RESUMEN
Basal electroretinogram (ERG) oscillations have shown predictive value for modifiable risk factors for type 2 diabetes. However, their origin remains unknown. Here, we seek to establish the pharmacological profile of the low delta-like (δ1) wave in the mouse because it shows light sensitivity in the form of a decreased peak frequency upon photopic exposure. Applying neuropharmacological drugs by intravitreal injection, we eliminated the δ1 wave using lidocaine or by blocking all chemical and electrical synapses. The δ1 wave was insensitive to the blockade of photoreceptor input, but was accelerated when all inhibitory or ionotropic inhibitory receptors in the retina were antagonized. The sole blockade of GABAA, GABAB, GABAC, and glycine receptors also accelerated the δ1 wave. In contrast, the gap junction blockade slowed the δ1 wave. Both GABAA receptors and gap junctions contribute to the light sensitivity of the δ1 wave. We further found that the day light-activated neuromodulators dopamine and nitric oxide donors mimicked the effect of photopic exposure on the δ1 wave. All drug effects were validated through light flash-evoked ERG responses. Our data indicate that the low δ-like intrinsic wave detected by the non-photic ERG arises from an inner retinal circuit regulated by inhibitory neurotransmission and nitric oxide/dopamine-sensitive gap junction-mediated communication.
Asunto(s)
Diabetes Mellitus Tipo 2 , Dopamina , Ratones , Animales , Dopamina/farmacología , Fotofobia , Estimulación Luminosa , Retina , Electrorretinografía , Neurotransmisores/farmacología , Receptores de GABA-A , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
This study was conducted to evaluate how sterubin affects rotenone-induced Parkinson's disease (PD) in rats. A total of 24 rats were distributed into 4 equal groups: normal saline control and rotenone control were administered saline or rotenone (ROT), respectively, orally; sterubin 10 received ROT + sterubin 10 mg/kg po; and sterubin alone was administered to the test group (10 mg/kg). Rats of the normal saline and sterubin alone groups received sunflower oil injection (sc) daily, 1 h after receiving the treatments cited above, while rats of the other groups received rotenone injection (0.5 mg/kg, sc). The treatment was continued over the course of 28 days daily. On the 29th day, catalepsy and akinesia were assessed. The rats were then euthanized, and the brain was extracted for estimation of endogenous antioxidants (MDA: malondialdehyde, GSH: reduced glutathione, CAT: catalase, SOD: superoxide dismutase), nitrative (nitrite) stress markers, neuroinflammatory cytokines, and neurotransmitter levels and their metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA), norepinephrine (NE), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA)). Akinesia and catatonia caused by ROT reduced the levels of endogenous antioxidants (GSH, CAT, and SOD), elevated the MDA level, and altered the levels of nitrites, neurotransmitters, and their metabolites. Sterubin restored the neurobehavioral deficits, oxidative stress, and metabolites of altered neurotransmitters caused by ROT. Results demonstrated the anti-Parkinson's activities of sterubin in ROT-treated rats.
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Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratas , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/prevención & control , Antioxidantes/farmacología , Rotenona/farmacología , Solución Salina/farmacología , Estrés Oxidativo , Neurotransmisores/metabolismo , Neurotransmisores/farmacología , Superóxido Dismutasa , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Menopause is a physiological event that marks the end of a woman's reproductive stage in life. Vasomotor symptoms and changes in mood are among its most important effects. Homeopathy has been used for many years in treating menopausal complaints, though clinical and pre-clinical research in this field is limited. Homeopathy often bases its prescription on neuropsychiatric symptoms, but it is unknown if homeopathic medicines (HMs) exert a neuroendocrine effect that causes an improvement in vasomotor symptoms and mood during menopause. OBJECTIVES: The study's objectives were to address the pathophysiological changes of menopause that could help in the understanding of the possible effect of HMs at a neuroendocrine level, to review the current evidence for two of the most frequently prescribed HMs for menopause (Lachesis mutus and Sepia officinalis), and to discuss the future directions of research in this field. METHODS: An extensive literature search for the pathophysiologic events of menopause and depression, as well as for the current evidence for HMs in menopause and depression, was performed. RESULTS: Neuroendocrine changes are involved in the pathophysiology of vasomotor symptoms and changes in mood during menopause. Gonadal hormones modulate neurotransmitter systems. Both play a role in mood disorders and temperature regulation. It has been demonstrated that Gelsemium sempervirens, Ignatia amara and Chamomilla matricaria exert anxiolytic effects in rodent models. Lachesis mutus and Sepia officinalis are frequently prescribed for important neuropsychiatric and vasomotor symptoms. Dopamine, a neurotransmitter involved in mood, is among the constituents of the ink of the common cuttlefish, Sepia officinalis. CONCLUSION: Based on all the pathophysiologic events of menopause and the improvement in menopausal complaints that certain HMs show in daily practice, these medicines might have a direct or indirect neuroendocrine effect in the body, possibly triggered via an as-yet unidentified biological mechanism. Many unanswered questions in this field require further pre-clinical and clinical research.
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Homeopatía , Materia Medica , Femenino , Humanos , Menopausia/fisiología , Menopausia/psicología , Materia Medica/farmacología , Trastornos del Humor , Neurotransmisores/farmacologíaRESUMEN
Striatal medium-sized spiny neurons express mRNA and protein of GPR55 receptors that stimulate neurotransmitter release; thus, GPR55 could be sent to nigral striatal projections, where it might modulate GABA release and motor behavior. Here, we study the presence of GPR55 receptors at striato-nigral terminals, their modulation of GABA release, their signaling pathway, and their effect on motor activity. By double immunohistochemistry, we found the colocation of GPR55 protein and substance P in the dorsal striatum. In slices of the rat substantia nigra, the GPR55 agonists LPI and O-1602 stimulated [3 H]-GABA release induced by high K+ depolarization in a dose-dependent manner. The antagonists CID16020046 and cannabidiol prevented agonist stimulation in a dose-dependent way. The effect of GPR55 on nigral [3 H]-GABA release was prevented by lesion of the striatum with kainic acid, which was accompanied by a decrement of GPR55 protein in nigral synaptosomes, indicating the presynaptic location of receptors. The depletion of internal Ca2+ stores with thapsigargin did not prevent the effect of LPI on [3 H]-GABA release, but the remotion or chelation of external calcium did. Blockade of Gi, Gs, PLC, PKC, or dopamine D1 receptor signaling proteins did not prevent the effect of GPR55 on release. However, the activation of GPR55 stimulated [3 H]-cAMP accumulation and PKA activity. Intranigral unilateral injection of LPI induces contralateral turning. This turning was prevented by CID16020046, cannabidiol, and bicuculline but not by SCH 23390. Our data indicate that presynaptic GPR55 receptors stimulate [3 H]-GABA release at striato-nigral terminals through [3 H]-cAMP production and stimulate motor behavior.
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Cannabidiol , Receptores de Cannabinoides , Receptores Acoplados a Proteínas G , Receptores Presinapticos , Animales , Compuestos de Azabiciclo , Benzoatos , Bicuculina/farmacología , Calcio/metabolismo , Cannabidiol/metabolismo , Cannabidiol/farmacología , Ácido Kaínico/metabolismo , Ácido Kaínico/farmacología , Neurotransmisores/farmacología , ARN Mensajero/metabolismo , Ratas , Receptores de Cannabinoides/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Presinapticos/metabolismo , Sustancia P/metabolismo , Sustancia Negra/metabolismo , Tapsigargina/metabolismo , Tapsigargina/farmacología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Benzodiazepines are highly effective in combating anxiety; however, they have considerable adverse effects, so it is important to discover new safe anxiolytic agents. This study was designed to investigate the effect of the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone (HTMCX) on anxiety and seizure behavior in adult zebrafish and its possible mechanisms of action. The acute toxicity of 96 h of HTMCX was analyzed, and the open and light/dark field tests (n = 6 animals/group) were used to assess the anxiety behavior of animals treated with HTMCX. In addition, the mechanisms of action were investigated with antagonists of the GABAA, 5-HT receptors, and molecular anchorage study. Pentylenetetrazole (PTZ) was used to induce seizure by immersion. As a result, acetophenone HTMCX (1, 3 and 10 mg/kg; v.o.) was non-toxic and affected locomotor activity. The higher doses (3 and 10 mg/kg; v.o.) produced signs of anxiolytic action in the light/dark test, and this effect was reversed by the pizotifen (antagonist 5HTR1 and 5HTR2A/2C), having the potential to form a complex with 5HTR1B. However, the anxiolytic effect of HTMCX has not been abolished by flumazenil (antagonist GABAA), cyproheptadine (antagonist 5HTR2A), and granisetron (antagonist 5HTR3A/3B). Therefore, HTMCX demonstrated an anxiolytic effect, suggesting that the 5HTR1 and 5HTR2C receptors may be involved in the pharmacological performance of this acetophenone in the central nervous system.
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Acetofenonas/uso terapéutico , Ansiolíticos/uso terapéutico , Ansiedad/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Croton , Neurotransmisores/uso terapéutico , Acetofenonas/farmacología , Acetofenonas/toxicidad , Animales , Ansiolíticos/farmacología , Ansiolíticos/toxicidad , Ansiedad/metabolismo , Productos Biológicos/farmacología , Productos Biológicos/toxicidad , Femenino , Masculino , Simulación del Acoplamiento Molecular , Neurotransmisores/farmacología , Neurotransmisores/toxicidad , Pentilenotetrazol , Receptores de Serotonina/metabolismo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Serotonina/metabolismo , Pez CebraRESUMEN
Dopamine (DA) is an important molecule that plays a role in the nervous and immune systems. DA is produced by a wide variety of animals and it is considered one of the oldest neurotransmitters. However, its specific function in immune cells has not been completely revealed. In a group of chordate animals, the ascidians, DA is reported to be produced by cells in the central nervous system (CNS); however, no dopaminergic receptor in their genomes has been described until now. Because this is an integrating characteristic of the ascidian dopamine system, here it was investigated the pharmacology, function, and phylogeny of DA and dopaminergic receptors (DRs) in the modulation of nitric oxide (NO) in the Phallusia nigra immune cells. The data disclosed, for the first time, that DA modulates NO production by immune cells. Its modulation probably occurs though adrenergic receptors, which display a special characteristic, in that they are capable of binding to noradrenaline (NA) and DA. A pharmacological analysis revealed that receptors present on the ascidian immune cells showed a high affinity to butaclamol, a non-selective D2-class receptor, increasing NO production. In addition, calcium intracellular mobilization was observed when DA was added to immune cells. In conclusion, the data revealed novel insights about the presence of catecholaminergic receptors (CRs) on the P. nigra immune cells, indicating that ascidian CRs have special pharmacological characteristics that are worth highlighting from an evolutionary point of view.
Asunto(s)
Dopamina/farmacología , Neurotransmisores/farmacología , Receptores de Dopamina D2/metabolismo , Transducción de Señal/efectos de los fármacos , Urocordados/inmunología , Animales , Dopamina/metabolismo , FilogeniaRESUMEN
Major depression disorder (MDD) is one of the most widespread and debilitating psychiatric diseases and may be associated with other mental disorders such as anxiety. Despite advances in neurobiology studies, currently no established mechanism can explain all facets of MDD, and available drugs often show therapeutic delay for clinical effectiveness and response rates in patients are around 50 %. Previous activities of piperazine derivatives on CNS are indicators of its therapeutic potential for treating mental disorders. In this regard, we have previously shown that the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) has anxiolytic-like activity which involves serotonergic pathway, nicotinic receptors and BZD-site of GABAA receptor, without cognitive impairments. Herein, was evaluated the potential antidepressant-like effect of LQFM212 on forced swimming test (FST) after a single dose of 54 µmol/kg and after repeated treatment for 15 days in mice. Pretreatment with WAY-100635, PCPA, prazosin, SCH-23390, sulpiride or AMPT reversed the antidepressant-like effect on FST, suggesting that monoaminergic pathway contributes for effects of LQFM212. Furthermore, repeated treatment with LQFM212 increased hippocampal BDNF levels dosed by ELISA kit. In assessment of possible adverse effects, repeated treatment with LQFM212 did not alter the body weight of the animals, glutathione levels in the liver, and serum levels of AST, ALT, urea, and creatinine. Taken together, the results showed that LQFM212 has an antidepressant-like effect that involves monoaminergic pathway and increased BDNF levels. This compound represents promising candidate for prototype of psychoactive drugs for treatment of anxiety and depression disorders since these pathological conditions may exist in comorbidities.
Asunto(s)
Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Monoaminas Biogénicas , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Depresión/tratamiento farmacológico , Neurotransmisores/farmacología , Piperazinas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Monoaminas Biogénicas/agonistas , Monoaminas Biogénicas/antagonistas & inhibidores , Modelos Animales de Enfermedad , Masculino , Ratones , Neurotransmisores/administración & dosificación , Piperazinas/administración & dosificación , Piperazinas/efectos adversosRESUMEN
BACKGROUND: Previous studies suggested that Cg1 area of the cingulate cortex of rats controls glutamate-mediated fear-induced defensive behaviour and antinociception organised at the posterior hypothalamus. In turn, microinjection of the nitric oxide donor SIN-1 into the anterior hypothalamus of mice produced defensive behaviours and fear-induced antinociception. However, it remains unknown whether Cg1 also modulates the latter mechanisms in mice. AIMS: The present study examined the influence of Cg1 on SIN1-evoked fear-induced defensive behaviour and antinociception organised at the anterior hypothalamus of mice. METHODS: The fear-like behavioural and antinociceptive responses to the microinjection of SIN-1 (300 nmol) into the anterior hypothalamus were evaluated after the microinjection of either N-methyl-D-aspartic acid receptor agonist (0.1, 1 and 10 nmol) or physiological saline into the cingulate cortex of C57BL/6 male mice. In addition, neurotracing and immunohistochemistry were used to characterise Cg1-anterior hypothalamus glutamatergic pathways. RESULTS: The data showed that activation of Cg1 N-methyl-D-aspartic acid receptors increased escape while reducing freezing and antinociceptive responses to SIN-1 microinjections into the anterior hypothalamus. Anterograde neural tract tracer co-localised with VGLUT2-labelled fibres suggests these responses are mediated by glutamatergic synapses at the anterior hypothalamus. CONCLUSIONS: In contrast with previous studies showing that Cg1 facilitates both escape and antinociception to chemical stimulation of the posterior hypothalamus in rats, the present data suggest that Cg1 facilitates escape while inhibiting defensive antinociception produced by the microinjection of SIN-1 in the anterior hypothalamus of mice. Accordingly, Cg1 may have opposite effects on antinociceptive responses organised in the anterior and posterior hypothalamus of mice and rats, respectively.
Asunto(s)
Miedo , Giro del Cíngulo , Hipotálamo Anterior , Donantes de Óxido Nítrico/metabolismo , Óxido Nítrico/metabolismo , Percepción del Dolor/fisiología , Receptores de N-Metil-D-Aspartato/agonistas , Analgesia/psicología , Animales , Conducta Animal/efectos de los fármacos , Miedo/efectos de los fármacos , Miedo/fisiología , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/metabolismo , Hipotálamo Anterior/efectos de los fármacos , Hipotálamo Anterior/fisiología , Ratones , Ratones Endogámicos C57BL , Microinyecciones/métodos , Molsidomina/análogos & derivados , Molsidomina/farmacología , Vías Nerviosas , Neurotransmisores/farmacologíaRESUMEN
The bed nucleus of the stria terminalis (BNST) is a forebrain structure, involved in the modulation of neuroendocrine, cardiovascular and autonomic responses. One of the responses is baroreflex activity, which consists in a neural mechanism responsible for keeping the blood pressure within a narrow range of variation. It has been reported that blockade of BNST α1-adrenoceptors increased the bradycardic component of baroreflex. In addition, such receptors are able to modulate glutamate release in this structure. Interestingly, BNST NMDA receptor antagonism and neuronal nitric oxide synthase (nNOS) inhibition led to the same effect of the α1-adrenoceptors blockade on baroreflex bradycardic response. Therefore, the hypothesis of the present study is that BNST noradrenergic transmission interacts with NMDA/NO pathway through α1 adrenoceptors to modulate the baroreflex activity. Male Wistar rats had stainless steel guide cannulas bilaterally implanted in the BNST. Subsequently, a catheter was inserted into the femoral artery for cardiovascular recordings, and into the femoral vein for assessing baroreflex activation. Injection of the noradrenaline reuptake inhibitor reboxetine in the BNST did not modify the tachycardic, but significantly decreased the bradycardic component of baroreflex. Administration of an α1, but not an α2 antagonist into the BNST prior to reboxetine prevented this effect. Likewise, previous injection of NMDA/NO pathway blockers inhibited the effect of reboxetine on bradycardic response. In conclusion, it was demonstrated for the first time the existence of an interaction between BNST noradrenergic, glutamatergic and nitrergic neurotransmissions in the modulation of bradycardic baroreflex response.
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Sistema Nervioso Autónomo/fisiología , Barorreflejo , Corazón/inervación , Óxido Nítrico/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleos Septales/metabolismo , Animales , Presión Arterial , Sistema Nervioso Autónomo/efectos de los fármacos , Barorreflejo/efectos de los fármacos , Frecuencia Cardíaca , Masculino , Neurotransmisores/farmacología , Ratas Wistar , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Núcleos Septales/efectos de los fármacos , Factores de TiempoRESUMEN
Despite decades of intense research to understand the phenomenon of anesthesia and its membrane-related changes in neural transmission, where lipids and proteins have been proposed as primary targets of anesthetics, the involved action mechanisms remain unclear. Based on the overall agreement that anesthetics and neurotransmitters induce particular modifications in the plasma membrane of neurons, triggering specific responses and changes in their energetic states, we present here a thermal study to investigate membrane effects in a lipid-protein model made of 1,2-dimyristoyl-sn-glycero-3-phosphocholine and albumin from chicken egg white under the influence of neurotransmitters and anesthetics. First, we observe how ovalbumin, ovotransferrin, and lysozyme (main albumin constituents from chicken egg white) interact with the lipid membrane enhancing their lipophilic character while exposing their hydrophobic domains. This produces a lipid separation and a more ordered hybrid lipid-protein assembly. Second, we measured the thermotropic changes of this assembly induced by acetylcholine, γ-aminobutiric acid, tetracaine, and pentobarbital. Although the protein in our study is not a receptor, our results are striking, for they give evidence of the great importance of non-specific interactions in the anesthesia mechanism.
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Anestésicos/farmacología , Membranas Artificiales , Modelos Biológicos , Neurotransmisores/farmacología , Temperatura , Albúminas , Animales , Pollos , Dimiristoilfosfatidilcolina , Proteínas del Huevo , Interacciones Hidrofóbicas e Hidrofílicas , Lípidos de la Membrana , Proteínas de la MembranaRESUMEN
Hypertension represents an autonomic dysfunction, characterized by increased sympathetic and decreased parasympathetic cardiovascular tone leading to resting tachycardia. Therefore, studies assessing hypertension-associated changes in isolated cardiac tissues were conducted under electric field stimulation to stimulate the neurons. Herein, we characterize the influence of the autonomic neurotransmitter on the baseline atrial chronotropism of unpaced isolated right atria of normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR). Our results revealed a resting bradycardia in tissues from SHR in comparison to NWR. The release of autonomic neurotransmitters, acetylcholine or norepinephrine, still occurs in the electrically unstimulated right atrium, after excision of the sympathetic nerve, which could explain differences in basal heart rate between NWR and SHR. Nicotine and the acetylcholinesterase inhibitor physostigmine reduced the chronotropism of right atria from either NWR or SHR. Conversely, the muscarinic receptor antagonist atropine did not affect the basal chronotropism of tissues from both strains. Furthermore, tyramine increased the chronotropism of NWR and SHR atria indicating availability of the neuronal stocks of noradrenaline. Although the monoamine uptake inhibitor cocaine increased right atrium chronotropism in both strains, the basal heart rate was not affected by the ß-adrenoceptor antagonist propranolol. In summary, after acute section of the sympathetic nerve, autonomic neurotransmitters are still released either in resting conditions or upon pharmacological stimulation of right atria from both strains. Nevertheless, autonomic neurotransmission does not affect resting chronotropism, nor is the responsible for reduced basal heart rate of the isolated right atrium of hypertensive rats.
Asunto(s)
Función del Atrio Derecho , Sistema Nervioso Autónomo/fisiopatología , Presión Sanguínea , Bradicardia/fisiopatología , Atrios Cardíacos/inervación , Frecuencia Cardíaca , Hipertensión/fisiopatología , Acetilcolina/metabolismo , Adaptación Fisiológica , Animales , Función del Atrio Derecho/efectos de los fármacos , Sistema Nervioso Autónomo/efectos de los fármacos , Sistema Nervioso Autónomo/metabolismo , Bradicardia/diagnóstico , Bradicardia/etiología , Modelos Animales de Enfermedad , Estimulación Eléctrica , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/complicaciones , Hipertensión/diagnóstico , Masculino , Neurotransmisores/farmacología , Norepinefrina/metabolismo , Ratas Endogámicas SHR , Ratas Wistar , Factores de TiempoRESUMEN
Studies about the pathogenesis of mood disorders have consistently shown that multiple factors, including genetic and environmental, play a crucial role on their development and neurobiology. Multiple pathological theories have been proposed, of which several ultimately affects or is a consequence of dysfunction in brain neuroplasticity and homeostatic mechanisms. However, current clinical available pharmacological intervention, which is predominantly monoamine-based, suffers from a partial and lacking response even after weeks of continuous treatment. These issues raise the need for better understanding of aetiologies and brain abnormalities in depression, as well as developing novel treatment strategies. Nitric oxide (NO) is a gaseous unconventional neurotransmitter, which regulates and governs several important physiological functions in the central nervous system, including processes, which can be associated with the development of mood disorders. This review will present general aspects of the NO system in depression, highlighting potential targets that may be utilized and further explored as novel therapeutic targets in the future pharmacotherapy of depression. In particular, the review will link the importance of neuroplasticity mechanisms governed by NO to a possible molecular basis for the antidepressant effects.
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Antidepresivos/farmacología , Encéfalo , Trastornos del Humor/tratamiento farmacológico , Trastornos del Humor/metabolismo , Neurotransmisores/farmacología , Óxido Nítrico/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Humanos , Ratones , Plasticidad Neuronal , Ratas , Transducción de SeñalRESUMEN
The nuclear distribution element genes are conserved from fungus to humans. The nematode Caenorhabditis elegans expresses two isoforms of nuclear distribution element genes, namely nud-1 and nud-2. While nud-1 was functionally demonstrated to be the worm nudC ortholog, bioinformatic analysis revealed that the nud-2 gene encodes the worm ortholog of the mammalian NDE1 (Nuclear Distribution Element 1 or NudE) and NDEL1 (NDE-Like 1 or NudEL) genes, which share overlapping roles in brain development in mammals and also mediate the axon guidance in mammalian and C. elegans neurons. A significantly higher NDEL1 enzyme activity was shown in treatment non-resistant compared to treatment resistant SCZ patients, who essentially present response to the therapy with atypical clozapine but not with typical antipsychotics. Using C. elegans as a model, we tested the consequence of nud genes suppression in the effects of typical and atypical antipsychotics. To assess the role of nud genes and antipsychotic drugs over C. elegans behavior, we measured body bend frequency, egg laying and pharyngeal pumping, which traits are controlled by specific neurons and neurotransmitters known to be involved in SCZ, as dopamine and serotonin. Evaluation of metabolic and behavioral response to the pharmacotherapy with these antipsychotics demonstrates an important unbalance in serotonin pathway in both nud-1 and nud-2 knockout worms, with more significant effects for nud-2 knockout. The present data also show an interesting trend of mutant knockout worm strains to present a metabolic profile closer to that observed for the wild-type animals after the treatment with the typical antipsychotic haloperidol, but which was not observed for the treatment with the atypical antipsychotic clozapine. Paradoxically, behavioral assays showed more evident effects for clozapine than for haloperidol, which is in line with previous studies with rodent animal models and clinical evaluations with SCZ patients. In addition, the validity and reliability of using this experimental animal model to further explore the convergence between the dopamine/serotonin pathways and neurodevelopmental processes was demonstrated here, and the potential usefulness of this model for evaluating the metabolic consequences of treatments with antipsychotics is also suggested.
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Antipsicóticos/farmacología , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas Portadoras/metabolismo , Animales , Animales Modificados Genéticamente , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Caenorhabditis elegans , Clozapina/farmacología , Modelos Animales de Enfermedad , Haloperidol/farmacología , Movimiento/efectos de los fármacos , Movimiento/fisiología , Neurotransmisores/farmacología , Faringe/efectos de los fármacos , Faringe/metabolismo , Espectroscopía de Protones por Resonancia Magnética , Reproducibilidad de los Resultados , Reproducción/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Serotonina/farmacologíaRESUMEN
The role of spinal cord neurons in renal sympathoexcitation remains unclear in renovascular hypertension, represented by the 2-kidney, 1-clip (2K1C) model. Thus, we aimed to assess the influence of spinal glutamatergic and AT1 angiotensin II receptors on renal sympathetic nerve activity (rSNA) in 2K1C Wistar rats. Hypertension was induced by clipping the renal artery with a silver clip. After six weeks, a catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of intrathecally (i.t.) injected kynurenic acid (KYN) or losartan (Los) on blood pressure (BP) and rSNA were analysed over 2 consecutive hours. KYN induced a significantly larger drop in rSNA among 2K1C rats than among control (CTL) rats (CTL vs. 2K1C: -8⯱â¯3 vs. -52⯱â¯9 spikes/s after 120'). Los also evoked a significantly larger drop in rSNA among 2K1C rats than among CTL rats starting at 80' after administration (CTL vs. 2K1C - 80â¯min: -10⯱â¯2 vs. -32⯱â¯6∗; 100â¯min: -15⯱â¯4 vs. -37⯱â¯9∗; 120â¯min: -12⯱â¯5 vs. -37⯱â¯8∗ spikes/s). KYN decreased BP similarly in the CTL and 2K1C groups; however, Los significantly decreased BP in the 2K1C group only. We found upregulation of AT1 gene expression in the T11-12 spinal segments in the 2K1C group but no change in gene expression for AT2 or ionotropic glutamate (NMDA, kainate and AMPA) receptors. Thus, our data show that spinal ionotropic glutamatergic and AT1 receptors contribute to increased rSNA in the 2K1C model, leading to the maintenance of hypertension; however, the participation of spinal AT1 receptors seems to be especially important in the establishment of sympathoexcitation in this model. The origins of those projections, i.e., the brain areas involved in establishing the activity of spinal glutamatergic and angiotensinergic pathways, remain unclear.
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Hipertensión Renovascular/fisiopatología , Riñón/efectos de los fármacos , Médula Espinal/fisiología , Animales , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Fármacos actuantes sobre Aminoácidos Excitadores/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión Renovascular/metabolismo , Riñón/inervación , Ácido Quinurénico/farmacología , Losartán/farmacología , Masculino , Neurotransmisores/farmacología , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
Stimulation of the midbrain periaqueductal gray matter (PAG) in humans elicits sensations of fear and impending terror, and mediates predator defensive responses in rodents. In rats, pharmacological stimulation of the dorsolateral portion of the PAG (dlPAG) with N-Methyl-d-Aspartate (NMDA) induces aversive conditioning that acts as an unconditioned stimulus (US). In the present work, we investigated the interplay between the vanilloid TRPV1 and cannabinoid CB1 receptors in the NMDA-dlPAG defensive response and in subsequent aversive learning. Rats were subjected to dlPAG NMDA infusion in an olfactory conditioned stimulus (CS) task allowing the evaluation of immediate and long-term defensive behavioral responses during CS presentation. The results indicated that an intermediate dose of NMDA (50â¯pmol) induced both immediate and long-term effects. A sub-effective dose of NMDA (25â¯pmol) was potentiated by the TRPV1 receptor agonist capsaicin (CAP, 1â¯nmol) and the CB1 receptor antagonist, AM251 (200â¯pmol). CAP (10â¯nmol) or the combination of CAP (1â¯nmol) and AM251 (200â¯pmol) induced long-term effects without increasing immediate defensive responses. The glutamate release inhibitor riluzole (2 or 4â¯nmol) and the AMPA/kainate receptor antagonist DNQX (2 or 4â¯nmol) potentiated the immediate effects but blocked the long-term effects. The results showed that immediate defensive responses rely on NMDA receptors, and aversive learning on the fine-tuning of TRPV1, CB1, metabotropic glutamate and AMPA receptors located in pre- and postsynaptic membranes. In conclusion, the activity of the dlPAG determines core affective aspects of aversive memory formation controlled by local TRPV1/CB1 balance.
Asunto(s)
Reacción de Prevención/fisiología , Memoria/fisiología , Sustancia Gris Periacueductal/metabolismo , Receptores de Cannabinoides/metabolismo , Receptores de Glutamato/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Masculino , Memoria/efectos de los fármacos , Neurotransmisores/farmacología , Percepción Olfatoria/efectos de los fármacos , Percepción Olfatoria/fisiología , Sustancia Gris Periacueductal/efectos de los fármacos , Distribución Aleatoria , Ratas WistarRESUMEN
The most common cause of dementia is Alzheimer's disease. The etiology of the disease is unknown, although considerable evidence suggests a critical role for the soluble oligomers of amyloid beta peptide (Aß). Because Aß increases the expression of purinergic receptors (P2XRs) in vitro and in vivo, we studied the functional correlation between long-term exposure to Aß and the ability of P2XRs to modulate network synaptic tone. We used electrophysiological recordings and Ca2+ microfluorimetry to assess the effects of chronic exposure (24 h) to Aß oligomers (0.5 µM) together with known inhibitors of P2XRs, such as PPADS and apyrase on synaptic function. Changes in the expression of P2XR were quantified using RT-qPCR. We observed changes in the expression of P2X1R, P2X7R and an increase in P2X2R; and also in protein levels in PC12 cells (143%) and hippocampal neurons (120%) with Aß. In parallel, the reduction on the frequency and amplitude of mEPSCs (72% and 35%, respectively) were prevented by P2XR inhibition using a low PPADS concentration. Additionally, the current amplitude and intracellular Ca2+ signals evoked by extracellular ATP were increased (70% and 75%, respectively), suggesting an over activation of purinergic neurotransmission in cells pre-treated with Aß. Taken together, our findings suggest that Aß disrupts the main components of synaptic transmission at both pre- and post-synaptic sites, and induces changes in the expression of key P2XRs, especially P2X2R; changing the neuromodulator function of the purinergic tone that could involve the P2X2R as a key factor for cytotoxic mechanisms. These results identify novel targets for the treatment of dementia and other diseases characterized by increased purinergic transmission.
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Péptidos beta-Amiloides/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Receptores Purinérgicos P2X/metabolismo , Adenosina Trifosfato/farmacología , Péptidos beta-Amiloides/química , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/citología , Homólogo 4 de la Proteína Discs Large/metabolismo , Embrión de Mamíferos , Femenino , Proteínas Asociadas a Microtúbulos/metabolismo , Neurotransmisores/farmacología , Técnicas de Placa-Clamp , Inhibidores de Agregación Plaquetaria/farmacología , Embarazo , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2X/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: Recent neurobiological evidences along with clinical observations justify the use of N-acetylcysteine (NAC) as a medication for craving. The objective of our study was to assess the evidence of efficacy of NAC for craving in substance use disorders in randomized clinical trials (RCTs). METHODS: Systematic review of the RCTs literature (PROSPERO number 56698) until February, 2017, using MEDLINE, Cochrane Library and clinicaltrials.gov. We included seven RCTs (n = 245); most with small-to-moderate sample sizes. The main outcome was the Hedges' g for continuous scores in a random-effects model. Heterogeneity was evaluated with the I2 and the χ2 test. Publication bias was evaluated using the Begg's funnel plot and the Egger's test. Meta-regression was performed using the random-effects model. RESULTS: Comparing NAC versus placebo, NAC was significantly superior for craving symptoms (Hedges' g = 0.94; 95%CI 0.55-1.33). The funnel plot showed the risk of publication bias was low and between-study heterogeneity was not significant (I2 = 44.4%, p = 0.07 for the χ2 test). A subgroup analysis performed using meta-regression showed no particular influence. DISCUSSION AND CONCLUSIONS: NAC was superior to placebo for craving reduction in SUDs. The relatively small number of trials and their heterogeneous methodology were possible limitations; however, these positive thrilling results stimulate further studies for clarifying the potential impact of NAC for craving symptoms in SUDs. SCIENTIFIC SIGNIFICANCE: The safety profile of NAC and favorable tolerability, in addition to being an over-the-counter medication, presents with an interesting potential clinical use for craving in SUDs. SCIENTIFIC SIGNIFICANCE: The safety profile of NAC and its favorable tolerability, in addition to being anover-the-counter medication, presents with an interesting potential clinical use for craving in SUDs. (Am J Addict 2017;26:660-666).
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Acetilcisteína/farmacología , Ansia/efectos de los fármacos , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Humanos , Neurotransmisores/farmacología , Trastornos Relacionados con Sustancias/psicología , Resultado del TratamientoRESUMEN
The insular cortex (IC) receives projections from prefrontal, entorhinal and cingulate cortex, olfactory bulb and basal nuclei and has reciprocal connections with the amygdala and entorhinal cortex. These connections suggest a possible involvement in memory processes; this has been borne out by data on several behaviors. Social recognition memory (SRM) is essential to form social groups and to establish hierarchies and social and affective ties. Despite its importance, knowledge about the brain structures and the neurotransmitter mechanisms involved in its processing is still scarce. Here we study the participation of NMDA-glutamatergic, D1/D5-dopaminergic, H2-histaminergic, ß-adrenergic and 5-HT1A-serotoninergic receptors of the IC in the consolidation of SRM. Male Wistar rats received intra-IC infusions of substances acting on these receptors immediately after the sample phase of a social discrimination task and 24h later were exposed to a 5-min retention test. The intra-IC infusion of antagonists of D1/D5, ß-adrenergic or 5-HT1A receptors immediately after the sample phase impaired the consolidation of SRM. These effects were blocked by the concomitant intra-IC infusion of agonists of these receptors. Antagonists and agonists of NMDA and H2 receptors had no effect on SRM. The results suggest that the dopaminergic D1/D5, ß-adrenergic and serotonergic 5-HT1A receptors in the IC, but not glutamatergic NMDA and the histaminergic H2 receptors, participate in the consolidation of SRM in the IC.
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Corteza Cerebral/metabolismo , Consolidación de la Memoria/fisiología , Receptores de Neurotransmisores/metabolismo , Reconocimiento en Psicología/fisiología , Percepción Social , Animales , Catéteres de Permanencia , Corteza Cerebral/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Discriminación en Psicología/fisiología , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Masculino , Consolidación de la Memoria/efectos de los fármacos , Neurotransmisores/farmacología , Pruebas Psicológicas , Ratas Wistar , Receptores de Neurotransmisores/agonistas , Receptores de Neurotransmisores/antagonistas & inhibidores , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
Pentylenetetrazole (PTZ) is one of the most valuable drugs used to induce seizure-like state in zebrafish especially considering the pharmacological screening for anticonvulsants and the study of basic mechanisms of epilepsy. Here, the effect of gender, weight and changes in temperature on latency to adult zebrafish reach classical seizure states induced by PTZ (10mM) was evaluated. Gender and weight (200-250mg versus 400-500mg) did not affect the profile of response to PTZ. When water temperature was changed from 22 to 30°C the lower temperature increased the latency time to reach seizure states and the higher temperature significantly decreased it, in comparison to the control group maintained at 26°C. The blockage of kainate receptors by DNQX (10µM) were unable to prevent the increased susceptibility of adult zebrafish exposed to hyperthermia and PTZ-induced seizures. The NMDA block by MK-801 (2.5µM) prevented the additive effect of hyperthermia on PTZ effects in adult zebrafish. This report emphasize that PTZ model in adult zebrafish exhibits no confounder factors from gender and weight, but water temperature is able to directly affect the response to PTZ, especially through a mechanism related to NMDA receptors.
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Convulsivantes/farmacología , Pentilenotetrazol/farmacología , Convulsiones/inducido químicamente , Convulsiones/fisiopatología , Temperatura , Animales , Anticonvulsivantes/farmacología , Peso Corporal , Maleato de Dizocilpina/farmacología , Femenino , Fiebre/tratamiento farmacológico , Fiebre/fisiopatología , Masculino , Modelos Animales , Neurotransmisores/farmacología , Caracteres Sexuales , Agua , Pez CebraRESUMEN
Depression is extremely harmful to modern society. Despite its complex spectrum of symptoms, previous studies have mostly focused on the monaminergic system in search of pharmacological targets. However, other neurotransmitter systems have also been linked to the pathophysiology of depression. In this study, we provide evidence for a role of the cholinergic system in depressive-like behavior of female mice. We evaluated mice knockdown for the vesicular acetylcholine transporter (VAChT KD mice), which have been previously shown to exhibit reduced cholinergic transmission. Animals were subjected to the tail suspension and marble burying tests, classical paradigms to assess depressive-like behaviors and to screen for novel antidepressant drugs. In addition, brain levels of serotonin and dopamine were measured by high performance liquid chromatography. We found that female homozygous VAChT KD mice spent less time immobile during tail suspension and buried less marbles, indicating a less depressive phenotype. These differences in behavior were reverted by central, but not peripheral, acetylcholinesterase inhibition. Moreover, female homozygous VAChT KD mice exhibited higher levels of dopamine and serotonin in the striatum, and increased dopamine in the hippocampus. Our study thus shows a connection between depressive-like behaviors and the cholinergic system, and that the latter interacts with the monoaminergic system.