Ritmo Teta/efectos de los fármacos
2.
J Pharmacol Toxicol Methods ; 57(2): 114-30, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18155613

RESUMEN

INTRODUCTION: In search for a suitable rat model to study potentially affected blood-brain barrier (BBB) transport mechanisms in the course of Parkinsons disease (PD) progression, experiments were performed to characterise Parkinsons disease markers following subcutaneous (SC) and intracerebral (IC) infusion of the toxin rotenone in the rat. METHODS: Studies were performed using Male Lewis rats. SC infusion of rotenone (3 mg/kg/day) was performed via an osmotic minipump. IC infusion of rotenone occurred directly into the right medial forebrain bundle at three different dosages. At different times following rotenone infusion, behaviour, histopathology (tyrosine hydroxylase and alpha-synuclein immunocytochemistry), peripheral organ pathology (adrenals, heart, kidney, liver, lung, spleen and stomach) were assessed. In part of the SC and IC rats, BBB transport profiles of the permeability marker sodium fluorescein were determined using microdialysis. RESULTS: SC rotenone failed to produce dopaminergic lesions and led to extensive peripheral organ toxicity. BBB permeability for fluorescein following SC rotenone was changed, however due peripheral toxicity. In contrast, IC rotenone produced a progressive lesion of the nigrostrial dopaminergic pathway over 28 days with no associated peripheral toxicity. IC rotenone also exhibited a large increase in amphetamine induced rotational behaviour. In addition, a few IC rats showed alpha-synuclein immunoreactivity and aggregation. Following IC rotenone, no changes in BBB permeability were detected after 14 days. DISCUSSION: SC rotenone only produced peripheral toxicity. IC rotenone appeared to create a progressive lesion of the rat nigrostrial pathway, and may therefore be a more appropriate model of Parkinson's disease progression, compared with the most commonly used 6-OH-DA rat model.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Fluoresceína/farmacocinética , Colorantes Fluorescentes/farmacocinética , Neurotoxinas , Enfermedad de Parkinson Secundaria/inducido químicamente , Rotenona , Análisis de Varianza , Animales , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Conducta Animal , Transporte Biológico , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Bombas de Infusión Implantables , Masculino , Microdiálisis , Actividad Motora , Neurotoxinas/administración & dosificación , Neurotoxinas/toxicidad , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/psicología , Ratas , Ratas Endogámicas Lew , Rotenona/administración & dosificación , Rotenona/toxicidad
3.
Psychopharmacology (Berl) ; 186(1): 64-81, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16550385

RESUMEN

RATIONALE: Ketamine induces, in both humans and rodents, behaviours analogous to some of the symptoms of schizophrenia. OBJECTIVES: To utilise pharmacological magnetic resonance imaging (phMRI) techniques that identify changes in blood-oxygenation-level-dependent (BOLD) contrast to determine the temporal and spatial neuronal activation profile of ketamine in the rat brain. METHOD: To obtain a pharmacodynamic profile of the drug, we assessed changes in locomotor activity after vehicle and 10 and 25 mg/kg ketamine. Separate animals were then anaesthetised and placed in a 4.7-T magnetic resonance (MR) system before receiving the same doses of ketamine during serial MR image acquisition. Subsequent statistical parametric mapping of the main effect of the drug was then undertaken to identify changes in BOLD contrast. Levels of gamma-aminobutyric acid (GABA) and dopamine (DA) in brain areas showing localised changes in BOLD contrast were then assessed via microdialysis. RESULTS: Both doses of ketamine produced increases in BOLD image contrast in frontal, hippocampal, cortical and limbic areas. A further investigation of the release of DA and its metabolites in the nucleus accumbens, both in anaesthesised and freely moving rats, corroborated these findings. However, an investigation of GABA and DA levels in the ventral pallidum gave no indication of changes in activity. CONCLUSIONS: Ketamine produced localised dose-dependent alterations in BOLD MR signal, which correlate with the pharmacodynamic profile of the drug. These results can be, at least, partially substantiated with complementary techniques but consideration must be given to the input function applied to the MR signal and the use of anaesthesia during phMRI experimentation.


Asunto(s)
Encéfalo/efectos de los fármacos , Ketamina/farmacología , Actividad Motora/efectos de los fármacos , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Encéfalo/fisiología , Dopamina/metabolismo , Imagen por Resonancia Magnética , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Ácido gamma-Aminobutírico/metabolismo
4.
Nat Neurosci ; 5(8): 796-804, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12080343

RESUMEN

Developments in the molecular biology and pharmacology of GLU(K5), a subtype of the kainate class of ionotropic glutamate receptors, have enabled insights into the roles of this subunit in synaptic transmission and plasticity. However, little is known about the possible functions of GLU(K5)-containing kainate receptors in pathological conditions. We report here that, in hippocampal slices, selective antagonists of GLU(K5)-containing kainate receptors prevented development of epileptiform activity--evoked by the muscarinic agonist, pilocarpine--and inhibited the activity when it was pre-established. In conscious rats, these GLU(K5) antagonists prevented and interrupted limbic seizures induced by intra-hippocampal pilocarpine perfusion, and attenuated accompanying rises in extracellular L-glutamate and GABA. This anticonvulsant activity occurred without overt side effects. GLU(K5) antagonism also prevented epileptiform activity induced by electrical stimulation, both in vitro and in vivo. Therefore, we propose that subtype-selective GLU(K5) kainate receptor antagonists offer a potential new therapy for epilepsy.


Asunto(s)
Epilepsia/prevención & control , Antagonistas de Aminoácidos Excitadores/farmacología , Sistema Límbico/efectos de los fármacos , Pilocarpina , Receptores de Ácido Kaínico/antagonistas & inhibidores , Potenciales de Acción/efectos de los fármacos , Animales , Línea Celular , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Estimulación Eléctrica , Electrochoque , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Humanos , Técnicas In Vitro , Isoquinolinas/farmacología , Ácido Kaínico/farmacología , Sistema Límbico/fisiopatología , Masculino , Ratones , Ratas , Ratas Wistar , Especificidad por Sustrato , Resultado del Tratamiento
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