RESUMO
Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3H)-one (A9-7, ALX-171, mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment.
Assuntos
Antipsicóticos , Quinazolinonas , Receptores de Glutamato Metabotrópico , Esquizofrenia , Animais , Humanos , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Maleato de Dizocilpina , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Desenho de FármacosRESUMO
A stressor can trigger lasting adaptations that contribute to neuropsychiatric disorders. Predator odor (TMT) exposure is an innate stressor that may activate the metabotropic glutamate receptor 3 (mGlu3) to produce stress adaptations. To evaluate functional involvement, the mGlu3 negative allosteric modulator (NAM, VU6010572; 3 mg/kg, i.p.) was administered before TMT exposure in male, Long Evans rats. Two weeks after, rats underwent context re-exposure, elevated zero maze (ZM), and acoustic startle (ASR) behavioral tests, followed by RT-PCR gene expression in the insular cortex and bed nucleus of the stria terminalis (BNST) to evaluate lasting behavioral and molecular adaptations from the stressor. Rats displayed stress-reactive behaviors in response to TMT exposure that were not affected by VU6010572. Freezing and hyperactivity were observed during the context re-exposure, and mGlu3-NAM pretreatment during stressor prevented the context freezing response. TMT exposure did not affect ZM or ASR measures, but VU6010572 increased time spent in the open arms of the ZM and ASR habituation regardless of stressor treatment. In the insular cortex, TMT exposure increased expression of mGlu (Grm3, Grm5) and NMDA (GriN2A, GriN2B, GriN2C, GriN3A, GriN3B) receptor transcripts, and mGlu3-NAM pretreatment blocked GriN3B upregulation. In the BNST, TMT exposure increased expression of GriN2B and GriN3B in vehicle-treated rats, but decreased expression in the mGlu3-NAM group. Similar to the insular cortex, mGlu3-NAM reversed the stressor-induced upregulation of GriN3B in the BNST. mGlu3-NAM also upregulated GriN2A, GriN2B, GriN3B and Grm2 in the control group, but not the TMT group. Together, these data implicate mGlu3 receptor signaling in some lasting adaptations of predator odor stressor and anxiolytic-like effects.
Assuntos
Adaptação Fisiológica/fisiologia , Comportamento Animal/fisiologia , Córtex Insular/metabolismo , Neurotransmissores/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleos Septais/metabolismo , Tiazóis/farmacologia , Adaptação Fisiológica/efeitos dos fármacos , Regulação Alostérica , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico , Cadeia Alimentar , Córtex Insular/efeitos dos fármacos , Masculino , Odorantes , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Núcleos Septais/efeitos dos fármacosRESUMO
BACKGROUND: Metabolic syndrome patients are commonly prone to major health problems as cardiovascular diseases, diabetes mellitus, chronic kidney disease, cancer and neuropsychological complications including dementia. OBJECTIVES: This research investigates mechanisms linking metabolic syndrome to cognitive impairment and possible impact of vitamin D supplementation. METHODS: Forty male Wistar rats were divided into 4 groups. Control, metabolic syndrome (20% fructose solution in drinking water for 12 weeks, vitamin D supplemented (500 IU/kg/day)) and metabolic syndrome supplemented with vitamin D. Animals were assessed for spatial memory, hippocampal expression of SNAP 25, VAMP and mGlut2 receptor and hippocampus histological examination. Animals with metabolic syndrome showed prolonged acquisition and retention latencies in morris water maze, decreased hippocampal expression of SNAP 25 and VAMP and increased mGlut2 expression. Histologically CA1, CA3 regions and dentate nucleus revealed increase in degenerated neurons and glia cells with decreased pyramidal cell layer thickness. Vitamin D supplementation mitigated alterations induced by metabolic syndrome. CONCLUSIONS: Metabolic syndrome decreased hippocampal synaptic proteins and altered glutamatergic transmission and increased hippocampal neuronal degeneration. Vitamin D supplementation offered neuroprotective effects.
Assuntos
Disfunção Cognitiva/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Vitamina D/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/etiologia , Síndrome Metabólica/complicações , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Wistar , Vitamina D/administração & dosagemRESUMO
On the occasion of the 40 year anniversary of the hugely impactful review by Richard (Dick) Evans and Jeff Watkins, we describe how their work has impacted the field of synaptic plasticity. We describe their influence in each of the major glutamate receptor subtypes: AMPARs, NMDARs, KARs and mGluRs. Particular emphasis is placed on how their work impacted our own studies in the hippocampus. For example, we describe how the tools and regulators that they identified for studying NMDARs (e.g., NMDA, D-AP5 and Mg2+) led to the understanding of the molecular basis of the induction of LTP. We also describe how other tools that they introduced (e.g., (1S,3R)-ACPD and MCPG) helped lead to the concept of metaplasticity.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/metabolismo , Magnésio/farmacologia , Plasticidade Neuronal/fisiologia , Neurofarmacologia/história , Receptores Ionotrópicos de Glutamato/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Hipocampo/efeitos dos fármacos , História do Século XX , Humanos , Plasticidade Neuronal/efeitos dos fármacos , Receptores Ionotrópicos de Glutamato/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/efeitos dos fármacosRESUMO
BACKGROUND: Stressful episodes and high alcohol consumption during adolescence are considered major risk factors for the development of psychiatric disorders in adulthood. Identification of mechanisms underlying these early events, which enhanced vulnerability to mental illness, is essential for both their prevention and treatment. METHODS: Male Wistar rats were used to investigate the long-term effects of early restraint stress and intermittent alcohol exposure (intragastric administration of 3 g/kg ethanol; 4 days/week for 4 weeks during adolescence) on anxiety-like behavior and the expression of signaling systems associated with emotional behaviors [e.g., corticosterone, fatty acid-derived molecules and endocannabinoid enzymes, glutamate receptor subunits, corticotropin releasing hormone receptors (CRHR1 and CRHR2) and neuropeptide Y receptors (NPY1R and NPYR2)] in the blood and amygdala. RESULTS: Overall, both stress and alcohol exposure during adolescence induced anxiogenic-like behaviors, increased plasma levels of corticosterone and increases in the amygdalar expression of the cannabinoid CB2 receptor and certain subunits of glutamate receptors (i.e., mGluR1, mGluR5 and NMDAR1) in young adult rats. In addition, there were specific main effects of alcohol exposure on the expression of the cannabinoid CB1 receptor, monoacylglycerol lipase (MAGL) and NPY2R in the amygdala, and significant increases were observed in rats exposed to alcohol. Interestingly, there were significant interaction effects between restraint stress and alcohol exposure on the expression of plasma 2-arachidonoyl glycerol (2-AG), and both CRHR1,2 and NPY1R in the amygdala. Thus, the restraint stress was associated with increased 2-AG levels, which was not observed in rats exposed to alcohol. The alcohol exposure was associated with an increased expression of CRHR1,2 but the restraint stress prevented these increases (stress alcohol rats). In contrast, NPY1R was only increased in rats exposed to stress and alcohol. Finally, we did not observe any potentiation of the behavioral and molecular effects by the combination of stress and alcohol, which is concordant with an overall ceiling effect on some of the variables. CONCLUSION: Separate and combined early stress and alcohol induced a common anxious phenotype with increased corticosterone in adulthood. However, there were differences in the amygdalar expression of signaling systems involved in maladaptive changes in emotional behavior. Therefore, our results suggest the existence of partially different mechanisms for stress and alcohol exposures.
Assuntos
Alcoolismo , Ansiedade/etiologia , Endocanabinoides , Ácido Glutâmico , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Masculino , Transtornos Mentais/prevenção & controle , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/efeitos dos fármacosRESUMO
PURPOSE: Antagonising serotonin (5-HT) type 2A receptors (5-HT2AR) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson's disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR2), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT2AR antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT2AR antagonism with concurrent mGluR2 orthosteric stimulation and mGluR2 positive allosteric modulation. METHODS: Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT2AR antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR2 orthosteric agonist (OA) LY-354,740, the mGluR2 positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated. RESULTS: EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed. CONCLUSION: Our results suggest that combining 5-HT2AR antagonism with mGluR2 activation results in greater reduction of L-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR2 OA and a mGluR2 PAM are combined with a 5-HT2AR antagonist than when a mGluR2 OA or a mGluR2 PAM are added to a 5-HT2AR antagonist.
Assuntos
Antiparkinsonianos/farmacologia , Levodopa/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Psicóticos/tratamento farmacológico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/toxicidade , Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/farmacologia , Callithrix , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/prevenção & controle , Feminino , Indóis/administração & dosagem , Indóis/farmacologia , Levodopa/administração & dosagem , Levodopa/toxicidade , Masculino , Transtornos Parkinsonianos/psicologia , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Transtornos Psicóticos/etiologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologiaRESUMO
There are many nonopioid central nervous system depressant substances that share a gamma-aminobutyric acid (GABA) receptor-related mechanism of action. These sedatives-hypnotics can be indicated to treat anxiety, seizures, depression, and insomnia but are also used as substances of abuse and used to facilitate sexual assault. Barbiturates, methaqualone, and glutethimide were among the first type A GABA receptor-mediated sedative-hypnotics. Their clinical use was limited for most indications by serious adverse events and strong abuse potential but continue to be used illicitly around the world. The benzodiazepines supplanted barbiturates for most indications because they were less likely to cause severe adverse events in monotherapy. Flunitrazepam is a newer benzodiazepine that is preferentially used recreationally and to facilitate sexual assault. Flunitrazepam has greater potency and higher affinity for the type A GABA receptor than most benzodiazepines. Gamma-hydroxybutyric acid is sought illicitly for its hypnotic, euphoric and anabolic effects as well as to facilitate sexual assault. When any of these GABAergic drugs are used in high doses or with other sedative hypnotic agents, respiratory depression, coma, and death have occurred. Chronic use of these GABAergic drugs can lead to significant withdrawal syndromes. Phenibut and selank are poorly studied Russian drugs with GABAergic mechanisms that are inexplicably sold to US consumers as dietary supplements. Poison control center calls regarding phenibut have increased substantially over the past 5 years. Desired euphoriant effects account for the recreational and illicit use of many GABA-modulating agents. However, illicit use can lead to significant toxicities related to abuse, dependence, and subsequent withdrawal syndromes. Significant evaluation of developing agents with GABA properties should be conducted to determine abuse potential before public access ensues.
Assuntos
Hipnóticos e Sedativos/farmacologia , Receptores de GABA/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Overdose de Drogas/fisiopatologia , Flunitrazepam/farmacologia , Humanos , Oligopeptídeos/farmacologia , Receptores de GABA/metabolismo , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/farmacologiaRESUMO
Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), an RNA-binding protein that can regulate the translation of specific mRNAs. In this study, we developed an FXS human forebrain organoid model and observed that the loss of FMRP led to dysregulated neurogenesis, neuronal maturation and neuronal excitability. Bulk and single-cell gene expression analyses of FXS forebrain organoids revealed that the loss of FMRP altered gene expression in a cell-type-specific manner. The developmental deficits in FXS forebrain organoids could be rescued by inhibiting the phosphoinositide 3-kinase pathway but not the metabotropic glutamate pathway disrupted in the FXS mouse model. We identified a large number of human-specific mRNAs bound by FMRP. One of these human-specific FMRP targets, CHD2, contributed to the altered gene expression in FXS organoids. Collectively, our study revealed molecular, cellular and electrophysiological abnormalities associated with the loss of FMRP during human brain development.
Assuntos
Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/patologia , Neurogênese/genética , Prosencéfalo/patologia , Adulto , Encéfalo/patologia , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Fenômenos Eletrofisiológicos , Humanos , Masculino , Modelos Neurológicos , Neurogênese/efeitos dos fármacos , Neurônios/patologia , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Ligação Proteica , Inibidores de Proteínas Quinases/uso terapêutico , RNA Mensageiro/genética , Receptores de Glutamato Metabotrópico/efeitos dos fármacosRESUMO
Presynaptic kainate (KA) receptors (KARs) modulate GABA and glutamate release in the central nervous system of mammals. While some of the actions of KARs are ionotropic, metabotropic actions for these receptors have also been seen to modulate both GABA and glutamate release. In general, presynaptic KARs modulate glutamate release through their metabotropic actions in a biphasic manner, with low KA concentrations producing an increase in glutamate release and higher concentrations of KA driving weaker release of this neurotransmitter. Different molecular mechanisms are involved in this modulation of glutamate release, with a G-protein independent, Ca2+-calmodulin adenylate cyclase (AC) and protein kinase A (PKA) dependent mechanism facilitating glutamate release, and a G-protein, AC and PKA dependent mechanism mediating the decrease in neurotransmitter release. Here, we describe the events underlying the KAR modulation of glutamatergic transmission in different brain regions, addressing the possible functions of this modulation and proposing future research lines in this field. This article is part of the special Issue on 'Glutamate Receptors - Kainate receptors'.
Assuntos
Ácido Glutâmico/metabolismo , Receptores de Ácido Caínico/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Humanos , Receptores de Ácido Caínico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismoRESUMO
Kainate receptors (KARs) constitute a family of ionotropic glutamate receptors (iGluRs) with distinct physiological roles in synapses and neuronal circuits. Despite structural and biophysical commonalities with the other iGluRs, AMPA receptors and NMDA receptors, their role as post-synaptic receptors involved in shaping EPSCs to transmit signals across synapses is limited to a small number of synapses. On the other hand KARs regulate presynaptic release mechanisms and control ion channels and signaling pathways through non-canonical metabotropic actions. We review how these different KAR-dependent mechanisms concur to regulate the activity and plasticity of neuronal circuits in physiological conditions of activation of KARs by endogenous glutamate (as opposed to pharmacological activation by exogenous agonists). KARs have been implicated in neurological disorders, based on genetic association and on physiopathological studies. A well described example relates to temporal lobe epilepsy for which the aberrant recruitment of KARs at recurrent mossy fiber synapses takes part in epileptogenic neuronal activity. In conclusion, KARs certainly represent an underestimated actor in the regulation of neuronal circuits, and a potential therapeutic target awaiting more selective and efficient genetic tools and/or ligands. This article is part of the special Issue on 'Glutamate Receptors - Kainate receptors'.
Assuntos
Rede Nervosa/fisiologia , Receptores de Ácido Caínico/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Humanos , Rede Nervosa/efeitos dos fármacos , Receptores de Ácido Caínico/efeitos dos fármacos , Receptores de Ácido Caínico/genética , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.
Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Giro do Cíngulo/citologia , Giro do Cíngulo/fisiologia , Células Piramidais/fisiologia , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/efeitos dos fármacos , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Expressão Gênica/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Humanos , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/fisiologia , Transdução de SinaisRESUMO
The activity of central pattern-generating networks (CPGs) may change under the control exerted by various neurotransmitters and modulators to adapt its behavioral outputs to different environmental demands. Although the mechanisms underlying this control have been well established in invertebrates, most of their synaptic and cellular bases are not yet well understood in vertebrates. Gymnotus omarorum, a pulse-type gymnotiform electric fish, provides a well-suited vertebrate model to investigate these mechanisms. G. omarorum emits rhythmic and stereotyped electric organ discharges (EODs), which function in both perception and communication, under the command of an electromotor CPG. This nucleus is composed of electrotonically coupled intrinsic pacemaker cells, which pace the rhythm, and bulbospinal projecting relay cells that contribute to organize the pattern of the muscle-derived effector activation that produce the EOD. Descending influences target CPG neurons to produce adaptive behavioral electromotor responses to different environmental challenges. We used electrophysiological and pharmacological techniques in brainstem slices of G. omarorum to investigate the underpinnings of the fast transmitter control of its electromotor CPG. We demonstrate that pacemaker, but not relay cells, are endowed with ionotropic and metabotropic glutamate receptor subtypes. We also show that glutamatergic control of the CPG likely involves two types of synapses contacting pacemaker cells, one type containing both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors and the other one only-NMDA receptor. Fast neurotransmitter control of vertebrate CPGs seems to exploit the kinetics of the involved postsynaptic receptors to command different behavioral outputs. The prospect of common neural designs to control CPG activity in vertebrates is discussed.NEW & NOTEWORTHY Underpinnings of neuromodulation of central pattern-generating networks (CPG) have been well characterized in many species. The effects of fast neurotransmitter systems remain, however, poorly understood. This research uses in vitro electrophysiological and pharmacological techniques to show that the neurotransmitter control of a vertebrate CPG in gymnotiform fish involves the convergence of only-NMDA and AMPA-NMDA glutamatergic synapses onto neurons that pace the rhythm. These inputs may organize different behavioral outputs according to their distinct functional properties.
Assuntos
Relógios Biológicos/fisiologia , Geradores de Padrão Central/metabolismo , Fenômenos Eletrofisiológicos/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Gimnotiformes/fisiologia , Receptores Ionotrópicos de Glutamato/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Relógios Biológicos/efeitos dos fármacos , Geradores de Padrão Central/efeitos dos fármacos , Estimulação Elétrica , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Gimnotiformes/metabolismo , Receptores Ionotrópicos de Glutamato/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/efeitos dos fármacosRESUMO
In rodent models of smoking during pregnancy, early postnatal nicotine exposure results in impaired hippocampus-dependent memory, but the underlying mechanism remains elusive. Given that hippocampal cholinergic systems modulate memory and rapid development of hippocampal cholinergic systems occurs during nicotine exposure, here we investigated its impacts on cholinergic function. Both nicotinic and muscarinic activation produce transient or long-lasting depression of excitatory synaptic transmission in the hippocampal CA1 region. We found that postnatal nicotine exposure impairs both the induction and nicotinic modulation of NMDAR-dependent long-term depression (LTD). Activation of muscarinic receptors decreases excitatory synaptic transmission and CA1 network activity in both wild-type and α2 knockout mice. These muscarinic effects are still observed in nicotine-exposed mice. M1 muscarinic receptor activity is required for mGluR-dependent LTD. Early postnatal nicotine exposure has no effect on mGluR-dependent LTD induction, suggesting that it has no effect on the function of m1 muscarinic receptors involved in this form of LTD. Our results demonstrate that early postnatal nicotine exposure has more pronounced effects on nicotinic function than muscarinic function in the hippocampal CA1 region. Thus, impaired hippocampus-dependent memory may arise from the developmental disruption of nicotinic cholinergic systems in the hippocampal CA1 region.
Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptor Muscarínico M1/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Região CA1 Hipocampal/crescimento & desenvolvimento , Região CA1 Hipocampal/metabolismo , Fumar Cigarros , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Lactação , Depressão Sináptica de Longo Prazo/fisiologia , Masculino , Exposição Materna , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , Camundongos Knockout , Receptor Muscarínico M1/metabolismo , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Nicotínicos/metabolismoRESUMO
INTRODUCTION: Group II metabotropic glutamate (mGlu) receptors have emerged as an attractive potential target for the development of novel CNS therapeutics in areas such as Alzheimer's disease (AD), anxiety, cognitive disorders, depression, and others. Several small molecules that act as negative allosteric modulators (NAMs) on these receptors have demonstrated efficacy and/or target engagement in animal models, and one molecule (decoglurant) has been advanced into clinical trials. AREAS COVERED: This review summarizes patent applications published between January 2015 and November 2020. It is divided into three sections: (1) small molecule nonselective mGlu2/3 NAMs, (2) small molecule selective mGlu2 NAMs, and (3) small molecule selective mGlu3 NAMs. EXPERT OPINION: Much progress has been made in the discovery of novel small molecule mGlu2 NAMs. Still, chemical diversity remains somewhat limited and room for expansion remains. Progress with mGlu3 NAMs has been more limited; however, some promising molecules have been disclosed. The process of elucidating the precise role of each receptor in the diseases associated with group II receptors has begun. Continued studies in animals with selective NAMs for both receptors will be critical in the coming years to inform researchers on the right compound profile and patient population for clinical development.
Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Desenvolvimento de Medicamentos , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/fisiopatologia , Descoberta de Drogas , Humanos , Patentes como Assunto , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
Metabotropic glutamate receptor 7 (mGlu7) is an inhibitory heterotrimeric G-protein-coupled receptor that modulates neurotransmitter release and synaptic plasticity at presynaptic terminals in the mammalian central nervous system. Recent studies have shown that rare mutations in glutamate receptors and synaptic scaffold proteins are associated with neurodevelopmental disorders (NDDs). However, the role of presynaptic mGlu7 in the pathogenesis of NDDs remains largely unknown. Recent whole-exome sequencing (WES) studies in families with NDDs have revealed that several missense mutations (c.1865G>A:p.R622Q; c.461T>C:p.I154T; c.1972C>T:p.R658W and c.2024C>A:p.T675K) or a nonsense mutation (c.1757G>A:p.W586X) in the GRM7 gene may be linked to NDDs. In the present study, we investigated the mechanistic links between GRM7 point mutations and NDD pathology. We find that the pathogenic GRM7 I154T and R658W/T675K mutations lead to the degradation of the mGlu7 protein. In particular, the GRM7 R658W/T675K mutation results in a lack of surface mGlu7 expression in heterologous cells and cultured neurons isolated from male and female rat embryos. We demonstrate that the expression of mGlu7 variants or exposure to mGlu7 antagonists impairs axon outgrowth through the mitogen-activated protein kinase (MAPK)-cAMP-protein kinase A (PKA) signaling pathway during early neuronal development, which subsequently leads to a decrease in the number of presynaptic terminals in mature neurons. Treatment with an mGlu7 agonist restores the pathologic phenotypes caused by mGlu7 I154T but not by mGlu7 R658W/T675K because of its lack of neuronal surface expression. These findings provide evidence that stable neuronal surface expression of mGlu7 is essential for neural development and that mGlu7 is a promising therapeutic target for NDDs.SIGNIFICANCE STATEMENT Neurodevelopmental disorders (NDDs) affect brain development and function by multiple etiologies. Metabotropic glutamate receptor 7 (mGlu7) is a receptor that controls excitatory neurotransmission and synaptic plasticity. Since accumulating evidence indicates that the GRM7 gene locus is associated with NDD risk, we analyzed the functional effects of human GRM7 variants identified in patients with NDDs. We demonstrate that stable neuronal surface expression of mGlu7 is essential for axon outgrowth and presynaptic terminal development in neurons. We found that mitogen-activated protein kinase (MAPK)-cAMP-protein kinase A (PKA) signaling and subsequent cytoskeletal dynamics are defective because of the degradation of mGlu7 variants. Finally, we show that the defects caused by mGlu7 I154T can be reversed by agonists, providing the rationale for proposing mGlu7 as a potential therapeutic target for NDDs.
Assuntos
Axônios/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Mutação Puntual/genética , Terminações Pré-Sinápticas , Receptores de Glutamato Metabotrópico/genética , Animais , Axônios/efeitos dos fármacos , Contagem de Células , Sobrevivência Celular , Proteínas Quinases Dependentes de AMP Cíclico/biossíntese , Proteínas Quinases Dependentes de AMP Cíclico/genética , Feminino , Regulação da Expressão Gênica , Masculino , Neurônios/metabolismo , Neurônios/patologia , Gravidez , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/biossíntese , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Transdução de Sinais/genética , Sinapses/patologia , Sequenciamento do ExomaRESUMO
Current treatments for Parkinson's disease (PD) are mainly dopaminergic drugs. However, dopaminergic drugs are only symptomatic treatments and limited by several side effects. Recent studies into drug development focused on emerging new molecular mechanisms, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nuclear receptor-related 1 (Nurr1), adenosine receptor A2, nicotine receptor, metabotropic glutamate receptors (mGluRs), and glucocerebrosidase (GCase). Also, immunotherapy and common pathological mechanisms shared with Alzheimer's Disease (AD) and diabetes have attracted much attention. In this review, we summarized the development of preclinical and clinical studies of novel drugs and the improvement of dopaminergic drugs to provide a prospect for PD treatment.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Neurônios Dopaminérgicos/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Preparações Farmacêuticas , Animais , Humanos , NADPH Oxidases/efeitos dos fármacos , Doença de Parkinson/patologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacosRESUMO
INTRODUCTION: Depression is a highly debilitating psychiatric disorder and a worldwide health issue. Functional deficits in glutamatergic cortico-limbic areas are hypothesized to play a key role in the pathogenesis of the disease. Consistently, the clinical antidepressant efficacy of the N-Methyl-D-aspartate (NMDA) receptor antagonist ketamine gives hope for a new class of glutamatergic rapid-acting antidepressants. In this context, metabotropic glutamate (mGlu) receptors have received attention as interesting targets for new antidepressants. AREAS COVERED: The present review summarizes the preclinical evidence supporting the antidepressant effect of the pharmacological modulation of mGlu receptors. Antidepressant properties in animal models of mGlu1 antagonists, mGlu5 negative allosteric modulators (NAMs) and positive allosteric modulators (PAMs), mGlu2/3 agonists, PAMs, orthosteric antagonists and NAMs, mGlu4 and mGlu7 PAMs are reviewed. To date, orthosteric mGlu2/3 antagonists are the most promising compounds in development as antidepressants. EXPERT OPINION: Although accumulating clinical and preclinical evidence concur to confirm a primary role of glutamate transmission modulation for the induction of a rapid antidepressant effect, very little is still known about the cellular mechanisms involved. More mechanistic studies are required to understand the role of glutamate in depression and the therapeutic potential of drugs directly targeting the glutamate synapse.
Assuntos
Antidepressivos/farmacologia , Descoberta de Drogas/métodos , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Animais , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Ketamina/farmacologia , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
INTRODUCTION: Approximately 40% of Parkinson's disease (PD) patients that take mostly dopamine receptor agonists for motor fluctuations, experience the return of symptoms between regular doses. This is a phenomenon known as 'OFF periods.' Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) are a promising non-dopaminergic mechanism with potential to address the unmet need of patients suffering from OFF periods. Foliglurax is the first mGluR4 PAM that has advanced into clinical testing in PD patients. AREAS COVERED: We summarize the chemistry, pharmacokinetics, and preclinical pharmacology of foliglurax. Translational PET imaging studies, clinical efficacy data, and a competitive landscape analysis of available therapies are presented to the readers. In this Perspective article, foliglurax is used as a case study to illustrate the inherent R&D challenges that companies face when developing drugs. These challenges include the delivery of drugs acting through novel mechanisms, long-term scientific investment, and commercial success and shorter-term positive financial returns. EXPERT OPINION: Failure to meet the primary and secondary endpoints in a Phase 2 study led Lundbeck to discontinue the development of foliglurax. Understanding the evidence supporting compound progression into Phase 2 will enable the proper assessment of the therapeutic potential of mGluR4 PAMs.
Assuntos
Antiparkinsonianos/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Regulação Alostérica/efeitos dos fármacos , Animais , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Doença de Parkinson/fisiopatologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
Psychosis and dyskinesia significantly diminish the quality of life of patients with advanced Parkinson's disease (PD). Available treatment options are unfortunately few and their use is limited by adverse effects. We have recently shown that activation of metabotropic glutamate 2 and 3 (mGlu2/3) receptors produced significant relief of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced psychosis-like behaviours (PLBs) and dyskinesia in experimental models of PD. Here, using the highly-selective mGlu2 positive allosteric modulator (PAM) LY-487,379, we seek to determine the contribution of selective mGlu2 activation on both L-DOPA-induced PLBs and dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We first determined the pharmacokinetic (PK) profile of LY-487,379 in the common marmoset, following which we administered it (0.1, 1 and 10 mg/kg) or its vehicle to 6 MPTP-lesioned marmosets previously exposed to L-DOPA to elicit stable PLBs and dyskinesia. We found that LY-487,379 provided a ≈45% reduction of the global PLBs observed and reduced global dyskinesia score by ≈ 55%. Moreover, LY-487,379 enhanced the anti-parkinsonian effect of L-DOPA, by reducing global parkinsonian score by ≈ 15%. Our data suggest that selective mGlu2 positive allosteric modulation with LY-487,379 may represent a potential therapeutic approach to alleviate both L-DOPA-induced PLBs and dyskinesia in PD.
Assuntos
Antipsicóticos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Moduladores GABAérgicos/uso terapêutico , Levodopa , Intoxicação por MPTP/tratamento farmacológico , Psicoses Induzidas por Substâncias/tratamento farmacológico , Piridinas/uso terapêutico , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Animais , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Callithrix , Feminino , Moduladores GABAérgicos/farmacocinética , Intoxicação por MPTP/psicologia , Masculino , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/psicologia , Psicoses Induzidas por Substâncias/psicologia , Piridinas/farmacocinética , Sulfonamidas/farmacocinéticaRESUMO
Developing central synapses exhibit robust plasticity and undergo experience-dependent remodeling. Evidently, synapses in sensory systems such as auditory brainstem circuits mature rapidly to achieve high-fidelity neurotransmission for sound localization. This depends on a developmental switch in AMPAR composition from slow-gating GluA1-dominant to fast-gating GluA4-dominant, but the mechanisms underlying this switch remain unknown. We hypothesize that patterned stimuli mimicking spontaneous/sound evoked activity in the early postnatal stage drives this gating switch. We examined activity-dependent changes in evoked and miniature excitatory postsynaptic currents (eEPSCs and mEPSCs) at the calyx of Held synapse by breaking through the postsynaptic membrane at different time points following 2 min of theta burst stimulation (TBS) to afferents in mouse brainstem slices. We found the decay time course of eEPSCs accelerated, but this change was not apparent until > 30 min after TBS. Histogram analyses of the decay time constants of mEPSCs for naive and tetanized synapses revealed two populations centered around τfast ≈ 0.4 and 0.8 ms, but the relative weight of the τ0.4 population over the τ0.8 population increased significantly only in tetanized synapses. Such changes are blocked by NMDAR or mGluR1/5 antagonists or inhibitors of CaMKII, PKC and protein synthesis, and more importantly precluded in GluA4-/- synapses, suggesting GluA4 is the substrate underlying the acceleration. Our results demonstrate a novel form of plasticity working through NMDAR and mGluR activation to trigger a gating switch of AMPARs with a temporally delayed onset of expression, ultimately enhancing the development of high-fidelity synaptic transmission.