RESUMEN
Fipronil, a pesticide widely used to control agricultural and household insect pests, blocks insect GABAA and glutamate (GluCl) ionotropic receptors, resulting in uncontrolled hyperexcitation and paralysis that eventually leads to death. The use of fipronil is controversial because unintentional exposure to this compound may contribute to the ongoing global decline of insect pollinator populations. Although the sublethal effects of fipronil have been linked to aberrant behavior and impaired olfactory learning in insects, the precise mechanisms involved in these responses remain unclear. In this article, we highlight recent studies that have investigated the interaction among different pathways involved in the ability of fipronil to modulate insect behavior, with particular emphasis on the role of GABAergic neurotransmission in fine-tuning the integration of sensorial responses and insect behavior. Recent findings suggest that fipronil can also cause functional alterations that affect synaptic organization and the availability of metal ions in the brain.
Asunto(s)
Conducta Animal , Insectos , Insecticidas , Pirazoles , Animales , Pirazoles/toxicidad , Insectos/efectos de los fármacos , Insectos/fisiología , Insecticidas/toxicidad , Conducta Animal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
There is evidence that astrocytes modulate synaptic transmission in the nucleus tractus solitarius (NTS) interacting with glutamatergic and purinergic mechanisms. Here, using in situ working heart-brainstem preparations, we evaluated the involvement of astrocyte and glutamatergic/purinergic neurotransmission in the processing of autonomic and respiratory pathways in the NTS of control and rats exposed to sustained hypoxia (SH). Baseline autonomic and respiratory activities and the responses to chemoreflex activation (KCN) were evaluated before and after microinjections of fluorocitrate (FCt, an astrocyte metabolic inhibitor), kynurenic acid, and pyridoxalphosphate-6-azophenyl-2',4'-disulfonate (PPADS) (nonselective antagonists of glutamatergic and purinergic receptors) into the rostral aspect of the caudal commissural NTS. FCt had no effects on the baseline parameters evaluated but reduced the bradycardic response to chemoreflex activation in SH rats. FCt combined with kynurenic acid and PPADS in control rats reduced the baseline duration of expiration, which was attenuated after SH. FCt produced a large increase in PN frequency discharge in control rats, which was reduced after SH, indicating a reduction in the astrocyte modulation after SH. The data show that 1) the bradycardic component of the peripheral chemoreflex is reduced in SH rats after astrocytes inhibition, 2) the inhibition of astrocytes in the presence of double antagonists in the NTS affects the modulation of baseline duration of expiration in control but not in SH rats, and 3) the autonomic and respiratory responses to chemoreflex activation are mediated by glutamatergic and purinergic receptors in the rostral aspect of the caudal commissural NTS.NEW & NOTEWORTHY Our findings indicate that the neurotransmission of autonomic and respiratory components of the peripheral chemoreflex in the nucleus tractus solitarius (NTS) is mediated by glutamatergic and purinergic mechanisms and reveal a selective involvement of NTS astrocytes in controlling the chemoreflex parasympathetic response in rats exposed to sustained hypoxia (SH) and the baseline duration of expiration mainly in control rats, indicating a selective role for astrocytes modulation in the NTS of control and SH rats.
Asunto(s)
Astrocitos , Ácido Glutámico , Hipoxia , Receptores Purinérgicos , Núcleo Solitario , Transmisión Sináptica , Animales , Núcleo Solitario/metabolismo , Núcleo Solitario/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Hipoxia/fisiopatología , Hipoxia/metabolismo , Masculino , Ácido Glutámico/metabolismo , Receptores Purinérgicos/metabolismo , Ratas , Ratas Wistar , Ácido Quinurénico/farmacología , Células Quimiorreceptoras/metabolismo , Células Quimiorreceptoras/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacología , Citratos/farmacología , Factores de TiempoRESUMEN
Omega-3 (n3) is a polyunsaturated fatty acid well known for its anti-inflammatory and neuroprotective properties. Obesity is linked to chronic inflammation that disrupts metabolism, the intestine physiology and the central nervous system functioning. This study aims to determine if n3 supplementation can interfere with the effects of obesity on the mitochondrial activity, intestinal barrier, and neurotransmitter levels in the brain of Wistar rats that received cafeteria diet (CAF). We examined adipose tissue, skeletal muscle, plasma, intestine, and the cerebral cortex of four groups: CT (control diet), CTn3 (control diet with n3 supplementation), CAF, and CAFn3 (CAF and n3). Diets were offered for 13 weeks, with n3 supplementation in the final 5 weeks. Adipose tissue Electron Transport Chain complexes I, II, and III showed higher activity in CAF groups, as did complexes III and IV in skeletal muscle. Acetate levels in plasma were reduced in CAF groups, and Lipopolysaccharide (LPS) was higher in the CAF group but reduced in CAFn3 group. Claudin-5 in the intestine was lower in CAF groups, with no n3 supplementation effect. In the cerebral cortex, dopamine levels were decreased with CAF, which was reversed by n3. DOPAC, a dopamine metabolite, also showed a supplementation effect, and HVA, a diet effect. Serotonin levels increased in the CAF group that received supplementation. Therefore, we demonstrate disturbances in mitochondria, plasma, intestine and brain of rats submitted to CAF and the potential benefit of n3 supplementation in endotoxemia and neurotransmitter levels.
Asunto(s)
Ácidos Grasos Omega-3 , Obesidad , Ratas Wistar , Transmisión Sináptica , Animales , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-3/metabolismo , Obesidad/metabolismo , Masculino , Transmisión Sináptica/efectos de los fármacos , Ratas , Suplementos Dietéticos , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacosRESUMEN
BACKGROUND: Spreading depression (SD) is an intriguing phenomenon characterized by massive slow brain depolarizations that affect neurons and glial cells. This phenomenon is repetitive and produces a metabolic overload that increases secondary damage. However, the mechanisms associated with the initiation and propagation of SD are unknown. Multiple lines of evidence indicate that persistent and uncontrolled opening of hemichannels could participate in the pathogenesis and progression of several neurological disorders including acute brain injuries. Here, we explored the contribution of astroglial hemichannels composed of connexin-43 (Cx43) or pannexin-1 (Panx1) to SD evoked by high-K+ stimulation in brain slices. RESULTS: Focal high-K+ stimulation rapidly evoked a wave of SD linked to increased activity of the Cx43 and Panx1 hemichannels in the brain cortex, as measured by light transmittance and dye uptake analysis, respectively. The activation of these channels occurs mainly in astrocytes but also in neurons. More importantly, the inhibition of both the Cx43 and Panx1 hemichannels completely prevented high K+-induced SD in the brain cortex. Electrophysiological recordings also revealed that Cx43 and Panx1 hemichannels critically contribute to the SD-induced decrease in synaptic transmission in the brain cortex and hippocampus. CONCLUSIONS: Targeting Cx43 and Panx1 hemichannels could serve as a new therapeutic strategy to prevent the initiation and propagation of SD in several acute brain injuries.
Asunto(s)
Astrocitos , Conexina 43 , Conexinas , Depresión de Propagación Cortical , Transmisión Sináptica , Animales , Astrocitos/fisiología , Conexinas/metabolismo , Depresión de Propagación Cortical/fisiología , Depresión de Propagación Cortical/efectos de los fármacos , Transmisión Sináptica/fisiología , Transmisión Sináptica/efectos de los fármacos , Conexina 43/metabolismo , Masculino , Proteínas del Tejido Nervioso/metabolismo , Corteza Cerebral , Neuronas/fisiología , Hipocampo , Ratas Sprague-Dawley , Ratas , Potasio/metabolismoRESUMEN
Quercetin is a flavonol widely distributed in plants and has various described biological functions. Several studies have reported on its ability to restore neuronal function in a wide variety of disease models, including animal models of neurodegenerative disorders such as Parkinson's disease. Quercetin per se can act as a neuroprotector/neuromodulator, especially in diseases related to impaired dopaminergic neurotransmission. However, little is known about how quercetin interacts with the dopaminergic machinery. Here we employed the nematode Caenorhabditis elegans to study this putative interaction. After observing behavioral modulation, mutant analysis and gene expression in C. elegans upon exposure to quercetin at a concentration that does not protect against MPTP, we constructed a homology-based dopamine transporter protein model to conduct a docking study. This led to suggestive evidence on how quercetin may act as a dopaminergic modulator by interacting with C. elegans' dopamine transporter and alter the nematode's exploratory behavior. Consistent with this model, quercetin controls C. elegans behavior in a way dependent on the presence of both the dopamine transporter (dat-1), which is up-regulated upon quercetin exposure, and the dopamine receptor 2 (dop-2), which appears to be mandatory for dat-1 up-regulation. Our data propose an interaction with the dopaminergic machinery that may help to establish the effects of quercetin as a neuromodulator.
Asunto(s)
Dopamina , Quercetina , Transmisión Sináptica , Animales , Caenorhabditis elegans , Quercetina/farmacología , Dopamina/metabolismo , Proteínas de Caenorhabditis elegans , Fármacos Neuroprotectores/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Neuronas/metabolismo , Estrés Oxidativo , Transmisión Sináptica/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , 1-Metil-4-fenil-1,2,3,6-TetrahidropiridinaRESUMEN
Fluoride is an essential chemical found in dental preparations, pesticides and drinking water. Excessive fluoride exposure is related to toxicological and neurological disruption. Zebrafish are used in translational approaches to understand neurotoxicity in both biomedical and environmental areas. However, there is no complete knowledge about the cumulative effects of fluoride on neurotransmission systems. Therefore, the aim of this study was to evaluate whether prolonged exposure to sodium fluoride (NaF) alters cholinergic and glutamatergic systems and oxidative stress homeostasis in the zebrafish brain. Adult zebrafish were used, divided into four experimental groups, one control group and three groups exposed to NaF at 30, 50 and 100 mg.L-1 for a period of 30 days. After NaF at 30 mg.L-1 exposure, there were significant decreases in acetylcholinesterase (29.8 %) and glutamate uptake (39.3 %). Furthermore, thiobarbituric acid-reactive species were decreased at NaF 50 mg.L-1 (32.7 %), while the group treated with NaF at 30 mg.L-1 showed an increase in dichlorodihydrofluorescein oxidation (41.4 %). NaF at 30 mg.L-1 decreased both superoxide dismutase (55.3 %) and catalase activities (26.1 %). The inhibitory effect observed on cholinergic and glutamatergic signalling mechanisms could contribute to the neurodegenerative events promoted by NaF in the zebrafish brain.
Asunto(s)
Encéfalo , Fluoruros , Estrés Oxidativo , Transmisión Sináptica , Pez Cebra , Acetilcolinesterasa/metabolismo , Animales , Encéfalo/efectos de los fármacos , Fluoruros/efectos adversos , Transmisión Sináptica/efectos de los fármacos , Pez Cebra/metabolismoRESUMEN
The endocannabinoid neurotransmission acting via local CB1 receptor in the bed nucleus of the stria terminalis (BNST) has been implicated in behavioral and physiological responses to emotional stress. However, the neural network related to this control is poorly understood. In this sense, the lateral hypothalamus (LH) is involved in stress responses, and BNST GABAergic neurons densely innervate this hypothalamic nucleus. However, a role of BNST projections to the LH in physiological responses to stress is unknown. Therefore, using male rats, we investigated the role of LH GABAergic neurotransmission in the regulation of cardiovascular responses to stress by CB1 receptors within the BNST. We observed that microinjection of the selective CB1 receptor antagonist AM251 into the BNST decreased the number of Fos-immunoreactive cells within the LH of rats submitted to acute restraint stress. Treatment of the BNST with AM251 also enhanced restraint-evoked tachycardia. Nevertheless, arterial pressure increase and sympathetically-mediated cutaneous vasoconstriction to restraint was not affected by CB1 receptor antagonism within the BNST. The effect of AM251 in the BNST on restraint-evoked tachycardia was abolished in animals pretreated with the selective GABAA receptor antagonist SR95531 in the LH. These results indicate that regulation of cardiovascular responses to stress by CB1 receptors in the BNST is mediated by GABAergic neurotransmission in the LH. Present data also provide evidence of the BNST endocannabinoid neurotransmission as a mechanism involved in LH neuronal activation during stressful events.
Asunto(s)
Endocannabinoides/fisiología , Área Hipotalámica Lateral/fisiología , Distrés Psicológico , Núcleos Septales/fisiología , Animales , Antagonistas de Receptores de Cannabinoides/administración & dosificación , Antagonistas del GABA/administración & dosificación , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Área Hipotalámica Lateral/efectos de los fármacos , Masculino , Modelos Neurológicos , Piperidinas/administración & dosificación , Pirazoles/administración & dosificación , Piridazinas/administración & dosificación , Ratas , Ratas Wistar , Núcleos Septales/efectos de los fármacos , Estrés Psicológico/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Taquicardia/fisiopatologíaRESUMEN
Lithium chloride has been widely used as a therapeutic mood stabilizer. Although cumulative evidence suggests that lithium plays modulatory effects on postsynaptic receptors, the underlying mechanism by which lithium regulates synaptic transmission has not been fully elucidated. In this work, by using the advantageous neuromuscular synapse, we evaluated the effect of lithium on the stability of postsynaptic nicotinic acetylcholine receptors (nAChRs) in vivo. We found that in normally innervated neuromuscular synapses, lithium chloride significantly decreased the turnover of nAChRs by reducing their internalization. A similar response was observed in CHO-K1/A5 cells expressing the adult muscle-type nAChRs. Strikingly, in denervated neuromuscular synapses, lithium led to enhanced nAChR turnover and density by increasing the incorporation of new nAChRs. Lithium also potentiated the formation of unstable nAChR clusters in non-synaptic regions of denervated muscle fibres. We found that denervation-dependent re-expression of the foetal nAChR γ-subunit was not altered by lithium. However, while denervation inhibits the distribution of ß-catenin within endplates, lithium-treated fibres retain ß-catenin staining in specific foci of the synaptic region. Collectively, our data reveal that lithium treatment differentially affects the stability of postsynaptic receptors in normal and denervated neuromuscular synapses in vivo, thus providing novel insights into the regulatory effects of lithium on synaptic organization and extending its potential therapeutic use in conditions affecting the peripheral nervous system.
Asunto(s)
Cloruro de Litio/farmacología , Unión Neuromuscular/efectos de los fármacos , Sinapsis/efectos de los fármacos , Potenciales Sinápticos/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Animales , Células CHO , Cricetinae , Cricetulus , Desnervación/métodos , Ratones , Microscopía Fluorescente/métodos , Unión Neuromuscular/fisiología , Unión Neuromuscular/cirugía , Transporte de Proteínas/efectos de los fármacos , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Sinapsis/metabolismo , Sinapsis/fisiología , Potenciales Sinápticos/fisiologíaRESUMEN
Mounting evidence implicates dysfunctional GABAAR-mediated neurotransmission as one of the underlying causes of learning and memory deficits observed in the Ts65Dn mouse model of Down syndrome (DS). The specific origin and nature of such dysfunction is still under investigation, which is an issue with practical consequences to preclinical and clinical research, as well as to the care of individuals with DS and anxiety disorder or those experiencing seizures in emergency room settings. Here, we investigated the effects of GABAAR positive allosteric modulation (PAM) by diazepam on brain activity, synaptic plasticity, and behavior in Ts65Dn mice. We found Ts65Dn mice to be less sensitive to diazepam, as assessed by electroencephalography, long-term potentiation, and elevated plus-maze. Still, diazepam pre-treatment displayed typical effectiveness in reducing susceptibility and severity to picrotoxin-induced seizures in Ts65Dn mice. These findings fill an important gap in the understanding of GABAergic function in a key model of DS.
Asunto(s)
Diazepam/farmacología , Síndrome de Down/tratamiento farmacológico , Fenómenos Electrofisiológicos/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Femenino , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Picrotoxina/farmacología , Convulsiones/inducido químicamente , Transmisión Sináptica/efectos de los fármacosRESUMEN
The endocannabinoid 2-arachidonoylglycerol (2-AG) is an atypical neurotransmitter synthesized on demand in response to a wide range of stimuli, including exposure to stress. Through the activation of cannabinoid receptors, 2-AG can interfere with excitatory and inhibitory neurotransmission in different brain regions and modulate behavioural, endocrine and emotional components of the stress response. Exposure to chronic or intense unpredictable stress predisposes to maladaptive behaviour and is one of the main risk factors involved in developing mood disorders, such as major depressive disorder (MDD). In this review, we describe the molecular mechanisms involved in 2-AG signalling in the brain of healthy and stressed animals and discuss how such mechanisms could modulate stress adaptation and susceptibility to depression. Furthermore, we review preclinical evidence indicating that the pharmacological modulation of 2-AG signalling stands as a potential new therapeutic target in treating MDD. Particular emphasis is given to the pharmacological augmentation of 2-AG levels by monoacylglycerol lipase (MAGL) inhibitors and the modulation of CB2 receptors.
Asunto(s)
Antidepresivos/farmacología , Ácidos Araquidónicos/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Endocannabinoides/metabolismo , Glicéridos/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Animales , Antidepresivos/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Mayor/psicología , Modelos Animales de Enfermedad , Humanos , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/metabolismo , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/metabolismo , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Transmisión Sináptica/efectos de los fármacosRESUMEN
The endocannabinoid system is implicated in anxiety, but the brain sites involved are not completely understood. The bed nucleus of the stria terminalis (BNST) has been related to anxiety and responses to aversive threats. Besides, endocannabinoid neurotransmission acting via CB1 receptors was identified in the BNST. However, the presence of CB2 receptors and the role of BNST endocannabinoid system in anxiety-like behaviors have never been reported. Therefore, this study investigated the presence of CB1 and CB2 receptors in the BNST and their role in anxiety-like behaviors. For this, gene expression of the endocannabinoid receptors was evaluated in samples from anterior and posterior BNST. Besides, behaviors were evaluated in the elevated plus-maze (EPM) in unstressed rats (trait anxiety-like behavior) and after exposure to restraint stress (restraint-evoked anxiety-like behavior) in rats treated with either the CB1 receptor antagonist AM251 or the CB2 receptor antagonist JTE907 into the anterior BNST. The presence of CB1 and CB2 receptors gene expression was identified in anterior and posterior divisions of the BNST. Bilateral microinjection of AM251 into the anterior BNST dose-dependently increased EPM open arms exploration in unstressed animals and inhibited the anxiety-like behavior in the EPM evoked by restraint. Conversely, intra-BNST microinjection of JTE907 decreased EPM open arms exploration in a dose-dependent manner and inhibited restraint-evoked behavioral changes in the EPM. Taken together, these results indicate that CB1 and CB2 receptors present in the BNST are involved in control of anxiety-like behaviors, and control by the latter is affected by previous stress experience.
Asunto(s)
Ansiedad/psicología , Endocannabinoides/metabolismo , Núcleos Septales/efectos de los fármacos , Estrés Psicológico/metabolismo , Transmisión Sináptica/efectos de los fármacos , Animales , Antagonistas de Receptores de Cannabinoides , Dioxoles/administración & dosificación , Expresión Génica , Masculino , Modelos Neurológicos , Piperidinas/administración & dosificación , Pirazoles/administración & dosificación , Quinolonas/administración & dosificación , Ratas , Ratas Wistar , Restricción Física/efectos adversos , Núcleos Septales/metabolismoRESUMEN
The lateral hypothalamus (LH) is a diencephalic structure that has been considered part of the central circuitry regulating the baroreflex function. However, the local neurochemical mechanisms involved in baroreflex control by this hypothalamic area are poorly understood. Therefore, in the present study we investigated the role of corticotropin-releasing factor (CRF) neurotransmission within the LH acting via local CRF1 and CRF2 receptors in cardiac baroreflex responses in unanesthetized rats. For this, the baroreflex activity was assessed using two approaches: i) the pharmacological approach via intravenous infusion of vasoactive agents, and ii) the sequence analysis technique that evaluates reflex responses during spontaneous arterial pressure variations. The sequence analysis technique indicated that LH treatment with the selective CRF1 receptor antagonist CP376395 decreased the baroreflex effectiveness index, whereas the selective CRF2 receptor antagonist antisauvagine-30 increased the reflex shortening of pulse interval during spontaneous arterial pressure decreases. However, the pharmacological approach did not indicate effect of the bilateral microinjection of either CP376395 or antisauvagine-30 into the LH in the tachycardia evoked by blood pressure decrease or the reflex bradycardia caused by blood pressure increase. Overall, these findings indicate that CRF neurotransmission within the LH controls baroreflex function during a narrow range of physiological arterial pressure variations. Besides, results provide evidence that CRF1 and CRF2 receptors in the LH oppositely modulate the spontaneous baroreflex activity through different mechanisms.
Asunto(s)
Barorreflejo/fisiología , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Aminopiridinas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Bradicardia , Fármacos Cardiovasculares/farmacología , Hormona Liberadora de Corticotropina/metabolismo , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Área Hipotalámica Lateral/metabolismo , Área Hipotalámica Lateral/fisiología , Masculino , Fragmentos de Péptidos/farmacología , Ratas , Ratas Wistar , Receptores de Hormona Liberadora de Corticotropina/genética , Transmisión Sináptica/efectos de los fármacos , TaquicardiaRESUMEN
Recent evidence indicates that soluble amyloid-ß (Aß) species induce imbalances in excitatory and inhibitory transmission, resulting in neural network functional impairment and cognitive deficits during early stages of Alzheimer's disease (AD). To evaluate the in vivo effects of two soluble Aß species (Aß 25-35 and Aß 1-40) on commissural CA3-to-CA1 (cCA3-to-CA1) synaptic transmission and plasticity, and CA1 oscillatory activity, we used acute intrahippocampal microinjections in adult anaesthetized male Wistar rats. Soluble Aß microinjection increased cCA3-to-CA1 synaptic variability without significant changes in synaptic efficiency. High-frequency CA3 stimulation was rendered inefficient by soluble Aß intrahippocampal injection to induce long-term potentiation and to enhance synaptic variability in CA1, contrasting with what was observed in vehicle-injected subjects. Although soluble Aß microinjection significantly increased the relative power of γ-band and ripple oscillations and significantly shifted the average vector of θ-to-γ phase-amplitude coupling (PAC) in CA1, it prevented θ-to-γ PAC shift induced by high-frequency CA3 stimulation, opposite to what was observed in vehicle-injected animals. These results provide further evidence that soluble Aß species induce synaptic dysfunction causing abnormal synaptic variability, impaired long-term plasticity, and deviant oscillatory activity, leading to network activity derailment in the hippocampus.
Asunto(s)
Péptidos beta-Amiloides/farmacología , Ondas Encefálicas/efectos de los fármacos , Región CA1 Hipocampal/diagnóstico por imagen , Región CA3 Hipocampal/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Sinapsis/efectos de los fármacos , Animales , Estimulación Eléctrica , Masculino , Vías Nerviosas/efectos de los fármacos , Neuronas/efectos de los fármacos , Ratas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacosRESUMEN
Several previous studies showed that hippocampus and cortex are affected in Alzheimer's disease (AD). However, other brain regions have also been found to be affected and could contribute with new critical information to the pathophysiological basis of AD. For example, volumetric studies in humans have shown a significant atrophy of the striatum, particularly in the nucleus Accumbens (nAc). The nAc is a key component of the limbic reward system and it is involved in cognition and emotional behaviors such as pleasure, fear, aggression and motivations, all of which are affected in neurodegenerative diseases such as AD. However, its role in AD has not been extensively studied. Therefore, using an AD mouse model, we investigated if the nAc was affected in 6 months old transgenic 2xTg (APP/PS1) mice. Immunohistochemistry (IHC) analysis in 2xTg mice showed increased intraneuronal Aß accumulation, as well as occasional extracellular amyloid deposits detected through Thioflavin-S staining. Interestingly, the intracellular Aß pathology was associated to an increase in membrane excitability in dissociated medium spiny neurons (MSNs) of the nAc. IHC and western blot analyses showed a decrease in glycine receptors (GlyR) together with a reduction in the pre- and post-synaptic markers SV2 and gephyrin, respectively, which correlated with a decrease in glycinergic miniature synaptic currents in nAc brain slices. Additionally, voltage-clamp recordings in dissociated MSNs showed a decrease in AMPA- and Gly-evoked currents. Overall, these results showed intracellular Aß accumulation together with an increase in excitability and synaptic alterations in this mouse model. These findings provide new information that might help to explain changes in motivation, anhedonia, and learning in the onset of AD pathogenesis.
Asunto(s)
Enfermedad de Alzheimer , Neuronas/fisiología , Núcleo Accumbens/fisiología , Transmisión Sináptica/fisiología , Enfermedad de Alzheimer/patología , Animales , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/patología , Técnicas de Placa-Clamp , Placa Amiloide/patología , Receptores de Glicina/metabolismo , Transmisión Sináptica/efectos de los fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Cocaine (COC) is a psychostimulant that acts by increasing catecholaminergic neurotransmission mainly due to its effects on the dopamine transporter (DAT). However, other neurotransmitter systems may also be regulated by COC, including the GABAergic system. Since the effect of COC in modulating gamma-aminobutyric acid (GABA) reuptake is not defined, we investigated the molecular mechanisms related to the increase in GABA uptake induced by acute COC exposure and its effects on locomotor activity in adolescent mice. Behavioral experiments showed that COC increased locomotor activity and decreased immobilization time in mice. A single COC exposure reduced both GABA uptake and GAT-1 protein levels. On the other hand, cyclic adenosine monophosphate (cAMP) levels increased after a COC challenge. The major changes induced by acute COC on behavioral and neurochemical assays were avoided by previous treatment with the selective D1 receptor antagonist SCH-23390 (0.5 mg/kg). Our findings suggest that GABA uptake naturally decreases during mice development from preadolescence until adulthood and that dopamine (DA) D1-like receptors are key players in the regulation of GABA uptake levels following a single COC exposure in adolescent mice.
Asunto(s)
Cocaína/farmacología , Dopamina/metabolismo , Lóbulo Frontal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Ácido gamma-Aminobutírico/efectos de los fármacos , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/administración & dosificación , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Lóbulo Frontal/metabolismo , Ratones , Actividad Motora/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Somatosensory afferent transmission strength is controlled by several presynaptic mechanisms that reduce transmitter release at the spinal cord level. We focused this investigation on the role of α-adrenoceptors in modulating sensory transmission in low-threshold myelinated afferents and in pathways mediating primary afferent depolarization (PAD) of neonatal mouse spinal cord. We hypothesized that the activation of α-adrenoceptors depresses low threshold-evoked synaptic transmission and inhibits pathways mediating PAD. Extracellular field potentials (EFPs) recorded in the deep dorsal horn assessed adrenergic modulation of population monosynaptic transmission, while dorsal root potentials (DRPs) recorded at root entry zone assessed adrenergic modulation of PAD. We found that noradrenaline (NA) and the α1-adrenoceptor agonists phenylephrine and cirazoline depressed synaptic transmission (by 15, 14 and 22%, respectively). DRPs were also depressed by NA, phenylephrine and cirazoline (by 62, 30, and 64%, respectively), and by the α2-adrenoceptor agonist clonidine, although to a lower extent (20%). We conclude that NA depresses monosynaptic transmission of myelinated afferents onto deep dorsal horn neurons via α1-adrenoceptors and inhibits interneuronal pathways mediating PAD through the activation of α1- and α2-adrenoceptors. The functional significance of these modulatory actions in shaping cutaneous and muscle sensory information during motor behaviors requires further study.
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Agonistas alfa-Adrenérgicos/farmacología , Fenómenos Electrofisiológicos/fisiología , Fibras Nerviosas Mielínicas/fisiología , Neuronas Aferentes/fisiología , Receptores Adrenérgicos alfa 1/fisiología , Receptores Adrenérgicos alfa 2/fisiología , Asta Dorsal de la Médula Espinal/fisiología , Transmisión Sináptica/fisiología , Animales , Animales Recién Nacidos , Fenómenos Electrofisiológicos/efectos de los fármacos , Técnicas In Vitro , Ratones , Ratones Endogámicos BALB C , Vías Nerviosas/fisiología , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
The new glucosyl sarpagan alkaloid designated as 21(R*)-(O-ß-glucosyl)-hydroxy-sarpagan-17-oic acid, along with eleven known alkaloids were isolated from a soluble alkaloidal fraction from the ethanol extract of Rauvolfia ligustrina. Their structures were elucidated by interpretation of spectroscopic data (1D and 2D NMR), HRESIMS experiment, GIAO 13C NMR calculations, and comparison with literature data. All the isolated alkaloids were screened by their neuroinhibitory effects using the electrically stimulated mice vas deferens bioassay. Compounds 1, 2 and 9 presented a potent inhibitory effect in the neurotransmission while 3 and 11 showed an acute neuroexcitatory effect. Compound 10 exhibited a very effective post-synaptic inhibitory activity.
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Alcaloides Indólicos/farmacología , Raíces de Plantas/química , Rauwolfia/química , Transmisión Sináptica/efectos de los fármacos , Animales , Brasil , Estimulación Eléctrica , Técnicas In Vitro , Alcaloides Indólicos/química , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Extractos Vegetales/química , Conducto Deferente/efectos de los fármacosRESUMEN
INTRODUCTION AND OBJECTIVES: Oxytocin (OT) has been widely linked to positive social interactions, and there is great interest in OT as a therapy for a variety of neuropsychiatric conditions. Recent evidence also suggests that OT can play an important role in the mediation of anxiety-associated defensive responses, including a role for serotonin (5-HT) neurotransmission in this action. However, it is presently unknown whether OT additionally regulates the expression of panic-related behaviors, such as escape, by acting in the dorsal periaqueductal gray (dPAG), a key panic-regulating area. This study aimed to investigate the consequence of OT injection in the dPAG on escape expression and whether facilitation of 5-HT neurotransmission in this midbrain area is implicated in this action. METHODS: Male Wistar rats were injected with OT in the dPAG and tested for escape expression in the elevated T-maze (ETM) and dPAG electrical stimulation tests. Using the latter test, OT's effect was also investigated after previous intra-dPAG injection of the OT receptor antagonist atosiban, the preferential antagonists of 5-HT1A and 5-HT2A receptors, WAY-100635 and ketanserin, respectively, or systemic pretreatment with the 5-HT synthesis inhibitor p-CPA. RESULTS: OT impaired escape expression in the two tests used, suggesting a panicolytic-like effect. In the ETM, the peptide also facilitated inhibitory avoidance acquisition, indicating an anxiogenic effect. Previous administration of atosiban, WAY-100635, ketanserin, or p-CPA counteracted OT's anti-escape effect. CONCLUSIONS: OT and 5-HT in the dPAG interact in the regulation of panic- and anxiety-related defensive responses. These findings open new perspectives for the development of novel therapeutic strategies for the treatment of anxiety disorders.
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Ansiolíticos/farmacología , Oxitocina/farmacología , Pánico/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Serotonina/fisiología , Animales , Conducta Animal/efectos de los fármacos , Estimulación Eléctrica , Electrodos Implantados , Reacción de Fuga/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptores de Oxitocina/antagonistas & inhibidores , Antagonistas de la Serotonina/farmacología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Vasotocina/análogos & derivados , Vasotocina/farmacologíaRESUMEN
For more than a century, epilepsy has remained an incapacitating neurological disorder with a high incidence worldwide. Mesial temporal lobe epilepsy (TLE) is a common type of epilepsy without an effective pharmacological treatment. An increase in excitability and hypersynchrony of electrical neuronal activity during development are typically associated with an excitatory/inhibitory imbalance in the neuronal network. Astrocytes release gliotransmitters, which can regulate neuronal excitability and synaptic transmission; therefore, the classical neurocentric vision of the cellular basis of epileptogenesis has begun to change. Growing evidence suggests that the key contribution of astrocyte-to-neuron signaling in the mechanisms underlies the initiation, propagation, and recurrence of seizure activity. The aim of this review was to summarize current evidence obtained from experimental models that suggest how alterations in astroglial modulation of synaptic transmission and neuronal activity contribute to the development of this brain disease. In this article, we will summarize the main pharmacological, Ca2+-imaging, and electrophysiological findings in the gliotransmitter-mediated modulation of neuronal activity and their possible regulation as a novel cellular target for the development of pharmacological strategies for treating refractory epilepsies.
Asunto(s)
Astrocitos/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Epilepsia/tratamiento farmacológico , Sinapsis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Señalización del Calcio/fisiología , Humanos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
BACKGROUND: Endocannabinoid neurotransmission in the bed nucleus of the stria terminalis is involved in the control of cardiovascular responses to stress. However, the local mechanisms involved is this regulation are not known. AIMS: The purpose of this study was to assess an interaction of bed nucleus of the stria terminalis endocannabinoid neurotransmission with local nitrergic signaling, as well as to investigate the involvement of local N-methyl-D-aspartate glutamate receptor and nitric oxide signaling in the control of cardiovascular responses to acute restraint stress by bed nucleus of the stria terminalis endocannabinoid neurotransmission in rats. METHODS: The first protocol evaluated the effect of intra-bed nucleus of the stria terminalis microinjection of the selective cannabinoid receptor type 1 receptor antagonist AM251 in nitrite/nitrate content in the bed nucleus of the stria terminalis following restraint stress. The other protocols evaluated the impact of local pretreatment with the selective N-methyl-D-aspartate glutamate receptor antagonist LY235959, the selective neuronal nitric oxide synthase inhibitor Nω-propyl-L-arginine, the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, or the protein kinase G inhibitor KT5823 in restraint-evoked cardiovascular changes following bed nucleus of the stria terminalis treatment with AM251. RESULTS: Bilateral microinjection of AM251 into the bed nucleus of the stria terminalis increased local nitric oxide release during restraint stress. Bed nucleus of the stria terminalis treatment with the cannabinoid receptor type 1 receptor antagonist also enhanced the tachycardia caused by restraint stress, but without affecting arterial pressure increase and sympathetic-mediated cutaneous vasoconstriction. The facilitation of restraint-evoked tachycardia following bed nucleus of the stria terminalis treatment with the cannabinoid receptor type 1 receptor antagonist was completely inhibited by local pretreatment with LY235959, Nω-propyl-L-arginine, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, or KT5823. CONCLUSIONS: Our results provide evidence that bed nucleus of the stria terminalis endocannabinoid neurotransmission inhibits local N-methyl-D-aspartate/neuronal nitric oxide synthase/soluble guanylate cyclase/protein kinase G signaling, and this mechanism is involved in the control of the cardiovascular responses to stress.