RESUMEN
INTRODUCTION: schizophrenia (SCH) is a heterogeneous syndrome characterized by positive and negative symptoms. Despite appropriate medication, about 1/4 of patients suffer for refractory positive and/or negative symptoms, which are associated with functional handicap, increase of duration and of the number of hospitalizations. Numerous studies have suggested that the pathophysiology of auditory hallucinations (AH) is related to a hyper activity of the left temporoparietal cortex (TPC). On the other hand, negative symptoms are associated with a prefrontal hypoactivity and the efficiency of pharmacological treatments is frequently partial. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation tool with excellent tolerability and safety. Given its hypothesized mechanisms of action and the clinical beneficial effects obtained in several types of pathology (Aleman et al. 2007), the efficacy of rTMS has been investigated for drug-resistant SCH symptoms. OBJECTIVE: our objective is to expose the knowledge concerning the rTMS use in the treatment of these symptoms and to purpose a critical analysis of these data. METHOD: a systematic review of the literature has been conducted using NIH Pubmed. The following search terms were used: TMS - rTMS - Schizophrenia - negative symptoms - hallucinations. RESULTS: concerning the treatment of AH, 16 publications and 4 meta analyses were selected. For the negative symptoms, we retained 16 studies and 3 meta analyses. The most extensively investigated application for rTMS in SCH is the use of low-frequency stimulation to the left TPC with the aim to improve AH symptomatology. When compared to sham, this type of acute course of rTMS has been proven to induce a substantial and significant reduction in AH. But this effect does not seem long-lasting and maintenance protocols must be developed. Concerning negative symptoms, the results are less solid but we find some works which demonstrate an improvement of these symptoms while various stimulation parameters were used. Recently, new parameters of stimulation in particular the theta burst stimulation have permitted us to obtain larger effects with longer duration. The interest of these new parameters will be discussed here. CONCLUSION: overall, rTMS studies have demonstrated some promise in the treatment of SCH. However, more research is required to enhance rTMS efficacy and increase its beneficial effect duration and to test new therapeutic strategies in this topic.
Asunto(s)
Esquizofrenia/terapia , Psicología del Esquizofrénico , Estimulación Magnética Transcraneal , Dominancia Cerebral/fisiología , Estudios de Seguimiento , Humanos , Lóbulo Parietal/fisiopatología , Esquizofrenia/diagnóstico , Esquizofrenia/fisiopatología , Lóbulo Temporal/fisiopatologíaRESUMEN
Recently evidence has accumulated that schizophrenia can arise from primary synaptic defects involving structural proteins particularly, microtubule associated proteins. Previous experiments have demonstrated that a STOP (stable tubule only peptide) gene deletion in mice leads to a phenotype mimicking some aspects of positive symptoms classically observed in schizophrenic patients. In the current study, we determined if STOP null mice demonstrate behavioral abnormalities related to the social and cognitive impairments of schizophrenia. Compared with wild-type mice, STOP null mice exhibited deficits in the non-aggressive component of social recognition, short term working memory and social and spatial learning. As described in humans, learning deficits in STOP null mice were poorly sensitive to long term treatment with typical neuroleptics. Since social and cognitive dysfunction have consistently been considered as central features of schizophrenia, we propose that STOP null mice may provide a useful model to understand the neurobiological correlates of social and cognitive defects in schizophrenia and to develop treatments that better target these symptoms.
Asunto(s)
Antipsicóticos/farmacología , Cognición/fisiología , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/fisiología , Esquizofrenia/genética , Psicología del Esquizofrénico , Conducta Social , Animales , Conducta Alimentaria/fisiología , Relaciones Interpersonales , Aprendizaje/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Noqueados , Desempeño Psicomotor/fisiología , Reconocimiento en Psicología/fisiología , Olfato/fisiología , Percepción Espacial/fisiologíaRESUMEN
We used intracerebral microdialysis coupled with electrophysiologic recordings to determine relative changes in the concentrations of several neurotransmitters in the medial prefrontal cortex and nucleus accumbens of freely moving rats during waking, slow-wave sleep, and rapid eye movement (REM) sleep. The concentrations of noradrenaline, dopamine, glutamate, and aspartate in 2-min dialysate samples were analyzed by capillary electrophoresis combined with laser-induced fluorescence detection. Changes in glutamate and aspartate concentrations were found only in the nucleus accumbens, in which a decrease was obtained during both slow-wave sleep and REM sleep compared to waking. A progressive reduction in the release of noradrenaline was observed from waking to REM sleep in both structures. In contrast, dopamine concentrations were higher during waking and REM sleep compared to that during slow-wave sleep. The latter results demonstrate that contrary to the findings of earlier electrophysiologic studies carried out on ventral tegmental area dopaminergic neurons, changes in the release of dopamine in projection areas occur across the sleep-wake cycle. The elevated levels of dopamine during waking and REM sleep in the medial prefrontal cortex and the nucleus accumbens could result from changes during these two states in afferent modulation at the level of cell bodies or at the level of dopaminergic terminals.
Asunto(s)
Ácido Aspártico/metabolismo , Dopamina/metabolismo , Espacio Extracelular/metabolismo , Ácido Glutámico/metabolismo , Norepinefrina/metabolismo , Núcleo Accumbens/metabolismo , Corteza Prefrontal/metabolismo , Sueño/fisiología , Vigilia/fisiología , Animales , Electroforesis Capilar , Electrofisiología , Masculino , Microdiálisis , Polisomnografía , Ratas , Ratas Wistar , Sueño REM/fisiologíaRESUMEN
An important concern about microdialysis methodology is the histological validation of the dialysis probe implantation site in brain tissue of rodents (rat, mouse). Several methods have been described on standard histological staining (i.e., cresyl violet, formalin fixation, fast green perfusion, etc.). However, this methodology is time consuming. These requirements are not compatible with a histological validation prior to analysis of microdialysis samples. Here, we developed a new method to locate the track of the dialysis probe in the rodent brain. This method is based on a digital photomicrograph of a coronal section of the rodent frozen brain. The fitting of an appropriate coronal diagram of the rats' and mice' brain atlas with this photomicrograph, allowed us to locate precisely and quickly the track of the dialysis probe.
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Anatomía Artística/métodos , Mapeo Encefálico/métodos , Encéfalo/anatomía & histología , Encéfalo/cirugía , Ilustración Médica , Microdiálisis/instrumentación , Microdiálisis/métodos , Fotomicrografía/métodos , Anatomía Artística/instrumentación , Animales , Encéfalo/fisiología , Mapeo Encefálico/instrumentación , Masculino , Ratones , Ratones Endogámicos C57BL , Microelectrodos/normas , Fotomicrografía/instrumentación , Ratas , Ratas Wistar , Especificidad de la Especie , Técnicas Estereotáxicas/tendencias , Factores de TiempoRESUMEN
In vivo microdialysis was used to investigate the interactions between dopamine (DA), glutamate (Glu) and aspartate (Asp) in anaesthetised-rat striatum. The combination of brain microdialysis and capillary electrophoresis with laser-induced fluorescence detection (CE-LIFD) allows the simultaneous monitoring of the efflux of these neurotransmitters up to every 10 s. DA and Glu reuptake inhibitors, nomifensine and L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) and, dopaminergic and glutamatergic receptor agonists, apomorphine and NMDA respectively, were administered by reverse dialysis. Reverse dialysis of 20 micro M nomifensine induced a rapid and marked increase (+3200% at 5 min) in extracellular DA, while a decrease in Glu and Asp (-11 and -25%, respectively) was observed simultaneously. Reverse dialysis of 10 micro M apomorphine led to progressive changes: -63% decrease in DA and +25% Glu increase at 36 min. Reverse dialysis of 1 mM NMDA induced a simultaneous increase in DA, Glu and Asp which peaked at +2 min (+840%, +40% and +150%, respectively). Surprisingly, a second increase in Glu was observed 5 min after the end of NMDA perfusion. Reverse dialysis of PDC (1 mM and 10 mM) induced a rapid increase in Glu and Asp levels, while DA increased with a 26-s delay. These findings indicate that, in the striatum, endogenous DA and Glu may act in opposition to regulate each other's efflux. These results have been obtained due to unique features offered by microdialysis coupled with CE-LIFD.
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Apomorfina/farmacología , Ácido Aspártico/metabolismo , Ácidos Dicarboxílicos/farmacología , Agonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Agonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/metabolismo , N-Metilaspartato/farmacología , Neostriado/metabolismo , Inhibidores de la Captación de Neurotransmisores/farmacología , Nomifensina/farmacología , Pirrolidinas/farmacología , Animales , Electrodos Implantados , Electroforesis Capilar , Masculino , Microdiálisis , Neostriado/efectos de los fármacos , Sistemas en Línea , Ratas , Ratas Sprague-DawleyRESUMEN
Continuous amperometry coupled with untreated carbon-fibre electrodes was used in anaesthetized rats to measure the noradrenaline release evoked in the anteroventral thalamic nucleus by electrical stimulation of the dorsal noradrenergic bundle. As expected, the variations in the oxidation current detected in the anteroventral thalamic nucleus exhibited the characteristics of the in vivo noradrenaline release. They were closely correlated with stimulation and consistent with the anatomy of the noradrenergic system involved. They were abolished by the ejection of tetrodotoxin in the vicinity of the carbon-fibre electrode, diminished by clonidine, an alpha-2 agonist, and restored by yohimbine, an alpha-2 antagonist. Furthermore, the time course of these variations was dramatically increased by desipramine, a specific noradrenaline reuptake blocker. In contrast, neither dopamine nor serotonin reuptake blockers, nor the monoamine oxidase inhibitor pargyline were able to alter them. The main advantage of the present approach is its excellent time resolution. We show here for the first time that after single pulse stimulation, noradrenaline is released and eliminated in 118 milliseconds, this time lapse corresponding to the maximal period beyond which subsequent noradrenaline releases could not add up. These observations are in good agreement with the physiological relationship previously observed between impulse flow and noradrenaline overflow.
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Núcleos Talámicos Anteriores/metabolismo , Norepinefrina/metabolismo , Inhibidores de Captación Adrenérgica/administración & dosificación , Agonistas alfa-Adrenérgicos/administración & dosificación , Antagonistas Adrenérgicos alfa/administración & dosificación , Animales , Estimulación Eléctrica , Electroquímica , Electrodos Implantados , Espacio Extracelular/química , Espacio Extracelular/metabolismo , Masculino , Microinyecciones , Inhibidores de la Monoaminooxidasa/administración & dosificación , Norepinefrina/análisis , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Tetrodotoxina/administración & dosificación , Factores de TiempoRESUMEN
SR-142948A belongs to the second generation of potent, selective, non-peptide antagonists of neurotensin receptors. It was used to investigate the role of endogenous neurotensin in the regulation of dopamine efflux in the nucleus accumbens and striatum of anaesthetized and pargyline-treated rats. All the data were obtained using in vivo electrochemistry. Electrically evoked (20 Hz, 10 s) dopamine efflux was monitored by differential pulse amperometry, whereas variations in basal (tonic) dopamine efflux were monitored by differential normal pulse voltammetry. Like the first-generation compound SR-48692, SR-142948A did not affect the tonic and evoked dopamine efflux, but dose-dependently enhanced haloperidol (50 microg/kg, i.p.) induced facilitation of the electrically evoked dopamine release in the nucleus accumbens. In contrast to SR-48692, SR-142948A dose-dependently potentiated haloperidol (50 microg/kg, i.p.) induced increase in the basal dopamine level in the nucleus accumbens. This potentiating effect did not appear in the striatum. When dopaminergic and/or neurotensinergic transmissions were modified by a higher dose of haloperidol (0.5 mg/kg, i.p.), apomorphine, amphetamine or nomifensine, SR-142948A pre-treatment affected only the effect of apomorphine on the basal dopamine level in the nucleus accumbens. These results strengthen the hypothesis that endogenous neurotensin could exert a negative control on mesolimbic dopamine efflux.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/farmacología , Dopamina/metabolismo , Imidazoles/farmacología , Neurotensina/metabolismo , Núcleo Accumbens/metabolismo , Receptores de Neurotensina/antagonistas & inhibidores , Animales , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Electroquímica , Haloperidol/farmacología , Masculino , Núcleo Accumbens/efectos de los fármacos , Pirazoles/farmacología , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley , Estimulación QuímicaRESUMEN
Ejections of 10(-5)-10(-3)M neurotensin into the ventral tegmental area increased dopamine efflux measured by electrochemical approaches in the prefrontal cortex of anaesthetized rats. In the same conditions, the effects evoked on dopamine efflux by 10(-5)M neurotensin(8-13) and [D-Tyr(11)]neurotensin were different from each other and depended on the explored area: the prefrontal cortex and the caudal and rostral nucleus accumbens. In the prefrontal cortex, neurotensin(8-13) was as potent as neurotensin, whereas [D-Tyr(11)]neurotensin was ineffective. In the caudal nucleus accumbens, when considering the initial intensity of the effect, neurotensin(8-13) and neurotensin appeared more potent than [D-Tyr(11)]neurotensin. In contrast, in the rostral nucleus accumbens, neurotensin(8-13) was less potent than [D-Tyr(11)]neurotensin and neurotensin. These results support the differential involvement of two pharmacologically distinct neurotensin receptor entities on ventral tegmental area neurons in the modulation of mesolimbic and mesocortical dopaminergic activity.
Asunto(s)
Dopamina/metabolismo , Neurotensina/farmacología , Núcleo Accumbens/metabolismo , Fragmentos de Péptidos/farmacología , Corteza Prefrontal/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Animales , Electroquímica , Espacio Extracelular/metabolismo , Masculino , Microinyecciones , Neurotensina/análogos & derivados , Ratas , Ratas Sprague-DawleyRESUMEN
The time-course of variations in extracellular dopamine concentration following local pressure ejection of 10(-7) to 10(-3) M neurotensin into the ventral tegmental area of the rat was determined in the minute range in the nucleus accumbens by means of differential normal pulse voltammetry associated with carbon fibre electrodes. The effects of neurotensin ejection into the ventral tegmental area were further investigated on the firing activity of the corresponding dopaminergic neurons. The lowest concentration of neurotensin (10(-7) M) enhanced the extracellular dopamine concentration throughout the nucleus accumbens and stimulated the discharge activity of ventral tegmental area dopaminergic neurons. The two highest concentrations of neurotensin (10(-5) M and 10(-3) M) evoked two patterns of responses on the extracellular dopamine concentration and on the discharge activity of dopaminergic neurons. The extracellular dopamine concentration was increased above basal levels in the caudal part of the nucleus accumbens. In the rostral part, the evoked changes exhibited a multiphasic time-course characterized by a decreasing phase below baseline. The firing rate of dopaminergic neurons was either increased or decreased, depending on the neuron being tested. In fact, neurotensin ejection was always followed by an exacerbation of bursting activity, the resulting effect on the mean firing rate being related to the duration of the interburst intervals. Indeed, short interburst intervals permitted an increase in mean firing rate whereas long interburst intervals, indicative of excessive depolarization, led to a decrease in mean firing rate. These results suggest that variations in extracellular dopamine concentration evoked by neurotensin administration into the ventral tegmental area are the result of neurotensin-evoked changes in dopaminergic activity. Moreover, the differential effects evoked by high concentrations of neurotensin could be attributable to two subpopulations of ventral tegmental area dopaminergic neurons which could project differentially to the caudal and the rostral parts of the nucleus accumbens.
Asunto(s)
Dopamina/metabolismo , Neurotensina/farmacología , Núcleo Accumbens/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Electroquímica , Electrofisiología , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Masculino , Neuronas/efectos de los fármacos , Núcleo Accumbens/citología , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Área Tegmental Ventral/fisiologíaRESUMEN
The dopamine overflow evoked by trains of electrical stimulation pulses applied to the ascending dopaminergic pathway was measured with continuous amperometry in the striatum of anesthetised rats. As previously observed in in vitro studies, a pulse by pulse analysis showed a fall in dopamine overflow evoked by pulses 2 to 6, compared to the response evoked by pulse 1. However, in contrast with in vitro findings, the present in vivo data showed that the dopamine receptor antagonist haloperidol i) completely reverses the fall in dopamine overflow between pulse 1 and subsequent pulses, ii) enhances the dopamine overflow elicited by pulse 1. These results suggest that in vivo, both basal and pulse-evoked dopamine overflow results in stimulation of dopamine D2-type autoreceptors and therefore in regulation of dopamine release.
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Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Receptores de Dopamina D2/fisiología , Animales , Cuerpo Estriado/ultraestructura , Antagonistas de Dopamina/farmacología , Estimulación Eléctrica , Haloperidol/farmacología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
SR 142948A, 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylc arbamoyl)-2-isopropylphenyl)-1H-pyrazole3-carbonyl]amino] adamantane-2-carboxylic acid, hydrochloride, a new and extremely potent neurotensin (NT) receptor antagonist, has been characterized in comparison with SR 48692. This selective compound possesses nanomolar affinities for NT receptors, recognizes the two binding sites described for the NT receptor and fully displaces [3H]SR 48692 specific binding. SR 142948A antagonizes the classical in vitro NT effects, i.e., inositol monophosphate formation in HT 29 cells (IC50 = 3.9 nM) or intracellular calcium mobilization in Chinese hamster ovary cells transfected with the human receptor. It dose-dependently (0.04-640 x 10(-3) mg/kg p.o.) inhibits the turning behavior induced by unilateral intrastriatal injection of NT in mice, with the biphasic profile previously seen for SR 48692. At 0.1 mg/kg (i.p.), it completely antagonizes NT-evoked acetylcholine release in the rat striatum. In contrast to SR 48692, SR 142948A (p.o.) blocks both hypothermia and analgesia induced by i.c.v. injection of NT (mice and/or rats) but is unable to modify the dopamine release evoked by NT injection into the ventral tegmental area. In summary, SR 142948A retains the properties of the lead compound SR 48692 (no intrinsic agonist activity, oral bioavailability, long duration of action and good brain access), reveals a wider spectrum of activity than SR 48692 (probably due to the inhibition of NT receptor subtypes) and represents an additional tool for further exploration of the therapeutic potential of this class of compounds.
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Adamantano/análogos & derivados , Encéfalo/fisiología , Imidazoles/farmacología , Imidazoles/farmacocinética , Neuronas/fisiología , Neurotensina/farmacología , Receptores de Neurotensina/fisiología , Adamantano/farmacocinética , Adamantano/farmacología , Animales , Transporte Axonal , Sitios de Unión , Células CHO , Calcio/metabolismo , Línea Celular , Membrana Celular/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Cricetinae , Dopamina/metabolismo , Femenino , Humanos , Fosfatos de Inositol/metabolismo , Masculino , Ratones , Ratones Endogámicos , Neuronas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Ratas , Ratas Endogámicas , Ratas Sprague-Dawley , Receptores de Neurotensina/antagonistas & inhibidores , Receptores de Neurotensina/biosíntesis , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Conducta Estereotipada/efectos de los fármacos , Sustancia Negra/fisiología , TransfecciónRESUMEN
The release of dopamine in the striatum, nucleus accumbens, and olfactory tubercle of anesthetized rats was evoked by electrical stimulation of the mesolimbic dopaminergic pathway (four pulses at 15 Hz or four pulses at 200 Hz). Carbon fiber electrodes were implanted in these regions to monitor evoked dopamine overflow by continuous amperometry. The kinetics of dopamine elimination were estimated by measuring the time to 50% decay of the dopamine oxidation current after stimulation ceased. This time ranged from 64 ms in the striatum to 113 ms in the nucleus accumbens. Inhibition of dopamine uptake by nomifensine (2-20 mg/kg), GBR 12909 (20 mg/kg), cocaine (20 mg/kg), mazindol (10 mg/kg), or bupropion (25 mg/kg) enhanced this decay time by up to +602%. Uptake inhibition also produced an increase in the maximal amplitude of dopamine overflow evoked by four pulses at 15 Hz. This latter effect was larger in the striatum (+420%) than in mesolimbic areas (+140%). These results show in vivo that these uptake inhibitors actually slow the clearance of dopamine released by action potentials and suggest that dopaminergic transmission is both prolonged and potentiated strongly by these drugs, in particular in the striatum.
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Cuerpo Estriado/metabolismo , Dopamina/farmacocinética , Sistema Límbico/metabolismo , Animales , Inhibidores de Captación de Dopamina/farmacología , Estimulación Eléctrica , Cinética , Masculino , Núcleo Accumbens/metabolismo , Bulbo Olfatorio/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
The paraventricular nucleus (PVN) of the hypothalamus, where the CRF-containing neurosecretory cells controlling the hypothalamo-pituitary-adrenal (HPA) axis are located, receives a dense noradrenergic innervation from the A1 group of the caudal ventrolateral medulla. In the present study we studied the relationship between release of noradrenaline (NA) in the PVN and activation of the HPA axis in response to electrical stimulation of the A1 region. In the urethane-anesthetized male rat, extracellular NA in the PVN was monitored on line by electrochemical recording while the activity of the HPA axis was estimated by measurement of ACTH in blood samples. A 1 min, 10 Hz stimulation evoked a significant increase of extracellular NA in the PVN as well as an ACTH surge in blood. The NA and ACTH response evoked by stimulation in the 3- to 14-Hz range were found to be frequency dependent. However, whilst the NA response increased in an exponential manner with respect to frequency, the ACTH response appeared to plateau between 10 and 14 Hz. Specific lesions of the noradrenergic terminals in the PVN, by bilateral local administration of 6-hydroxydopamine, markedly reduced the ACTH response to stimulation. Intracerebroventricular injection of desmethylimipramine, a NA uptake inhibitor, enhanced the increase in extracellular NA evoked by submaximal stimulation about 2.5-fold but did not modify the corresponding ACTH response. Combined intracerebroventricular injection of alpha- and beta-adrenergic antagonists, phentolamine and propanolol respectively, did not prevent the ACTH response evoked by stimulation. Following stimulation of the caudal ventrolateral medulla, the ACTH response thus appears to result from the stimulation of the A1 noradrenergic group projecting to the PVN. However, the inability of pharmacological manipulations which enhance or block central noradrenergic transmission to influence the ACTH response suggests that the noradrenergic endings in the PVN originating from the A1 group use a transmitter other than NA to activate the HPA axis at the PVN level.
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Estimulación Eléctrica , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Norepinefrina/farmacología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Hormona Adrenocorticotrópica/metabolismo , Animales , Masculino , Fentolamina/farmacología , Propranolol/farmacología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Central dopaminergic neurons exhibit two kinds of discharge activity: single spikes and bursts of two to six action potentials. Since these neurons can switch from one discharge pattern to the other whereas the mean discharge rate remains little affected, bursts may be more potent in triggering the release of their neurotransmitter, dopamine. Electrical stimulations mimicking the bursting pattern were actually twice as potent as regularly spaced stimulations to enhance the dopamine extracellular concentration. This suggested that dopamine release might be facilitated by increasing the impulse flow frequency. The high extracellular overflow evoked by a burst might also be due to accumulation of the released dopamine whereas, at lower frequencies, dopamine might be readily eliminated between every action potential. In the present study the dopamine overflow evoked by electrical stimulation of the dopaminergic pathway was measured in vivo by carbon fibre electrodes combined with continuous amperometry. We observed a small facilitation of the release per pulse during stimulations mimicking a burst but only in mesolimbic areas. The high extra-cellular dopamine level evoked by a burst was mainly due to accumulation of the released dopamine.
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Potenciales de Acción , Cuerpo Estriado/fisiología , Dopamina/fisiología , Neuronas/fisiología , Núcleo Accumbens/fisiología , Vías Olfatorias/fisiología , Animales , Estimulación Eléctrica , Masculino , Nomifensina/farmacología , Ratas , Ratas Sprague-Dawley , Tasa de Secreción/efectos de los fármacosRESUMEN
The release of dopamine in the nucleus accumbens of anaesthetized rats was evoked either by electrical stimulation of the mesolimbic dopaminergic pathway or by local ejection of N-methyl-D-aspartate in the ventral tegmental area. Untreated carbon-fibre electrodes implanted in the nucleus accumbens were held at +400 mV versus a reference electrode, and the oxidation current was continuously monitored. Despite a poor selectivity to dopamine versus other oxidizable compounds such as ascorbic acid, the evoked responses were solely due to dopamine overflow in the extracellular fluid since they were closely correlated with the stimulations and exhibited all the expected characteristics related to a dopamine release. First, these effects were closely consistent with the anatomy of the mesolimbic dopaminergic system. Second, the responses to electrical stimulations were abolished by a tetrodotoxin ejection in the vicinity of the carbon-fibre electrode and they were strongly, but reversibly, diminished (60% decrease) when cadmium was substituted for calcium in an artificial cerebrospinal fluid ejected close to the electrode. Third, their maximal amplitudes were enhanced by amphetamine, pargyline, nomifensine and haloperidol. Fourth, inhibition of dopamine reuptake by nomifensine induced a five-fold decrease in the rate of decline of the evoked oxidation current. Fifth, contribution of noradrenaline and serotonin to the observed effects seems unlikely since specific reuptake blockers (desipramine and sertraline, respectively) did not alter them. Dopaminergic neurons discharge either in a single spike mode with a mean firing rate below 5 Hz or in a bursting pattern (intraburst frequency: 10 to 20 Hz).(ABSTRACT TRUNCATED AT 250 WORDS)
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Dopamina/metabolismo , Electroquímica , Núcleo Accumbens/metabolismo , Fibras Simpáticas Posganglionares/metabolismo , Potenciales de Acción/efectos de los fármacos , Anfetamina/farmacología , Animales , Estimulación Eléctrica , Masculino , Compuestos Nitrosos/farmacología , Nomifensina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
The combination of electrochemically treated carbon-fiber electrodes with DPV, DNPV or DPA represents a wide range of possibilities. As shown in this review, the choice of treatment and measurement technique depends on the purpose. As regards in vivo monitoring of 5-HIAA or DOPAC from very small brain nuclei, electrochemically treated carbon-fiber electrodes appear very potent and inexpensive. The main limitation of the established electrochemical techniques, including those discussed here, is that the unequivocal measurement of the basal extracellular neurotransmitter level cannot be achieved unless animals are treated with pargyline. On the other hand, this monitoring is feasible with in vivo dialysis. Therefore, electrochemical techniques, on the one hand, and in vivo dialysis, on the other hand, present different advantages. The former are much more potent than the latter in two respects. First, due to the much smaller size of the sensor, electrochemical techniques are more suitable for studying small brain nuclei. Second, since electrochemical techniques exhibit a better temporal resolution, they are recommended for investigating the relationship between impulse flow and neurotransmitter release. However, when high anatomical or temporal resolution is not required, in vivo dialysis is more suitable for recording the basal monoamine release.
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Química Encefálica , Catecoles/análisis , Indoles/análisis , Animales , Carbono , Electroquímica , Electrodos , HumanosRESUMEN
The effects of desipramine on sensory-evoked (sciatic nerve stimulation) activation of locus coeruleus neurones were investigated in vivo by using treated carbon-fibre electrodes in conjunction with either differential normal pulse voltammetry or differential pulse amperometry. Firstly, the amplitude of the sensory-evoked increase in extracellular noradrenaline, monitored in thalamic locus coeruleus terminals, was not modified by desipramine (10 mg/kg), whereas that evoked by direct activation of locus coeruleus neurones was greatly increased: +143% for dorsal noradrenergic bundle stimulation and +761% for glutamate ejection in the locus coeruleus. Secondly, desipramine administered at the same dose significantly reduced (-48%) the activation of locus coeruleus neurones (monitored at the somato-dendritic level) evoked by prolonged sciatic nerve stimulation. Our results indicate that acute treatment with desipramine does not potentiate overall noradrenergic transmission by locus coeruleus neurones during sensory stimulation.
Asunto(s)
Desipramina/farmacología , Locus Coeruleus/efectos de los fármacos , Norepinefrina/metabolismo , Núcleos Talámicos/efectos de los fármacos , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Desipramina/administración & dosificación , Estimulación Eléctrica , Electrodos , Glutamatos/farmacología , Ácido Glutámico , Locus Coeruleus/metabolismo , Locus Coeruleus/patología , Masculino , Ratas , Ratas Sprague-Dawley , Nervio Ciático , Núcleos Talámicos/fisiologíaRESUMEN
Noradrenaline release from sympathetic nerve terminals was evoked by electrical nerve stimulation of an isolated segment of rat tail artery. This release was recorded by a carbon fiber electrode combined with differential pulse amperometry. The active part of the electrode (one carbon fiber 8 microns in diameter and 50 microns in length) was placed in close contact with the arterial surface. The oxidation current appearing at +120 mV and corresponding to the local noradrenaline concentration at the electrode surface was recorded every 0.5 s. No oxidation current was detected under resting conditions, but electrical stimulation evoked an immediate increase in this current. This response was suppressed when tetrodotoxin was added to the perfusion medium and was enhanced when noradrenaline reuptake was inhibited by cocaine. The amplitude of the response was increased with increasing stimulation frequencies (2-25 Hz) and train lengths (1-16 pulses). Finally, the time resolution of the method (0.5 s) was good enough to show that noradrenaline release precedes the postsynaptic response, i.e., the electrically evoked contraction of the artery.
Asunto(s)
Arterias/inervación , Terminaciones Nerviosas/metabolismo , Norepinefrina/metabolismo , Sistema Nervioso Simpático/metabolismo , Animales , Cocaína/farmacología , Estimulación Eléctrica , Electroquímica , Electrodos , Guanetidina/farmacología , Cinética , Contracción Muscular , Oxidación-Reducción , Ratas , Sistema Nervioso Simpático/efectos de los fármacos , Cola (estructura animal)/irrigación sanguínea , Tetrodotoxina/farmacologíaRESUMEN
The anteroventral thalamic nucleus is innervated by noradrenergic terminals exclusively originating in the locus coeruleus, a densely packed cell group located in the dorsotegmental part of the pons. In urethane-anaesthetized rats, electrical stimulations of locus coeruleus axons (dorsal noradrenergic bundle; 14 Hz, 20 s) evoked a rapid increase in the signal (catechol oxidation current) measured within the anteroventral thalamic nucleus by the use of carbon fibre electrodes combined with electrochemistry. This effect was reproducible and immediately reversible. Evoked changes in this current were found to be due to oxidation of noradrenaline released from terminals. The amplitude of the evoked noradrenaline release varied non-linearly with the frequency of stimulation. We investigated the influence of locus coeruleus activation on noradrenaline release measured in the anteroventral thalamic nucleus every second by means of differential pulse amperometry: (i) chemical activation of locus coeruleus by local injection of glutamate (0.2-0.8 nmol) immediately and consistently evoked noradrenaline release in a dose-dependent manner; and (ii) peripheral stimulation of the sciatic nerve (20 s)--known to enhance the firing rate of locus coeruleus neurons-evoked a noradrenaline release similar to that produced by a stimulation of the dorsal noradrenergic bundle at 8-10 Hz. Pharmacological and kinetic characteristics of the noradrenaline release were the same for central or peripheral stimulation of locus coeruleus neurons. Our results indicate that in vivo electrochemistry, because of its sensitivity and its high space and time resolution, is well suited for studies of evoked noradrenaline release from locus coeruleus terminals. This approach allowed us to describe the characteristics of central noradrenaline release evoked by central and peripheral stimulations of short duration. In particular, we observed a very close relationship between impulse flow and evoked noradrenaline release.
Asunto(s)
Locus Coeruleus/fisiología , Norepinefrina/metabolismo , Núcleos Talámicos/fisiología , Animales , Axones/fisiología , Clonidina/farmacología , Desipramina/farmacología , Estimulación Eléctrica , Electroquímica/métodos , Potenciales Evocados , Glutamatos/metabolismo , Ácido Glutámico , Masculino , Oxidación-Reducción , Pargilina/farmacología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/fisiología , Núcleos Talámicos/efectos de los fármacos , Yohimbina/farmacologíaRESUMEN
Differential pulse amperometry has previously been used in combination with electrochemically treated carbon fibre electrodes. In order to improve the time resolution, this technique was combined here with untreated electrodes. Dopamine release was evoked in the nucleus accumbens of rats anaesthetized with urethane by electrical stimulation of the mesolimbic dopaminergic pathway. The differential oxidation current appearing at +200 mV was recorded every 1 s and was proportional to the dopamine concentration from 0.5 to 50 microM. At this voltage these untreated electrodes were not sensitive to the main catechol metabolite (DOPAC) and poorly sensitive to ascorbic acid. The electrically evoked increase in the oxidation current corresponded exclusively to dopamine. It was enhanced by nomifensine, amphetamine, haloperidol and pargyline and reduced by alpha-methyl-p-tyrosine (A-MPT). The results show that the evoked DA release was facilitated by increasing the stimulation frequency from 10 to 40 Hz. The method was sufficiently sensitive to detect dopamine release evoked by electrical stimulation at 10 Hz and its time resolution was 1 s.