RESUMO
The striatum, an essential component of the brain's motor and reward systems, plays a pivotal role in a wide array of cognitive processes. Its dysfunction is a hallmark of neurodegenerative diseases like Parkinson's disease (PD) and Huntington's disease (HD), leading to profound motor and cognitive deficits. These conditions are often related to excitotoxicity, primarily due to overactivation of NMDA receptors (NMDAR). In the synaptic cleft, glycine transporter type 1 (GlyT1) controls the glycine levels, a NMDAR co-agonist, which modulates NMDAR function. This research explored the neuroprotective potential of NFPS, a GlyT1 inhibitor, in murine models of striatal injury. Employing models of neurotoxicity induced by 6-hydroxydopamine (PD model) and quinolinic acid (HD model), we assessed the effectiveness of NFPS pre-treatment in maintaining the integrity of striatal neurons and averting neuronal degeneration. The results indicated that NFPS pre-treatment conferred significant neuroprotection, reducing neuronal degeneration, protecting dopaminergic neurons, and preserving dendritic spines within the striatum. Additionally, this pre-treatment notably mitigated motor impairments resulting from striatal damage. The study revealed that GlyT1 inhibition led to substantial changes in the ratios of NMDAR subunits GluN2A/GluN1 and GluN2B/GluN1, 24 h after NFPS treatment. These findings underscore the neuroprotective efficacy of GlyT1 inhibition, proposing it as a viable therapeutic strategy for striatum-related damage.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina , Doença de Huntington , Camundongos , Animais , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Sarcosina/farmacologia , Neuroproteção , Glicina/farmacologia , Corpo Estriado/metabolismo , Doença de Huntington/tratamento farmacológicoRESUMO
Memories are stored into long-term representations through a process that depends on protein synthesis. However, a consolidated memory is not static and inflexible and can be reactivated under certain circumstances, the retrieval is able to reactivate memories and destabilize them engaging a process of restabilization known as reconsolidation. Although the molecular mechanisms that mediate fear memory reconsolidation are not entirely known, so here we investigated the molecular mechanisms in the hippocampus involved in contextual fear conditioning memory (CFC) reconsolidation in male Wistar rats. We demonstrated that the blockade of Src family kinases (SFKs), GluN2B-containing NMDA receptors and TrkB receptors (TrkBR) in the CA1 region of the hippocampus immediately after the reactivation session impaired contextual fear memory reconsolidation. These impairments were blocked by the neurotrophin BDNF and the NMDAR agonist, D-Serine. Considering that the study of the link between synaptic proteins is crucial for understanding memory processes, targeting the reconsolidation process may provide new ways of disrupting maladaptive memories, such as those seen in post-traumatic stress disorder. Here we provide new insights into the cellular mechanisms involved in contextual fear memory reconsolidation, demonstrating that SFKs, GluN2B-containing NMDAR, and TrkBR are necessary for the reconsolidation process. Our findings suggest a link between BDNF and SFKs and GluN2B-containing NMDAR as well as a link between NMDAR and SFKs and TrkBR in fear memory reconsolidation. These preliminary pharmacological findings provide new evidence of the mechanisms involved in the reconsolidation of fear memory and have the potential to contribute to the development of treatments for psychiatric disorders involving maladaptive memories.
Assuntos
Receptores de N-Metil-D-Aspartato , Quinases da Família src , Animais , Masculino , Ratos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Medo/fisiologia , Hipocampo/metabolismo , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Quinases da Família src/metabolismoRESUMO
Memories already consolidated when reactivated return to a labile state and can be modified, this process is known as reconsolidation. It is known the Wnt signaling pathways can modulate hippocampal synaptic plasticity as well as learning and memory. Yet, Wnt signaling pathways interact with NMDA (N-methyl-D-aspartate) receptors. However, whether canonical Wnt/ß-catenin and non-canonical Wnt/Ca2 + signaling pathways are required in the CA1 region of hippocampus for contextual fear memory reconsolidation remains unclear. So, here we verified that the inhibition of canonical Wnt/ß-catenin pathway with DKK1 (Dickkopf-1) into CA1 impaired the reconsolidation of contextual fear conditioning (CFC) memory when administered immediately and 2 h after reactivation session but not 6 h later, while the inhibition of non-canonical Wnt/Ca2+ signaling pathway with SFRP1 (Secreted frizzled-related protein-1) into CA1 immediately after reactivation session had no effect. Moreover, the impairment induced by DKK1 was blocked by the administration of the agonist of the NMDA receptors glycine site, D-Serine, immediately and 2 h after reactivation session. We found that hippocampal canonical Wnt/ß-catenin is necessary to the reconsolidation of CFC memory at least two hours after reactivation, while non-canonical Wnt/Ca2+ signaling pathway is not involved in this process and, that there is a link between Wnt/ß-catenin signaling pathway and NMDA receptors. In view of this, this study provides new evidence regarding the neural mechanisms underlying contextual fear memory reconsolidation and contributes to provide a new possible target for the treatment of fear related disorders.
Assuntos
Memória , Via de Sinalização Wnt , Memória/fisiologia , beta Catenina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Hipocampo/metabolismo , Medo/fisiologiaRESUMO
RATIONALE: Previous studies suggested that the dorsal column of the periaqueductal grey matter (dPAG) can be a target of neural pathways from hypothalamic nuclei involved in triggering fear-related defensive responses. In turn, evidence is provided suggesting that microinjection of the nitric oxide (NO) donor SIN-1 into the anterior hypothalamus (AH) of mice evokes panic-like behaviours and fear-induced antinociception. However, it is unknown whether the dPAG of mice mediates these latter defensive responses organised by AH neurons. OBJECTIVES: This study was designed to examine the role of dPAG in mediating SIN-1-evoked fear-induced defensive behavioural and antinociceptive responses organised in the AH of mice. METHODS: First, neural tract tracing was performed to characterise the AH-dPAG pathways. Then, using neuropharmacological approaches, we evaluated the effects of dPAG pretreatment with either the non-selective synaptic blocker cobalt chloride (CoCl2; 1 mM/0.1 µL) or the competitive N-methyl-D-aspartate (NMDA) receptor antagonist LY235959 (0.1 nmol/0.1 µL) on defensive behaviours and antinociception induced by microinjections of SIN-1 in the AH of male C57BL/6 mice. RESULTS: AlexaFluor488-conjugated dextran-labelled axonal fibres from AH neurons were identified in both dorsomedial and dorsolateral PAG columns. Furthermore, we showed that pre-treatment of the dPAG with either CoCl2 or LY235959 inhibited freezing and impaired oriented escape and antinociception induced by infusions of SIN-1 into the AH. CONCLUSIONS: These findings suggest that the panic-like freezing and oriented escape defensive behaviours, and fear-induced antinociception elicited by intra-AH microinjections of SIN-1 depend on the activation of dPAG NMDA receptors.
Assuntos
Óxido Nítrico , Substância Cinzenta Periaquedutal , Ratos , Camundongos , Masculino , Animais , Óxido Nítrico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Ratos Wistar , Camundongos Endogâmicos C57BL , Hipotálamo Anterior/metabolismo , MicroinjeçõesRESUMO
RATIONALE: Re-exposing an animal to an environment previously paired with an aversive stimulus evokes large alterations in behavioral and cardiovascular parameters. Dorsal hippocampus (dHC) receives important cholinergic inputs from the basal forebrain, and respective acetylcholine (ACh) levels are described to influence defensive behavior. Activation of muscarinic M1 and M3 receptors facilitates autonomic and behavioral responses along threats. Evidence show activation of cholinergic receptors promoting formation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in dHC. Altogether, the action of ACh and NO on conditioned responses appears to converge within dHC. OBJECTIVES: As answer about how ACh and NO interact to modulate defensive responses has so far been barely addressed, we aimed to shed additional light on this topic. METHODS: Male Wistar rats had guide cannula implanted into the dHC before being submitted to the contextual fear conditioning (3footshocks/085 mA/2 s). A catheter was implanted in the femoral artery the next day for cardiovascular recordings. Drugs were delivered into dHC 10 min before contextual re-exposure, which occurred 48 h after the conditioning procedure. RESULTS: Neostigmine (Neo) amplified the retrieval of conditioned responses. Neo effects (1 nmol) were prevented by the prior infusion of a M1-M3 antagonist (fumarate), a neuronal nitric oxide synthase inhibitor (NPLA), a NO scavenger (cPTIO), a guanylyl cyclase inhibitor (ODQ), and a NMDA antagonist (AP-7). Pretreatment with a selective M1 antagonist (pirenzepine) only prevented the increase in autonomic responses induced by Neo. CONCLUSION: The results show that modulation in the retrieval of contextual fear responses involves coordination of the dHC M1-M3/NO/cGMP/NMDA pathway.
Assuntos
N-Metilaspartato , Óxido Nítrico , Acetilcolina , Animais , Colinérgicos/farmacologia , Medo/fisiologia , Fumaratos/farmacologia , Guanosina Monofosfato/farmacologia , Guanilato Ciclase/metabolismo , Guanilato Ciclase/farmacologia , Hipocampo , Masculino , N-Metilaspartato/farmacologia , Neostigmina/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Pirenzepina/farmacologia , Ratos , Ratos Wistar , Receptores Colinérgicos/metabolismo , Receptores de N-Metil-D-Aspartato , Transmissão SinápticaRESUMO
Research on glutamatergic neurotransmission has focused mainly on the function of presynaptic and postsynaptic neurons, leaving astrocytes with a secondary role only to ensure successful neurotransmission. However, recent evidence indicates that astrocytes contribute actively and even regulate neuronal transmission at different levels. This review establishes a framework by comparing glutamatergic components between neurons and astrocytes to examine how astrocytes modulate or otherwise influence neuronal transmission. We have included the most recent findings about the role of astrocytes in neurotransmission, allowing us to understand the complex network of neuron-astrocyte interactions. However, despite the knowledge of synaptic modulation by astrocytes, their contribution to specific physiological and pathological conditions remains to be elucidated. A full understanding of the astrocyte's role in neuronal processing could open fruitful new frontiers in the development of therapeutic applications.
RESUMO
N-methyl-D-aspartate receptors are heterotetramers composed of two GluN1 obligatory subunits and two regulatory subunits. In cognitive-related brain structures, GluN2A and GluN2B are the most abundant regulatory subunits, and their expression is subjected to tight regulation. During development, GluN2B expression is characteristic of immature synapses, whereas GluN2A is present in mature ones. This change in expression induces a shift in GluN2A/GluN2B ratio known as developmental switch. Moreover, modifications in this relationship have been associated with learning and memory, as well as different pathologies. In this work, we used a specific shRNA to induce a reduction in GluN2A expression after the developmental switch, both in vitro in primary cultured hippocampal neurons and in vivo in adult male Wistar rats. After in vitro characterization, we performed a cognitive profile and evaluated seizure susceptibility in vivo. Our in vitro results showed that the decrease in the expression of GluN2A changes GluN2A/GluN2B ratio without altering the expression of other regulatory subunits. Moreover, rats expressing the anti-GluN2A shRNA in vivo displayed an impaired contextual fear-conditioning memory. In addition, these animals showed increased seizure susceptibility, in terms of both time and intensity, which led us to conclude that deregulation in GluN2A expression at the hippocampus is associated with seizure susceptibility and learning-memory mechanisms.
RESUMO
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.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Barorreflexo , Coração/inervação , Óxido Nítrico/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleos Septais/metabolismo , Animais , Pressão Arterial , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Frequência Cardíaca , Masculino , Neurotransmissores/farmacologia , Ratos Wistar , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Núcleos Septais/efeitos dos fármacos , Fatores de TempoRESUMO
Chemical inhibition and nitrergic stimulation of the left and right medial prefrontal cortex (L and RmPFC), respectively, provoke anxiety in mice. Moreover, LmPFC inhibition immediately followed by a single social defeat stress (SDS) led to anxiogenesis in mice exposed to the elevated plus maze (EPM) 24â¯h later. Given that glutamate NMDA (N-methyl-D-aspartate) receptors are densely present in the mPFC, we investigated (i) the time course of LmPFC inhibitionâ¯+â¯SDS-induced anxiogenesis and (ii) the effects of intra-RmPFC injection of AP-7 (a NMDA receptor antagonist) on this long-lasting anxiety. Male Swiss mice received intra-LmPFC injection of CoCl2 (1â¯mM) and 10â¯min later were subjected to a single SDS episode and then (i) exposed to the EPM 2, 5, or 10 days later or (ii) 2 days later, received intra-RmPFC injection of AP-7 (0.05â¯nmol) and were exposed to the EPM to observe the percentage of open arm entries and time (%OE; %OT) and frequency of closed arm entries (CE). Dorsal but not ventral LmPFC inhibitionâ¯+â¯SDS reduced open arm exploration 2, 5, and 10 days later relative to that of saline-treated or non-defeated mice. Moreover, this effect is not due to locomotor impairment as assessed using the general activity. Intra-RmPFC AP-7 injection 2 days after LmPFC inhibitionâ¯+â¯SDS prevented this type of anxiogenesis. These results suggest that the integrity of the LmPFC is important for mice to properly cope with SDS, and that NMDA receptor blockade in the RmPFC facilitates resilience to SDS-induced anxiogenesis in mice.
Assuntos
Ansiedade , Comportamento Animal , Antagonistas de Aminoácidos Excitatórios/farmacologia , Aprendizagem em Labirinto , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Derrota Social , Estresse Psicológico/complicações , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacocinética , Adaptação Psicológica/efeitos dos fármacos , Adaptação Psicológica/fisiologia , Animais , Ansiedade/etiologia , Ansiedade/fisiopatologia , Ansiedade/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Lateralidade Funcional/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , CamundongosRESUMO
The severity score of quinolinic acid (QA)-induced seizures was investigated after N-methyl-D-aspartate (NMDA) preconditioning associated with adenosine receptors. Also, the levels of adenosine A1 and A2A receptors and subunits of NMDA receptors in the hippocampi of mice were determined to define components of the resistance mechanism. Adult CF-1 mice were treated intraperitoneally with saline or NMDA (75 mg/kg), and some mice were treated intracerebroventricularly (i.c.v.) with 0.1 pmol of adenosine receptor antagonists 8-cyclopentyltheophylline (CPT; receptor A1) or ZM241385 (receptor A2A) 0, 1, or 6 h after NMDA administration. These adenosine receptor antagonists were administered to block NMDA's protective effect. Seizures and their severity scores were evaluated during convulsions induced by QA (36.8 nmol) that was administered i.c.v. 24 h after NMDA. The cell viability and content of subunits of the NMDA receptors were analyzed 24 h after QA administration. NMDA preconditioning reduced the maximal severity 6 displayed in QA-administered mice, inducing protection in 47.6% of mice after QA-induced seizures. CPT increased the latency of seizures when administered 0 or 6 h, and ZM241385 generated the same effect when administered 6 h after NMDA administration. The GluN1 content was lower in the hippocampi of the QA mice and the NMDA-preconditioned animals without seizures. GluN2A content was unaltered in all groups. The results demonstrated the components of resistance evoked by NMDA, in which adenosine receptors participate in a time-dependent mode. Similarly, the reduction on GluN1 expression in the hippocampus may contribute to this effect during the preconditioning period.
Assuntos
Anticonvulsivantes/uso terapêutico , N-Metilaspartato/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Purinérgicos P1/metabolismo , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , N-Metilaspartato/administração & dosagem , N-Metilaspartato/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Ácido Quinolínico/toxicidade , Convulsões/etiologiaRESUMO
The NMDA receptors has been described in the development of acute pain and maintenance of chronic pain; the knowledge of physiological processes has led to the growing interest in NMDA receptors antagonists, demonstrating optimal analgesic results. Inhibition of NMDA receptors is an effective therapeutic alternative in the management of pain; with beneficial results in the management of acute postoperative pain, chronic and neuropathic pain. The current scientific challenge is to identify antagonists that perform a selective inhibition of receptor subunits, achieving optimal analgesic results. For this non-systemic review, a search of the available scientific evidence was made in databases (Pubmed/Medline, Science Direct, OVID, SciELO) through the use of keywords (Pain, NMDA receptors, antagonists, ketamine).
Los receptores NMDA han sido descritos en el desarrollo del dolor agudo y mantenimiento del dolor crónico; el conocimiento de los procesos fisiológicos ha llevado al creciente interés en los antagonistas de los receptores NMDA, demostrando resultados analgésicos óptimos. La inhibición de los receptores NMDA es una alternativa terapéutica eficaz en el manejo del dolor; con resultados benéficos en el manejo del dolor agudo postoperatorio, dolor crónico y neuropático. El reto científico actual es identificar antagonistas que realicen una inhibición selectiva de las subunidades del receptor, logrando óptimos resultados analgésicos. Para esta revisión no sistemática se realizó una búsqueda de la evidencia científica disponible en bases de datos (Pubmed/Medline, Science Direct, OVID, SciELO) mediante el uso de palabras clave (dolor, receptores NMDA, antagonistas, ketamina).
Assuntos
Humanos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Manejo da Dor , Ketamina/uso terapêutico , Receptores de N-Metil-D-Aspartato/fisiologiaRESUMO
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) used to treat mood and anxiety disorders. Chronic treatment with this antidepressant drug is thought to favor functional recovery by promoting structural and molecular changes in several forebrain areas. At the synaptic level, chronic fluoxetine induces an increased size and density of dendritic spines and an increased ratio of GluN2A over GluN2B N-methyl-D-aspartate (NMDA) receptor subunits. The "maturation"-promoting molecular changes observed after chronic fluoxetine should also induce structural remodeling of the neuronal dendritic arbor and changes in the synaptic responses. We treated adult rats with fluoxetine (0.7 mg/kg i.p. for 28 days) and performed a morphometric analysis using Golgi stain in limbic and nonlimbic cortical areas. Then, we focused especially on the auditory cortex, where we evaluated the dendritic morphology of pyramidal neurons using a 3-dimensional reconstruction of neurons expressing mRFP after in utero electroporation. With both methodologies, a shortening and decreased complexity of the dendritic arbors was observed, which is compatible with an increased GluN2A over GluN2B ratio. Recordings of extracellular excitatory postsynaptic potentials in the auditory cortex revealed an increased synaptic response after fluoxetine and were consistent with an enrichment of GluN2A-containing NMDA receptors. Our results confirm that fluoxetine favors maturation and refinement of extensive cortical networks, including the auditory cortex. The fluoxetine-induced receptor switch may decrease GluN2B-dependent toxicity and thus could be applied in the future to treat neurodegenerative brain disorders characterized by glutamate toxicity and/or by an aberrant network connectivity.
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Rats readily learn to avoid a tasteless odorized solution if they experience visceral malaise after consuming it. This phenomenon is referred to as conditioned odor aversion (COA). Several studies have shown that COA depends on the functional integrity of the amygdala, with most studies focusing on the basolateral nucleus. On the other hand, the role of the central amygdala (CeA) which is known to be involved in the consolidation of conditioned taste aversion (CTA) remains to be established. To address this issue, we evaluated the effect of inhibiting NMDA receptor activity in this structure on COA memory formation. Intra-CeA infusions of non-competitive NMDA receptor inhibitor MK-801 prevented memory formation both when administered before and up to 15 min after COA conditioning, while no effect of this drug was observed when given before long-term memory test. We next evaluated the role of one of the main downstream effectors of brain NMDA receptor signaling, nitric oxide synthase (NOS), known to play a key role in a wide variety learning tasks including some types of olfactory conditioning. Similar results were obtained with inhibition of either NOS or neuron-specific NOS; which proved to be required both during and after COA training, though for a shorter time span than NMDA receptors. Also, neither isoform showed to be required to memory retrieval. These results suggest that the US signaling during acquisition and the initial consolidation step of COA depends on glutamate-NO system activation in the CeA.
Assuntos
Aprendizagem da Esquiva , Comportamento Animal , Núcleo Central da Amígdala/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Olfato , Animais , Condicionamento Psicológico , Masculino , Odorantes , Ratos WistarRESUMO
Undernourishment is a global issue, especially in developing countries, affecting newborns and children in a vulnerable period of brain development. Previous studies of undernourishment models suggested a relationship between undernourishment and epilepsy. The exposure to both undernourishment and recurrent seizures early in life appears to have detrimental effects on the developing brain. This study aims to investigate the neurobiological consequences of undernourishment and recurrent seizures exposure early in life, investigating Long-Term Potentiation (LTP) induction and gene expression of NMDA receptor subunits in the hippocampus during adulthood (P60). Animals were exposed to maternal deprivation protocol from P2 to P15 to control food intake in rat pups and Flurothyl-induced seizures from P7 to P10. Electrophysiological records of hippocampal slices were recorded and gene expression of NR1A, NR2A, NR2B, NR2C, NR2D and BDNF were investigated. Animals exposed to undernourishment or recurrent seizures failed to promote LTP after stimulation. Furthermore, seizure exposure early in life led to increased expression of hippocampal NR1A, NR2A, NR2B, NR2C and NR2D when compared to controls. Interestingly, when animals were exposed to undernourishment paradigm early in life, this upregulation of NDMA subunits was absent. In conclusion, our study showed impaired LTP after undernourishment and recurrent seizures early in life, together with differential expression of NDMA expression in the hippocampus during adulthood.
Assuntos
Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Desnutrição/fisiopatologia , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/fisiopatologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Flurotila , Expressão Gênica , Desnutrição/metabolismo , Privação Materna , Ratos , Receptores de AMPA/genética , Receptores de N-Metil-D-Aspartato/genética , Convulsões/induzido quimicamente , Convulsões/metabolismoRESUMO
Traumatic brain injury (TBI) is a public health problem characterized by a combination of immediate mechanical dysfunction of the brain tissue, and secondary damage. Based on the hypothesis that selected targets, such as Na+ K+-ATPase are involved in the secondary damage after TBI and modulation of this enzyme activity by triterpene 3ß, 6ß, 16ß-trihidroxilup-20 (29)-ene (TTHL) supports the ethnomedical applications of this plant, we decided to investigate whether previous TTHL treatment interrupts the progression of pathophysiology induced by TBI. Statistical analyses revealed that percussion fluid injury (FPI) increased Na+,K+-ATPase activity in all isoform (α1 and α2/3) 15â¯min after neuronal injury. The FPI protocol inhibited Na+,K+-ATPase activity total and α1 isoform, increased [3H]MK-801 binding but did not alter Dichloro-dihydro-fluorescein diacetate (DCFH-DA) oxidation, carbonylated proteins and free -SH groups 60â¯min after injury. The increase of immunoreactivity of protein PKC and state of phosphorylation of at Ser16 of Na+,K+-ATPase 60â¯min after FPI suggest the involvement of PKC on Na+,K+-ATPase activity oscillations characterized by inhibition of total and α1 isoform. Our experimental data also revealed that natural product rich in compounds such as triterpenes (TTHL; 30â¯mg/kg) attenuates [3H]MK-801 binding increase, phosphorylation of the PKC and the Na+,K+-ATPase alpha 1 subunit (Ser16) induced by FPI. The previous TTHL treatment had not effect on motor disability but protected against spatial memory deficit, BDNF, TrKB expression decrease, protein carbonylation and hippocampal cell death 7 days after FPI. These data suggest that TTHL-induced reduction on initial damage limits the long-term secondary degeneration and supports neural repair or behavioral compensation after neuronal injury.
Assuntos
Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Triterpenos/farmacologia , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Contagem de Células , Cognição/efeitos dos fármacos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Fatores de Tempo , Triterpenos/uso terapêuticoRESUMO
Successful memory involves not only remembering information over time but also keeping memories distinct and less confusable. Discrimination of overlapping representations has been investigated in the dentate gyrus (DG) of the hippocampus and largely in the perirhinal cortex (Prh). In particular, the DG was shown to be important for discrimination of overlapping spatial memories and Prh was shown to be important for discrimination of overlapping object memories. In the present study, we used both a DG-dependent and a Prh-dependent task and manipulated the load of similarity between either spatial or object stimuli during information encoding. We showed that N-methyl-D-aspartate-type glutamate receptors (NMDAr) and BDNF participate of the same cellular network during consolidation of both overlapping object and spatial memories in the Prh and DG, respectively. This argues in favor of conserved cellular mechanisms across regions despite anatomical differences.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Hipocampo/fisiologia , Córtex Perirrinal/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Reconhecimento Psicológico/fisiologia , Memória Espacial/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Comportamento Exploratório , Consolidação da Memória/fisiologia , Ratos Long-EvansRESUMO
The ventral medial prefrontal cortex (vMPFC) facilitates the cardiac baroreflex response through N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) formation by neuronal NO synthase (nNOS) and soluble guanylate cyclase (sGC) triggering. Glutamatergic transmission is modulated by the cannabinoid receptor type 1 (CB1) and transient receptor potential vanilloid type 1 (TRPV1) receptors, which may inhibit or stimulate glutamate release in the brain, respectively. Interestingly, vMPFC CB1 receptors decrease cardiac baroreflex responses, while TRPV1 channels facilitate them. Therefore, the hypothesis of the present study is that the vMPFC NMDA/NO pathway is regulated by both CB1 and TRPV1 receptors in the modulation of cardiac baroreflex activity. In order to test this assumption, we used male Wistar rats that had stainless steel guide cannulae bilaterally implanted in the vMPFC. Subsequently, a catheter was inserted into the femoral artery, for cardiovascular recordings, and into the femoral vein for assessing baroreflex activation. The increase in tachycardic and bradycardic responses observed after the microinjection of a CB1 receptors antagonist into the vMPFC was prevented by an NMDA antagonist as well as by the nNOS and sGC inhibition. NO extracellular scavenging also abolished these responses. These same pharmacological manipulations inhibited cardiac reflex enhancement induced by TRPV1 agonist injection into the area. Based on these results, we conclude that vMPFC CB1 and TRPV1 receptors inhibit or facilitate the cardiac baroreflex activity by stimulating or blocking the NMDA activation and NO synthesis.
Assuntos
Barorreflexo , Coração/fisiologia , Córtex Pré-Frontal/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Frequência Cardíaca , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Canais de Cátion TRPV/agonistasRESUMO
BACKGROUND: An excitatory imbalance in the hypothalamus of rodents caused by local chemical stimulation elicits fear-related defensive reactions such as escape and freezing. In addition, these panic attack-like defensive reactions induced by hypothalamic neurons may cause antinociception. However, there is a shortage of studies showing the participation of the anterior hypothalamic nucleus in these adaptive defensive mechanisms. Nitric oxide (NO) donors have been shown to evoke fear-related defensive responses when microinjected into paralimbic and limbic structures, and this excitatory neuromodulation can recruit the glutamatergic system. AIMS: The aim of this work was to investigate the influence of the glutamatergic system in the nitrergic effects on fear-related defensive responses organised by anterior hypothalamic neurons. METHODS: The present study evaluates the effects of the molsidomine active metabolite SIN-1 NO donor administered into the anterior hypothalamus (AH) of mice at different concentrations (75, 150 and 300 nmol/0.1 µL). Then, we investigated the effects of pre-treatment of the AH with AP-7 (an N-methyl-d-aspartate (NMDA) receptor-selective antagonist; 0.02, 0.2 and 2 nmol/0.1 µL) on the behavioural and antinociceptive effects provoked by AH chemical stimulation with SIN-1 microinjections. RESULTS: The 300 nmol dose of SIN-1 was the most effective at causing panic-like defensive behaviours followed by a significant antinociceptive response. In addition, both of these effects were attenuated or inhibited by AH pre-treatment with AP-7. CONCLUSIONS: These findings suggest that the panicogenic and antinociceptive effects evoked by intra-AH microinjections of SIN-1 depend on NMDA receptor activation.
Assuntos
Medo/efeitos dos fármacos , Molsidomina/análogos & derivados , Doadores de Óxido Nítrico/administração & dosagem , Pânico/efeitos dos fármacos , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipotálamo Anterior/efeitos dos fármacos , Hipotálamo Anterior/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microinjeções , Molsidomina/administração & dosagem , Molsidomina/farmacologia , Doadores de Óxido Nítrico/farmacologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
L-DOPA induced dyskinesias (LIDs) may affect up to 40% of Parkinson's disease (PD) and impact negatively health-related quality of life. Amantadine has demonstrated significant antidyskinetic effects in animal PD models and in randomized double-blind placebo-controlled trials (RCTs) in patients with PD. These effects are thought to be related to the blockade of NMDA receptors modulating cortico-striatal glutamatergic-dopaminergic interactions involved in the genesis of LIDs. There are three pharmaceutical forms of amantadine currently available in the market: an oral immediate-release (IR) formulation, which is widely available; an extended-release (ER) formulation (ADS-5102) which has been recently developed and approved by the FDA; and an intravenous infusion (IV) solution, which is not commonly used in clinical practice. RCTs with amantadine IR or ER, involving more than 650 patients have shown consistent and long-lasting reductions in LIDs. Interestingly, ADS-5102 not only reduced LIDs, but also reduced significantly at the same time the duration of daily OFF-time, a unique finding compared with other antiparkinsonian medications that usually reduce time spent OFF at the cost of worsening of LIDs. Amantadine IR might also have possible effects on other PD symptoms such as apathy or fatigue. The most common adverse reactions with amantadine are constipation, cardiovascular dysfunction including QT prolongation, orthostatic hypotension and edema, neuropsychiatric symptoms such as hallucinations, confusion and delirium, nausea and livedo reticularis. Corneal degeneration is rare but critical. In summary, amantadine immediate and extended-release are effective and safe for the treatment of LIDs.
Assuntos
Amantadina/farmacologia , Antiparkinsonianos/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Animais , Dopaminérgicos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Levodopa/efeitos adversos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacosRESUMO
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.