RESUMO
Previous studies showed a prominent role of the medial prefrontal cortex (mPFC), especially the prelimbic (PL) and infralimbic (IL) subregions, in behavioral and physiological responses to stressful stimuli. Nevertheless, the local neurochemical mechanisms involved are not completely understood. In this sense, previous studies identified cholinergic terminals within the mPFC, and stressful stimuli increased local acetylcholine release. Despite these pieces of evidence, the specific role of cholinergic neurotransmission in different subregions of the mPFC controlling the cardiovascular responses to stress has never been systematically evaluated. Therefore, the purpose of this study was to investigate the involvement of cholinergic neurotransmission present within PL and IL in cardiovascular responses to an acute session of restraint stress in rats. For this, rats received bilateral microinjection of the choline uptake inhibitor hemicholinium-3 before exposure to restraint stress. The arterial pressure and heart rate (HR) increases and the decrease in tail skin temperature as an indirect measurement of sympathetically-mediated cutaneous vasoconstriction were recorded throughout the restraint stress session. The results showed that the depletion of acetylcholine within the PL caused by local microinjection of hemicholinium-3 decreased the tachycardia to restraint stress, but without affecting the pressor response and the drop in tail skin temperature. Conversely, IL treatment with hemicholinium-3 decreased the restraint-evoked pressor response and the sympathetically-mediated cutaneous vasoconstriction without interfering with the HR response. Taken together, these results indicate functional differences of cholinergic neurotransmission within the PL and IL in control of cardiovascular and autonomic responses to stressful stimuli.
Assuntos
Acetilcolina/fisiologia , Sistema Nervoso Autônomo/fisiologia , Pressão Sanguínea/fisiologia , Colinérgicos/farmacologia , Frequência Cardíaca/fisiologia , Inibidores da Captação de Neurotransmissores/farmacologia , Córtex Pré-Frontal/fisiologia , Estresse Psicológico/fisiopatologia , Transmissão Sináptica/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hemicolínio 3/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Restrição FísicaRESUMO
Acute exposure to stress induces significant behavioural changes, while repeated exposure to the same stressor leads to the development of tolerance to stress. The development of tolerance appears to involve the serotonergic projections from the Median Raphe Nucleus (MnRN) to the dorsal Hippocampus (dH), since rats with lesions of this pathway does not develop tolerance to stress. Previous data from our laboratory showed that treatment with imipramine, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor, lead to the development of tolerance. However, it remains to be elucidated whether such tolerance involves the participation of the noradrenergic system, apart from the serotonergic projections. Therefore, the aim of this work was to investigate the behavioural and neurochemical effects of chronic treatment with desipramine (NA reuptake inhibitor) or fluoxetine (5-HT reuptake inhibitor) in chronically stressed rats with lesions of the serotonergic neurons of the MnRN. Male Wistar rats with or without lesion in the MnRN were submitted or not to acute (2â¯h) or chronic restraint (2â¯h/seven days) stress and tested in the elevated pus maze (EPM). Treatment with fluoxetine, desipramine (10â¯mg/kg) or saline was performed twice daily (12-12â¯h interval), for 7 consecutive days. EPM test was conducted 24â¯h after the treatment. Fluoxetine attenuated the anxiogenic-induced effect of lesion in chronically restrained rats, without changing serotonin and noradrenaline levels in the hippocampus of lesioned rats. A similar profile was also observed after treatment with desipramine. These results suggest that both the serotonergic and the noradrenergic systems are involved in the development of tolerance to chronic stress. Additionally, the integrity of the serotonergic pathway of the MnRN-dH is not essential for the anxiolytic-like effects of these drugs.
Assuntos
Núcleo Dorsal da Rafe/citologia , Núcleo Dorsal da Rafe/lesões , Norepinefrina/metabolismo , Neurônios Serotoninérgicos/fisiologia , Serotonina/metabolismo , Estresse Psicológico , 5,7-Di-Hidroxitriptamina/farmacologia , Análise de Variância , Animais , Desipramina/farmacologia , Modelos Animais de Doenças , Tolerância a Medicamentos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Ratos , Ratos Wistar , Serotoninérgicos/farmacologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologiaRESUMO
(1) Background: Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults. It is also the one with the highest percentage of drug-resistance to the current available anti-epileptic drugs (AED). Additionaly, most antiepileptic drugs are only able to control seizures in epileptogenesis, but do not decrease the hippocampal neurodegenerative process. TLE patients have a reduced population of interneuronal cells, which express Parvalbumin (PV) proteins. This reduction is directly linked to seizure frequency and severity in the chronic period of epilepsy. There is therefore a need to seek new therapies with a disease-modifying profile, and with efficient antiepileptic and neuroprotective properties. Parawixin2, a compound isolated from the venom of the spider Parawixia bistriata, has been shown to inhibit GABA transporters (GAT) and to have acute anticonvulsant effects in rats. (2) Methods: In this work, we studied the effects of Parawixin2 and Tiagabine (an FDA- approved GAT inhibitor), and compared these effects in a TLE model. Rats were subjected to lithium-pilocarpine TLE model and the main features were evaluated over a chronic period including: (a) spontaneous recurrent seizures (SRS), (b) neuronal loss, and (c) PV cell density in different regions of the hippocampus (CA1, CA3, DG and Hilus). (3) Results: Parawixin2 treatment reduced SRS frequency whereas Tiagabine did not. We also found a significant reduction in neuronal loss in CA3 and in the hilus regions of the hippocampus, in animals treated with Parawixin2. Noteworthy, Parawixin2 significantly reversed PV cell loss observed particularly in DG layers. (4) Conclusions: Parawixin2 exerts a promising neuroprotective and anti-epileptic effect and has potential as a novel agent in drug design.
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia do Lobo Temporal/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Inibidores da Captação de Neurotransmissores/uso terapêutico , Venenos de Aranha/uso terapêutico , Ureia/análogos & derivados , Animais , Anticonvulsivantes/farmacologia , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Hipocampo/efeitos dos fármacos , Lítio , Masculino , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Ácidos Nipecóticos/farmacologia , Ácidos Nipecóticos/uso terapêutico , Pilocarpina , Ratos Wistar , Venenos de Aranha/farmacologia , Tiagabina , Ureia/farmacologia , Ureia/uso terapêuticoRESUMO
This commentary addresses some of the diverse questions of current interest with regard to the health effects of air pollution, including exposure-response relationships, toxicity of inhaled particles and risks to health, multipollutant mixtures, traffic-related pollution, accountability research, and issues with susceptibility and vulnerability. It considers the challenges posed to researchers as they attempt to provide useful evidence for policy-makers relevant to these issues. This commentary accompanies papers giving the results from the ESCALA project, a multi-city study in Latin America that has an overall goal of providing policy-relevant results. While progress has been made in improving air quality, driven by epidemiological evidence that air pollution is adversely affecting public health, the research questions have become more subtle and challenging as levels of air pollution dropped. More research is still needed, but also novel methods and approaches to address these new questions.
Este comentario aborda algunos de los temas de interés actual en relación con los efectos de la contaminación del aire sobre la salud, tales como las relaciones exposición-respuesta, la toxicidad y riesgos para la salud de las partículas inhaladas, las mezclas de contaminantes múltiples, la contaminación relacionada con el tráfico, la investigación sobre responsabilidad, y los problemas de susceptibilidad y vulnerabilidad. Considera los retos que se presentan a los investigadores que intentan proporcionar evidencia para los responsables políticos en estas cuestiones. Este texto acompaña otros trabajos con resultados del proyecto ESCALA, un estudio en varias ciudades de América Latina que tiene como objetivo general proporcionar resultados relevantes para la política pública. Aunque ha habido avances para mejorar la calidad del aire, gracias a la evidencia epidemiológica de que la contaminación aérea está afectando negativamente a la salud pública, las preguntas de investigación se han vuelto más sutiles y difíciles a medida que los niveles de contaminación se reducen. Se necesita más investigación, pero también nuevos métodos y enfoques capaces de enfrentar estas preguntas.
Assuntos
Animais , Camundongos , Colina/análogos & derivados , Junção Neuromuscular/metabolismo , Neurotransmissores/metabolismo , Pró-Fármacos/metabolismo , Colina/metabolismo , Inibidores da Colinesterase/farmacologia , Edrofônio/farmacologia , Estimulação Elétrica , /farmacologia , Metilaminas/farmacologia , Camundongos Endogâmicos , Neostigmina/farmacologia , Fármacos Neuromusculares Despolarizantes/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Piperidinas/farmacologia , Rana pipiensRESUMO
This study was undertaken in order to characterize the role of the glutamate/aspartate transporter (GLAST) in the glutathione (GSH) efflux induced by glutamate. Our results demonstrated that retinal cell cultures exhibit two mechanisms of GSH release, one Na(+)-independent and other Na(+)-dependent. Glutamate and aspartate induced GSH efflux only in presence of Na(+). Treatment with PCD (L-trans-Pyrrolidine-2,4-dicarboxylate), a transportable glutamate uptake blocker, increased GSH release indicating that GSH can be carried by glutamate transporters in retinal cell cultures. Added to this, treatment with zinc ion cultures, a recognized inhibitor of GLAST blocked GSH efflux evoked by glutamate. Treatment with NMDA antagonist (MK-801) did not have any effect on the GSH release induced by glutamate. These results suggest that glutamate induces GLAST-mediated release of GSH from retinal cell cultures and this could represent an important mechanism of cellular protection against glutamate toxicity in the CNS.
Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Ácido Glutâmico/farmacologia , Glutationa/metabolismo , Retina/citologia , Animais , Ácido Aspártico/farmacologia , Células Cultivadas , Embrião de Galinha , Ácidos Dicarboxílicos/farmacologia , Ácido Glutâmico/metabolismo , Inibidores da Captação de Neurotransmissores/farmacologia , Pirrolidinas/farmacologia , Retina/efeitos dos fármacosRESUMO
RATIONALE: Conditioned fear to context causes freezing and cardiovascular changes in rodents and has been used to measure anxiety. It also activates the dorsolateral column of the periaqueductal gray (dlPAG). Microinjections of cannabinoid agonists into the dlPAG produced anxiolytic-like effects in the elevated plus maze, but the effects of these treatments on fear conditioning remains unknown. OBJECTIVE: The objective of this study was to verify if intra-dlPAG injection of the CB1 cannabinoid receptor agonist anandamide (AEA) or the anandamide transport inhibitor AM404 would attenuate behavioral (freezing) and cardiovascular (increase of arterial pressure and heart rate) responses of rats submitted to a contextual fear-conditioning paradigm. MATERIALS AND METHODS: Male Wistar rats with cannulae aimed at the dlPAG were re-exposed to a chamber where they had received footshocks 48 h before. Fifteen minutes before the test, the animals received a first intra-dlPAG injection of vehicle or AM251, a CB1 receptor antagonist (100 pmol/200 nl), followed 5 min later by vehicle, AEA (5 pmol/200 nl) or AM404 (50 pmol/200 nl). Freezing and cardiovascular responses were recorded for 10 min. RESULTS: Freezing and cardiovascular responses were reduced by administration of either AEA or AM404 into the dlPAG before re-exposition to the aversively conditioned context. These effects were abolished when the animals were locally pretreated with AM251. The latter drug, even at a higher dose (300 pmol), was ineffective when administered alone into the dlPAG. CONCLUSION: The results suggest that facilitation of endocannabinoid-mediated neurotransmission in the dlPAG, through activation of local CB1 receptors, attenuates the expression of contextual fear responses.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Medo/psicologia , Substância Cinzenta Periaquedutal/fisiologia , Receptor CB1 de Canabinoide/agonistas , Animais , Ácidos Araquidônicos/metabolismo , Ácidos Araquidônicos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Endocanabinoides , Frequência Cardíaca/efeitos dos fármacos , Masculino , Microinjeções , Inibidores da Captação de Neurotransmissores/farmacologia , Substância Cinzenta Periaquedutal/anatomia & histologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidoresRESUMO
A crude (ECH) and a purified cyclohexane extract (HCP) of Hypericum caprifoliatum and their main phloroglucinol derivative (HC1) were evaluated regarding their action on monoaminergic systems, more precisely on dopamine. In rats and mice forced swimming test, ECH and HCP dose-dependently reduced the immobility time. The effect of the highest dose was prevented by a prior administration of either sulpiride or SCH 23390 (D(2) and D(1) dopamine receptor antagonist, respectively). HCP (360 mg/kg) decreased the locomotor activity of mice. ECH (90 mg/kg) caused hypothermia and potentiated apomorphine-induced (16 mg/kg) hypothermia in mice. HCP and HC1 inhibited, in a concentration-dependent and monophasic manner, the [(3)H]-DA, [(3)H]-NA and [(3)H]-5HT synaptosomal uptakes, but did not prevent the binding of specific ligands to the monoamine transporters. Moreover, when tested at the concentrations corresponding to its IC(50) on [(3)H]-DA uptake, HC1 did not induce a significant [(3)H]-DA release, while at a higher concentration (200 ng/ml) it enhanced significantly (by 12%) the synaptosomal DA release. These data suggest that the antidepressant-like effect of H. caprifoliatum on the forced swimming test is due to an increase in monoaminergic transmission, resulting from monoamine uptake inhibition, more potently of dopamine, which may be related to their phloroglucinol contents.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Hypericum/química , Inibidores da Captação de Neurotransmissores/farmacologia , Animais , Apomorfina/farmacologia , Ligação Competitiva/efeitos dos fármacos , Depressão/etiologia , Depressão/psicologia , Dopamina/fisiologia , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Hipotermia/induzido quimicamente , Hipotermia/prevenção & controle , Técnicas In Vitro , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Norepinefrina/fisiologia , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Serotonina/fisiologia , Natação/psicologia , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismoRESUMO
The extracellular concentration of glutamate is highly regulated by transporter proteins, due to its neurotoxic properties. Dysfunction or reverse activation of these transporters is related to the extracellular accumulation of excitatory amino acids and neuronal damage associated with ischemia and hypoglycemia. We have investigated by microdialysis the effects of the substrate and the non-substrate inhibitors of glutamate transporters, l-trans-2,4-pyrrolidine dicarboxylate (PDC) and DL-threo-beta-benzyloxyaspartate (DL-TBOA), respectively, on the extracellular levels of amino acids in the rat hippocampus in vivo. In addition, we have studied the effect of both inhibitors on neuronal damage after direct administration into the hippocampus and striatum. Electroencephalographic activity was recorded after the intrahippocampal infusion of DL-TBOA or PDC. Microdialysis administration of 500 microM DL-TBOA into the hippocampus increased 3.4- and nine-fold the extracellular levels of aspartate and glutamate, respectively. Upon stereotaxic administration it induced neuronal damage dose-dependently in CA1 and dentate gyrus, and convulsive behavior. Electroencephalographic recording showed the appearance of limbic seizures in the hippocampus after DL-TBOA infusion. In the striatum it also induced dose-dependent neuronal damage. These effects were prevented by the i.p. administration of the glutamate receptor antagonists (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-iminemaleate and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline. In contrast to dl-TBOA, PDC (500 microM) induced a more discrete elevation of excitatory amino acids levels (2.6- and three-fold in aspartate and glutamate, respectively), no neuronal damage or behavioral changes, and no alterations in electroencephalographic activity. The differential results obtained with DL-TBOA and PDC might be attributed to their distinct effects on the extracellular concentration of amino acids. Results are relevant to the understanding of the role of glutamate transporters in amino acid removal or release and the induction of excitotoxic cell death.
Assuntos
Corpo Estriado/efeitos dos fármacos , Ácidos Dicarboxílicos/farmacologia , Hipocampo/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Pirrolidinas/farmacologia , Animais , Ácido Aspártico/farmacologia , Comportamento Animal/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Eletroencefalografia/efeitos dos fármacos , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Injeções Intraventriculares , Masculino , Microdiálise , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos WistarRESUMO
The mechanism by which muscarinic or nicotinic agonists produce antinociception has been the subject of several studies. In the present investigation, we used intrathecal administration of drugs to rats to show that muscarinic or nicotinic agonists such as bethanechol (BCh) and dimethylphenylpiperazinium (DM), respectively, dose-dependently increased the tail flick latency and reduced the pain produced by a surgical incision performed on the plantar aspect of a hind paw. The effects of BCh in both tests were inhibited by the previous intrathecal administration of atropine, but not mecamylamine (muscarinic and nicotinic antagonists, respectively). Mecamylamine significantly reduced the effects of DM in both tests. Atropine significantly reduced the effect of DM in the tail flick test and inhibited the effect of DM against the incisional pain. Intrathecal hemicholinium-3 (HC-3), a reversible inhibitor of choline transporter, did not change the effect of BCh in the tail flick test but produced a non-significant reduction of the effect of BCh against incisional pain. In contrast, HC-3 produced a non-significant reduction of the effect of DM in the tail flick test but fully inhibited the effect of DM against incisional pain. Therefore, the BCh-induced antinociception depends on a direct activation of muscarinic receptors, whereas DM-induced antinociception results in drug interaction with nicotinic receptors to activate the further release of acetylcholine from intrinsic spinal cholinergic terminals. The acetylcholine released by DM in turn induces antinociception via activation of muscarinic receptors.
Assuntos
Analgésicos/administração & dosagem , Betanecol/administração & dosagem , Agonistas Colinérgicos/administração & dosagem , Iodeto de Dimetilfenilpiperazina/administração & dosagem , Dor/tratamento farmacológico , Acetilcolina/fisiologia , Análise de Variância , Animais , Atropina/farmacologia , Antagonistas Colinérgicos/farmacologia , Modelos Animais de Doenças , Interações Medicamentosas , Hemicolínio 3/farmacologia , Injeções Espinhais , Masculino , Mecamilamina/farmacologia , Análise Multivariada , Inibidores da Captação de Neurotransmissores/farmacologia , Dor/etiologia , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Ferimentos e Lesões/complicaçõesRESUMO
OBJECTIVE: Amoxapine is marketed as an antidepressant. However, its receptor occupancy, in vitro and in vivo, and its effects in pre-clinical models are very similar to atypical antipsychotics. To examine if this leads to an atypical antipsychotic effect in the clinical context, the authors examined the antipsychotic and side-effect profile of amoxapine in acutely psychotic patients with schizophrenia. METHODS: Seventeen patients were enrolled and 15 completed a prospective open-label 6-week study of amoxapine starting with a fixed-starting dose (150 mg/h) with standardized titration up to 250 mg/h, if required. Positive, negative, affective symptoms and side-effects were monitored using standardized weekly assessments. RESULTS: Amoxapine (median final dose 210 mg/h) was well-tolerated and showed significant improvement in positive and negative symptoms (both p<0.001), with a trend towards improvement in mood symptoms and no treatment-emergent extrapyramidal side-effects, akathisia or weight gain. Prolactin elevation was observed. CONCLUSION: These clinical data lend support to the pre-clinical suggestions that amoxapine may be an atypical antipsychotic. Given its lack of weight gain and that it is considerably less expensive than current options, amoxapine could be a valuable alternative for some patients. These considerations strongly call for more systematic, double-blind studies of amoxapine as an atypical antipsychotic.
Assuntos
Amoxapina/uso terapêutico , Antipsicóticos/uso terapêutico , Inibidores da Captação de Neurotransmissores/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Amoxapina/efeitos adversos , Amoxapina/farmacologia , Análise de Variância , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Captação de Neurotransmissores/efeitos adversos , Inibidores da Captação de Neurotransmissores/farmacologia , Estudos ProspectivosRESUMO
Impairment of glutamate uptake or the reverse action of its transporters has been suggested as the mechanism responsible for the increased glutamate extracellular levels associated with ischemic neuronal damage. In previous studies we have shown that glutamate uptake inhibition by L-trans-pyrrolidine-2,4-dicarboxylate (PDC) in the rat striatum and hippocampus in vivo does not induce neuronal death despite the notable increase in the extracellular levels of glutamate and aspartate. However, PDC intracerebral administration leads to neuronal death in rats chronically injected with the mitochondrial toxin 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase (SDH). In the present study we have determined the time course of inhibition of SDH activity in the striatum of rats acutely injected with a single dose of 3-NP (20 mg/kg), and studied its relation to PDC neurotoxicity. PDC induced larger lesions when administered during maximum inhibition of SDH activity while smaller lesions were found when it was injected during recovery of enzyme activity. We also studied the neuroprotective effect of different energy substrates such as creatine, pyruvate, and the ketone bodies beta-hydroxybutyrate and acetoacetate in this experimental model. Our results show partial protection with all compounds except for beta-hydroxybutyrate that showed no protection, while MK-801 completely prevented PDC-induced neuronal damage. We believe that the present results might be of relevance for the understanding of the mechanisms responsible for ischemic neuronal death and its prevention.
Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Isquemia Encefálica/enzimologia , Metabolismo Energético/fisiologia , Degeneração Neural/enzimologia , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/farmacologia , Succinato Desidrogenase/metabolismo , Ácido 3-Hidroxibutírico/farmacologia , Acetoacetatos/farmacologia , Sistema X-AG de Transporte de Aminoácidos/antagonistas & inibidores , Animais , Isquemia Encefálica/fisiopatologia , Convulsivantes/farmacologia , Creatina/farmacologia , Ácidos Dicarboxílicos/farmacologia , Interações Medicamentosas/fisiologia , Metabolismo Energético/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Masculino , Neostriado/efeitos dos fármacos , Neostriado/enzimologia , Neostriado/fisiopatologia , Degeneração Neural/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Inibidores da Captação de Neurotransmissores/farmacologia , Nitrocompostos , Propionatos/farmacologia , Pirrolidinas/farmacologia , Ácido Pirúvico/farmacologia , Ratos , Ratos Wistar , Succinato Desidrogenase/antagonistas & inibidoresRESUMO
Neuronal damage associated with cerebral ischemia and hypoglycemia might be the consequence of the extracellular accumulation of excitatory amino acids. In previous studies we showed that elevation of glutamate and aspartate extracellular levels by inhibition of its uptake in vivo is not sufficient to induce neuronal damage unless mitochondrial energy metabolism is compromised. In the present study we show that chronic systemic administration of the glycolysis inhibitor iodoacetate (25 mg/kg) induces no damage to the brain per se but enhances neuronal vulnerability to glutamate-mediated neurotoxicity in the hippocampus. Tissue injury is well protected either by antagonizing NMDA glutamate receptors with MK-801 or by administration of pyruvate, a substrate of the tricarboxylic acid cycle. In contrast to systemic treatment, local infusions through a dialysis probe of 5 mM iodoacetate into the hippocampus induced acute lesions not sensitive to MK-801. Iodoacetate intrahippocampal perfusion induced substantial increases in the extracellular levels of glutamate (3.5-fold), taurine (8.8-fold), and particularly aspartate (35-fold). Neuronal damage under this conditions occurs very rapidly as revealed by the histological analysis of animals transcardially perfused immediately after iodoacetate perfusion. Aspartate might contribute to neuronal damage since intrahippocampal administration of this amino acid (600 nmol/microl) induces extensive lesions. The present study might suggest that impairment of glucose oxidation through the glycolytic pathway in vivo facilitates glutamate neurotoxicity. Additionally, the results indicate that pyruvate might prevent as efficiently as glutamate receptor antagonists glutamate-mediated neuronal damage associated with ischemia/hypoglycemia.
Assuntos
Inibidores Enzimáticos/farmacologia , Aminoácidos Excitatórios/metabolismo , Glicólise/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Iodoacetatos/farmacologia , Neurônios/efeitos dos fármacos , Animais , Ácidos Dicarboxílicos/farmacologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Glicólise/fisiologia , Hipocampo/lesões , Hipocampo/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Pirrolidinas/farmacologia , Ratos , Ratos WistarRESUMO
The effect of L-cysteine sulfinic acid (CSA) and L-homocysteic acid (HCA) on the release of tritiated gamma-amino butyric acid ([3H]GABA), from the external plexiform layer (EPL) of the rat olfactory bulb, was compared with that of glutamate. These amino acids induced release of GABA was strongly inhibited by the glutamate uptake blocker, pyrrolidine-2,4-dicarboxylate (2,4,PDC) (50 microM), while it was not inhibited by the specific GABA uptake blockers nipecotic acid (0.5 mM) or NO-711 (5 microM). Only the HCA induced GABA release was 60% inhibited by beta-alanine (0.5 mM), a glial GABA uptake blocker and 78% by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) (100 microM). The non-NMDA receptor antagonists 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline (CNQX) up to 500 microM had no effect on HCA or CSA stimulated GABA release. These results bring evidence for an excitatory role of HCA and CSA together with glutamate on GABAergic neuronal or glial elements, in the olfactory bulb. This role could be mediated through the reversal of the glutamate or/and the glial GABA transporter and through the activation of a NMDA type receptor.
Assuntos
Aminoácidos Excitatórios/farmacologia , Bulbo Olfatório/efeitos dos fármacos , Ácido gama-Aminobutírico/efeitos dos fármacos , Animais , Cisteína/análogos & derivados , Cisteína/farmacologia , Ácidos Dicarboxílicos/farmacologia , Relação Dose-Resposta a Droga , Homocisteína/análogos & derivados , Homocisteína/farmacologia , Técnicas In Vitro , Masculino , Neurotransmissores , Inibidores da Captação de Neurotransmissores/farmacologia , Bulbo Olfatório/metabolismo , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismoRESUMO
The pharmacology of memory has been recently studied by the infusion of drugs into the hippocampus (HIP), amygdala (AMY), medial septum (MS), and entorhinal cortex (EC) at various times after training or at the time of retention testing. It was found to be remarkably similar to that of long-term potentiation (LTP). Memory and LTP are blocked early on by antagonists of glutamate N-methyl-D-aspartate (NMDA) or metabotropic receptors (mGLUs), by the antagonist of the presynaptic membrane receptor to PAF, BN 52021, by the inhibitor of heme oxygenase, ZnPP, by the inhibitor of NO synthase, N-nitro-arginine, by GABA type A receptor agonists, or by muscarinic blockers. Both memory and LTP are enhanced, at this early stage, by glutamate, mGLU agonists, GABA-A antagonists, muscarinic agonists, and norepinephrine. In the next 1-3 h, memory and LTP are accompanied by enhanced activity of protein kinases and are blocked by specific inhibitors of calcium/calmodulin dependent protein kinase II and protein kinase C. At the time of expression, memory and LTP are blocked by antagonists of glutamate AMPA receptors and are accompanied by an enhanced sensitivity of these receptors. Memories that depend on HIP are affected by drugs given into the HIP but not the MS or AMY, memories that depend on the AMY are affected by drugs given into the AMY, and memories that depend on the HIP, AMY, and MS are affected by drugs given into the three structures.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Encéfalo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Memória/efeitos dos fármacos , Neurotransmissores/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Receptores de Neurotransmissores/efeitos dos fármacos , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Animais , Encéfalo/fisiologia , Mapeamento Encefálico , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Neurotransmissores/fisiologia , Receptores de Neurotransmissores/fisiologia , Septo Pelúcido/efeitos dos fármacos , Septo Pelúcido/fisiologiaRESUMO
The long-term effects of the systemic administration of DSP4 (N-(2-chloroethyl)N-ethyl-2-bromobenzylamine hydrochloride), a selective noradrenergic neurotoxin, on the endogenous levels of monoamines and their metabolites and on alpha- and beta-adrenoceptors in selected brain regions of the rat were examined. After 7 days, DSP4 caused a marked reduction (about 80%) of endogenous noradrenaline levels in locus coeruleus-innervated regions. At 90, 240 and 300 days after DSP4 injection, a partial and gradual recovery (50%, 41% and 25% of control values, respectively) of the noradrenaline cortical levels was evident. One year after DSP4 administration, brain regional noradrenaline stores were almost completely recovered. No changes in 5-hydroxytryptamine levels were observed in the three time intervals, but a mild decrease in cortical and hippocampal 5-hydroxyindolacetic acid levels was found 7 days after DSP4 injection. Following the profound noradrenaline depletion seen at 7 days, the cerebral cortical density of alpha 1-, alpha 2- and beta-adrenoceptors was significantly increased. Assessment of adrenergic receptors in cerebral cortex at 365 days after DSP4 injection, indicated that alpha 1- and alpha 2-adrenoceptor densities did not differ from control values; however, the density of beta-adrenoceptors remained increased. No changes were observed in the affinities of the three types of adrenoceptors studied. These results indicate that after a selective noradrenergic denervation induced by DSP4, there is a slow and gradual recovery of noradrenaline stores and of alpha 1- and alpha 2-adrenoceptor populations, suggesting a possible regrowth and/or collateral sprouting of noradrenergic terminals.
Assuntos
Benzilaminas/farmacologia , Encéfalo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Animais , Benzilaminas/administração & dosagem , Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Feminino , Cinética , Masculino , Neurônios/metabolismo , Neurotoxinas/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismoRESUMO
1. The in vitro effects of N-(2-chloroethyl)-N-ethyl-bromobenzylamine (DSP4) were studied in the rat vas deferens. 2. DSP4 inhibited the biphasic motor response induced by field stimulation in a concentration-dependent manner. The concentration of DSP4 that elicited 50% of the maximal inhibition of the twitch response induced by 3 Hz was 10 microM. 3. DSP4 10 microM abolished the motor response induced by exogenously applied noradrenaline and 0.1 mM ATP. Phentolamine (an alpha-adrenoceptor blocker) prevented DSP4 inhibitory effect. 4. DSP4 inhibitory effect was no due to the activation of alpha 2-presynaptic adrenoceptor mechanisms. 5. DSP4 impairs neurotransmission in the rat vas deferens by a postsynaptic alpha 1-adrenoceptor blockade and by an inhibition of the purinergic response.
Assuntos
Benzilaminas/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Ducto Deferente/inervação , Trifosfato de Adenosina/antagonistas & inibidores , Trifosfato de Adenosina/farmacologia , Animais , Estimulação Elétrica , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Masculino , Contração Muscular/efeitos dos fármacos , Norepinefrina/antagonistas & inibidores , Norepinefrina/farmacologia , Fentolamina/farmacologia , Ratos , Ratos Wistar , Reserpina/farmacologia , Ducto Deferente/efeitos dos fármacos , Ioimbina/farmacologiaRESUMO
Several studies have demonstrated that atrial natriuretic factor can bind to adrenal medulla cells. Furthermore, atrial natriuretic factor immunoreactivity has been identified in chromaffin cells. The aim of the present work was to investigate atrial natriuretic factor effects on the uptake, intracellular distribution, and release of norepinephrine in the rat adrenal medulla. Results showed that 100 nM atrial natriuretic factor induced a rapid increase of norepinephrine uptake during the first minute of the incubation period. This increase was maintained for up to 60 min. In addition, only neuronal norepinephrine uptake was increased by the natriuretic factor; non-neuronal norepinephrine uptake was unaltered. Atrial natriuretic factor modified the intracellular distribution of the amine store: the granular fraction of norepinephrine increased, while the cytosolic fraction decreased. On the other hand, different concentrations (10, 50, and 100 nM) of the atrial factor decreased spontaneous [3H]norepinephrine output in a concentration-dependent manner. Furthermore, atrial natriuretic factor (10 nM) also reduced high potassium solution evoked secretion of norepinephrine. These results suggest that atrial natriuretic factor modulates sympathetic activity in the rat adrenal medulla. These effects of atrial natriuretic factor may be related to the catecholamine peripheral mechanism involved in the regulation of arterial blood pressure, smooth muscle tone, metabolic activity, etc.
Assuntos
Medula Suprarrenal/metabolismo , Fator Natriurético Atrial/farmacologia , Norepinefrina/metabolismo , Norepinefrina/farmacocinética , Medula Suprarrenal/inervação , Animais , Líquido Intracelular/metabolismo , Masculino , Neurônios/metabolismo , Inibidores da Captação de Neurotransmissores/farmacologia , Ratos , Ratos Wistar , Estimulação Química , TrítioRESUMO
Angiotensin II and III have hypertensive effects. They induce vascular smooth muscle constriction, increase sodium reabsorption by renal tubules, stimulate the anteroventral third ventricle area, increase vasopressin and aldosterone secretions, and modify catecholamine metabolism. In this work, angiotensin II and III effects on norepinephrine uptake and release in rat adrenal medulla were investigated. Both angiotensins decreased total and neuronal norepinephrine uptake. Angiotensin II showed a biphasic effect only on evoked neuronal norepinephrine release (an earlier decrease followed by a later increase), while increasing the spontaneous norepinephrine release only after 12 min. On the other hand, angiotensin III showed a biphasic effect on evoked and spontaneous neuronal norepinephrine release. Both angiotensins altered norepinephrine distribution into intracellular stores, concentrating the amine into the granular pool and decreasing the cytosolic store. The results suggest a physiological biphasic effect of angiotensin II as well as angiotensin III that may be involved in the modulation of sympathetic activity in the rat adrenal medulla.
Assuntos
Medula Suprarrenal/metabolismo , Angiotensina III/farmacologia , Angiotensina II/farmacologia , Norepinefrina/farmacocinética , Animais , Técnicas In Vitro , Líquido Intracelular/metabolismo , Masculino , Neurônios/metabolismo , Inibidores da Captação de Neurotransmissores/farmacologia , Ratos , Ratos Wistar , Fatores de Tempo , Distribuição Tecidual , TrítioRESUMO
The effect of vesicular acetylcholine (ACh) transport blocker 2-(4-phenylpiperidino)cyclohexanol (AH-5183) on the subcellular storage and release of ACh was studied in rat brain cortical slices. AH-5183 reduced the release of ACh from cortical slices stimulated by tityustoxin and ouabain. Tissue stimulated in the presence of AH-5183 contained more ACh in both the nerve terminal synaptic vesicles and cytoplasmic fraction than did tissue stimulated in drug's absence. Thus, AH-5183 blocked the tityustoxin and ouabain induced release of ACh from both cytoplasmic and vesicular pools. AH-5183 also depressed the spontaneous release of ACh from incubated slices and, in this condition, the drug had no effect in the subcellular distribution of ACh. It is suggested that AH-5183 interferes with the process of ACh release independent of its blocking action on ACh transport into the synaptic vesicles.