RESUMO
Microdosing ketamine is a novel antidepressant for treatment-resistant depression. Traditional antidepressants, like selective serotonin reuptake inhibitors (SSRIs), inhibit serotonin reuptake, but it is not clear if ketamine shows a similar mechanism. Here, we tested the effects of feeding ketamine and SSRIs to Drosophila melanogaster larvae, which has a similar serotonin system to mammals and is a good model to track depressive behaviors, such as locomotion and feeding. Fast-scan cyclic voltammetry (FSCV) was used to measure optogenetically stimulated serotonin changes, and locomotion tracking software and blue dye feeding to monitor behavior. We fed larvae various doses (1-100 mM) of antidepressants for 24 h and found that 1 mM ketamine did not affect serotonin, but increased locomotion and feeding. Low doses (≤10 mM) of escitalopram and fluoxetine inhibited dSERT and also increased feeding and locomotion behaviors. At 100 mM, ketamine inhibited dSERT and increased serotonin concentrations, but decreased locomotion and feeding because of its anesthetic properties. Since microdosing ketamine causes behavioral effects, we further investigated behavioral changes with a SERT16 mutant and low doses of other NMDA receptor antagonists and 5-HT1A and 2 agonists. Feeding and locomotion changes were similar to ketamine in the mutant, and we found NMDA receptor antagonism increased feeding, while serotonin receptor agonism increased locomotion, which could explain these effects with ketamine. Ultimately, this work shows that Drosophila is a good model to discern antidepressant mechanisms, and that ketamine does not work on dSERT like SSRIs, but effects behavior with other mechanisms that should be investigated further.
Assuntos
Drosophila melanogaster , Ketamina , Locomoção , Receptores de Serotonina , Inibidores Seletivos de Recaptação de Serotonina , Animais , Ketamina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Receptores de Serotonina/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Receptores de Glutamato/metabolismo , Receptores de Glutamato/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Serotonina/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Relação Dose-Resposta a Droga , Larva , Fluoxetina/farmacologia , Antidepressivos/farmacologiaRESUMO
Parkinson's disease (PD) is the second-most prevalent central nervous system (CNS) neurodegenerative condition. Over the past few decades, suppression of BCR-Abelson tyrosine kinase (c-Abl), which serves as a marker of -synuclein aggregation and oxidative stress, has shown promise as a potential therapy target in PD. c-Abl inhibition has the potential to provide neuroprotection against PD, as shown by experimental results and the first-in-human trial, which supports the strategy in bigger clinical trials. Furthermore, glutamate receptors have also been proposed as potential therapeutic targets for the treatment of PD since they facilitate and regulate synaptic neurotransmission throughout the basal ganglia motor system. It has been noticed that pharmacological manipulation of the receptors can change normal as well as abnormal neurotransmission in the Parkinsonian brain. The review study contributes to a comprehensive understanding of the approach toward the role of c-Abl and glutamate receptors in Parkinson's disease by highlighting the significance and urgent necessity to investigate new pharmacotherapeutic targets. The article covers an extensive insight into the concept of targeting, pathophysiology, and c-Abl interaction with α-synuclein, parkin, and cyclin-dependent kinase 5 (Cdk5). Furthermore, the concepts of Nmethyl- D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPA) receptor, and glutamate receptors are discussed briefly. Conclusion: This review article focuses on in-depth literature findings supported by an evidence-based discussion on pre-clinical trials and clinical trials related to c-Abl and glutamate receptors that act as potential therapeutic targets for PD.
Assuntos
Doença de Parkinson , Proteínas Proto-Oncogênicas c-abl , Receptores de Glutamato , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-abl/metabolismo , Receptores de Glutamato/metabolismo , Receptores de Glutamato/efeitos dos fármacos , Animais , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
The nucleus tractus solitarii (NTS) receives afferent projections from the arterial baroreceptors, carotid chemoreceptors and cardiopulmonary receptors and as a function of this information produces autonomic adjustments in order to maintain arterial blood pressure within a narrow range of variation.The activation of each of these cardiovascular afferents produces a specific autonomic response by the excitation of neuronal projections from the NTS to the ventrolateral areas of the medulla (nucleus ambiguus, caudal and rostral ventrolateral medulla). The neurotransmitters at the NTS level as well as the excitatory amino acid (EAA) receptors involved in the processing of the autonomic responses in the NTS, although extensively studied, remain to be completely elucidated. In the present review we discuss the role of the EAA L-glutamate and its different receptor subtypes in the processing of the cardiovascular reflexes in the NTS. The data presented in this review related to the neurotransmission in the NTS are based on experimental evidence obtained in our laboratory in unanesthetized rats. The two major conclusions of the present review are that a) the excitation of the cardiovagal component by cardiovascular relfex activation (chemo- and Bezold-Jarisch reflexes) or by L-glutamatae microinjection into the NTS is mediated by N-methyl-D-aspartate (NMDA) receptors, and b) the sympatho-excitatory componente of the chemoreflex and the pressor response to L-glutamate microinjected into the NTS are not affected by an NMDA receptor antagonist, suggesting that the sympatho-excitatory component of these responses is mediated by non-NMDA receptors.
Assuntos
Ratos , Animais , Sistema Cardiovascular/efeitos dos fármacos , Células Quimiorreceptoras/fisiologia , Ácido Glutâmico/farmacologia , Glicina/farmacologia , Cianeto de Potássio/farmacologia , Pressorreceptores/fisiologia , Receptores de Glutamato/efeitos dos fármacos , Reflexo/fisiologia , Serotonina/farmacologia , Núcleo Solitário/fisiologia , Células Quimiorreceptoras/efeitos dos fármacos , Pressorreceptores/efeitos dos fármacosRESUMO
The overactivation of glutamate receptors is a major cause of Ca2+ overload in cells, potentially leading to cell damage and death. There is an abundance of agents and mechanisms by which glutamate receptor activation can be prevented or modulated in order to control these effects. They include the well-established, competitive and non-competitive antagonists at the N-methyl-D-aspartate (NMDA) receptors and modulators of desensitisation of the -amino-3-hydroxy-5-mmethyl-4-isoxazole-propionic acid (AMP) receptors. More recently, it has emerged that some compounds can acrt selectively at different subnuits of glutamate receptors,allowing a different blockade of subtypes. It is also becoming clear that a number of endogenous compounds, including purines, can modify glutamate receptor senistivity. The kynurenine pathway is an alternative but distinct pathway to the generation glutamate receptor ligands. The products of tryptophan metablism via kynurenine pathway include both quinolinic acid, a selective agonist at several glutamate receptor subtypes. The levels of these metabolites change as a result of the activation of inflammatory processes and immune-competent cells, and may have a significant impact on Ca2+ fluxes and neuronal damage. Drugs which target some of these various sites and processes, or which change the balance between the excitotoxin quinolinic acid and the neuroprotective kynurenic acid, could also have potential as neuroprotective drugs (AU)
Assuntos
Humanos , Cinurenina , Ácido Quinolínico , Ácido Cinurênico , Receptores de Glutamato/análise , Receptores de Glutamato/efeitos dos fármacos , Doenças Neurodegenerativas/diagnóstico , Fármacos Neuroprotetores/análiseRESUMO
Long-term potentiation (LTP) is a molecular engram of memory. Previous work has demonstrated that LTP decreases the sensitivity of glutamate receptors in the rat hippocampus. Glutamate has beem implicated in the pathogenesis of hypoxic/ischaemic damage. We therefore tested the hypothesis that LTP could reduce the effects of LTP on hypoxia in the rat hippocampus. The effects of LTP on hypoxia were measured by the changes in the extracellular potentials recorded from the hippocampal slice. Hypoxia was induced by perfusing the slice with artificial cerebrospinal fluid that contained varying concentrations of oxygen. Each slice was initially exposed to the hypoxic medium for 1.5-3.0 minutes. This led to a decrease in the potentials, which recovered to control levels within 5 minutes. Repeat exposure to the same hypoxic medium for the same duration as the first, also caused a reduction in the potentials. There was no significant difference between the degree of reduction caused by the first or second exposure for all types of hypoxic media tested (p >0.05; paired t test). In some slices, LTP was induced after the first hypoxic exposure. LTP brought about an inhibition of the reduction in potentials caused by the second hypoxic insult; the differences in reducation in potentials were highly significant for all the hypoxic media used (p <0.01; paired t test). The neuroprotective effects of LTP were not prevented by cyclothiazide (an inhibitor of AMPA receptor desensitization) or NOS inhibitors (antagonists of intracellular nitric oxide production). These compounds have been shown to be effective in blocking the effects of LTP on the actions of exogenously applied AMPA and NMDA, respectively. The neuroprotective effects of LTP were similar to that of propentofylline, a known neuroprotective compound. We conclude that LTP causes an appreciable protection of the hippocampus slices to in-vitro models of acute hypoxia. There have been reports that there is a possible inverse relationship between educational attainment and the development of dementia and the results of our study may have a role to play in this relationship. (AU)
Assuntos
Ratos , Técnicas In Vitro , 21003 , Hipóxia/prevenção & controle , Potenciação de Longa Duração/efeitos dos fármacos , Receptores de Glutamato/efeitos dos fármacos , Receptores de AMPA/efeitos dos fármacos , Estudo de AvaliaçãoRESUMO
Several experimental models have been used to study tolerance to ethanol. The development of tolerance to the motor incoordinating effect of a single administration of ethanol occurs within 8-24 h after the effect of the first dose has disappeared. This form of tolerance is designated rapid tolerance and seems to involve functional rather than pharmacokinetic mechanisms. Like chronic tolerance, rapid tolerance has been shown to be infiuenced by processes related to learning and memory. It is known that N-methyl-D-aspartate (NMDA) receptor systems are involved in the expression and maintenance of one form of long-term potentiation (LTP), a synaptic adaptive process which has been suggested to be the cellular basis of memory or associative memory. Considering the similarities between learning and tolerance, the effects of NMDA agonists and antagonists on tolerance to ethanol were investigated. Our studies demonstrated that NMDA antagonists that impair learning, such as dizocilpine or ketamine, inhibit tolerance, while NMDA agonists that improve learning, such as D-cycloserine, increase tolerance. Moreover, the nitric oxide synthase inhibitor L-nitroarginine blocks tolerance to the effects of ethanol. Taken together, these data confirm the involvement of the NMDA system in ethanol tolerance and emphasize the participation of leaming in this phenomenon.
Assuntos
Maleato de Dizocilpina/farmacologia , Etanol/farmacologia , Ketamina/farmacologia , Óxido Nítrico/farmacologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Serotonina/farmacologia , Tolerância a Medicamentos/fisiologia , Receptores de Glutamato/efeitos dos fármacosRESUMO
Ethanol exerts its behavioral effects largely by interacting with receptors to brain neurotransmitters. The molecular mechanisms involving these interactions are still not well known since an ideal model for their study is currently unavailable. In addition, responses to alcohol may vary due to factors such as genetic predisposition, ethanol concentration consumed, and stimuli such as stress, socialization, etc. The chronc consumption of alcohol, similar to that of other drugs such as benzodiazepines and barbiturates, is linked to GABAerigc neurotransmission. GABA is the predominant inhibitory neurotransmitter in the brain. In context of substance abuse, these three drugs first cause a gratifying effect, later tolerance and finally, physical and psychological dependence. If cosumption is interrupted abruptly, a withdrawal syndrome occurs. The Alcohol Withdrawal Syndrome (AWS) is state of hyperexcitability characterized by anxiety, fear, muscular rigidity and tonic-clonic seizures with epileptiform-type charactermental epilepsy models such as "Kindling" or GABA Withdrawal Syndrome (GWS) models. A possible correlation between these models and AWS will allow for a better understanding of the cellular and molecular effects that alcohol exerts on the brain