1,721,110 research outputs found
The Homer family and the signal transduction system at glutamatergic postsynaptic density: potential role in behavior and pharmacotherapy.
No full textThe Homer family and the signal transduction system at glutamatergic postsynaptic density: potential role in behavior and pharmacotherapy.
No full textFisiopatologia cellulare e molecolare
No full textQuesto volume approfondisce e sviluppa sul piano clinico l’approccio dimensionale della sintomatologia schizofrenica e fornisce a tutta la trattazione un principio organizzatore basato sui dati della ricerca nella patofisiologia cerebrale della schizofrenia, considerata non più come un “disturbo” ma come una “malattia”. I dati empirici oggi a supporto di questo approccio hanno portato gli autori a considerare alterazioni morfologiche, compromissione funzionale e fisiopatologia cellulare e molecolare come i protagonisti di un modello interpretativo globale basato sulle alterazioni di hardware e di software delle strutture cerebrali
Serotonin-glutamate and serotonin-dopamine reciprocal interactions as putative molecular targets for novel antipsychotic treatments: from receptor heterodimers to postsynaptic scaffolding and effector proteins
No full textThe physical and functional interactions between serotonin-glutamate and serotonin-dopamine signaling have been suggested to be involved in psychosis pathophysiology and are supposed to be relevant for antipsychotic treatment. Type II metabotropic glutamate receptors (mGluRs) and serotonin 5-HT(2A) receptors have been reported to form heterodimers that modulate G-protein-mediated intracellular signaling differentially compared to mGluR2 and 5-HT(2A) homomers. Additionally, direct evidence has been provided that D(2) and 5-HT(2A) receptors form physical heterocomplexes which exert a functional cross-talk, as demonstrated by studies on hallucinogen-induced signaling. Moving from receptors to postsynaptic density (PSD) scenario, the scaffolding protein PSD-95 is known to interact with N-methyl-D-aspartate (NMDA), D(2) and 5-HT(2) receptors, regulating their activation state. Homer1a, the inducible member of the Homer family of PSD proteins that is implicated in glutamatergic signal transduction, is induced in striatum by antipsychotics with high dopamine receptor affinity and in the cortex by antipsychotics with mixed serotonergic/dopaminergic profile. Signaling molecules, such as Akt and glycogen-synthase-kinase-3 (GSK-3), could be involved in the mechanism of action of antipsychotics, targeting dopamine, serotonin, and glutamate neurotransmission. Altogether, these proteins stand at the crossroad of glutamate-dopamine-serotonin signaling pathways and may be considered as valuable molecular targets for current and new antipsychotics. The aim of this review is to provide a critical appraisal on serotonin-glutamate and serotonin-dopamine interplay to support the idea that next generation schizophrenia pharmacotherapy should not exclusively rely on receptor targeting strategies
Dopamine-glutamate interaction and antipsychotics mechanism of action: implication for new pharmacological strategies in psychosis.
No full textSchizophrenia is a severe mental illness characterized by behavioral and cognitive symptoms. Several lines of evidence focus on a direct involvement of the glutamatergic system in the pathophysiology of psychosis. The hypofunction of the ionotropic glutamate N-methyl-D-Aspartate Receptor (NMDA-R) has been proposed as a model of schizophrenia in humans. Cortical and subcortical glutamate release seems to be modulated by dopaminergic and, to a lesser extent, serotoninergic circuitries, and tuned by intracellular pathways. Although dopamine D(2) receptor blockade is a crucial mechanism of antipsychotics pharmacodynamic profile, a putative glutamatergic impact of these compounds is suggested by animal pharmacological isomorphisms of psychosis as well as by clinical studies. According to this view, the balance between D(2) antagonism and NMDA-R modulation may be pivotal for the improvement of both positive and negative symptoms. Recently, many pharmacological strategies involving glutamate receptors have been suggested, and novel compounds and pharmacological strategies acting on glutamate transmission are currently under evaluation: i) augmentation strategies improving NMDA-R transmission (glycine, D-serine, D-cycloserine, glycine transporter inhibitors); ii) ampakines, positive modulators of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor complex; iii) agonists of glutamate metabotropic receptors; iv) drugs involved in subcellular adaptation both at pre- and post-synaptic sites. Furthermore, molecular markers, suggesting modulation of glutamate circuitries after antipsychotics administration, are an attractive tool to shed more light on glutamate involvement in antipsychotics mechanism of action. In this review we provide a critical update of recent preclinical and clinical data on dopamine-glutamate interaction and its role in new pharmacological strategies for psychosis treatment
Scaffolding Proteins of the Post-synaptic Density Contribute to Synaptic Plasticity by Regulating Receptor Localization and Distribution: Relevance for Neuropsychiatric Diseases
No full textSynaptic plasticity represents the long lasting activity-related strengthening or weakening of synaptic transmission, whose well-characterized types are the long term potentiation and depression. Despite this classical definition, however, the molecular mechanisms by which synaptic plasticity may occur appear to be extremely complex and various. The post-synaptic density (PSD) of glutamatergic synapses is a major site for synaptic plasticity processes and alterations of PSD members have been recently implicated in neuropsychiatric diseases where an impairment of synaptic plasticity has also been reported. Among PSD members, scaffolding proteins have been demonstrated to bridge surface receptors with their intracellular effectors and to regulate receptors distribution and localization both at surface membranes and within the PSD. This review will focus on the molecular physiology and pathophysiology of synaptic plasticity processes, which are tuned by scaffolding PSD proteins and their close related partners, through the modulation of receptor localization and distribution at post-synaptic sites. We suggest that, by regulating both the compartmentalization of receptors along surface membrane and their degradation as well as by modulating receptor trafficking into the PSD, postsynaptic scaffolding proteins may contribute to form distinct signaling micro-domains, whose efficacy in transmitting synaptic signals depends on the dynamic stability of the scaffold, which in turn is provided by relative amounts and post-translational modifications of scaffolding members. The putative relevance for neuropsychiatric diseases and possible pathophysiological mechanisms are discussed in the last part of this wor
The SPECTRA Project: Biomedical Data for Supporting the Detection of Treatment Resistant Schizophrenia
No full textIntracellular pathways of antipsychotic combined therapies: Implication for psychiatric disorders treatment
No full textDysfunctions in the interplay among multiple neurotransmitter systems have been implicated in the wide range of behavioral, emotional and cognitive symptoms displayed by major psychiatric disorders, such as schizophrenia, bipolar disorder or major depression. The complex clinical presentation of these pathologies often needs the use of multiple pharmacological treatments, in particular (1) when monotherapy provides insufficient improvement of the core symptoms; (2) when there are concurrent additional symptoms requiring more than one class of medication and (3) in order to improve tolerability, by using two compounds below their individual dose thresholds to limit side effects. To date, the choice of drug combinations is based on empirical paradigm guided by clinical response. Nonetheless, several preclinical studies have demonstrated that drugs commonly used to treat psychiatric disorders may impact common intracellular target molecules (e.g. Akt/GSK-3 pathway, MAP kinases pathway, postsynaptic density proteins). These findings support the hypothesis that convergence at crucial steps of transductional pathways could be responsible for synergistic effects obtained in clinical practice by the co-administration of those apparently heterogeneous pharmacological compounds. Here we review the most recent evidence on the molecular crossroads in antipsychotic combined therapies with antidepressants, mood stabilizers, and benzodiazepines, as well as with antipsychotics. We first discuss clinical clues and efficacy of such combinations. Then we focus on the pharmacodynamics and on the intracellular pathways underpinning the synergistic, or concurrent, effects of each therapeutic add-on strategy, as well as we also critically appraise how pharmacological research may provide new insights on the putative molecular mechanisms underlying major psychiatric disorders
The emerging role of dopamine-glutamate interaction and of the postsynaptic density in bipolar disorder pathophysiology: Implications for treatment
No full textAberrant synaptic plasticity, originating from abnormalities in dopamine and/or glutamate transduction pathways, may contribute to the complex clinical manifestations of bipolar disorder (BD). Dopamine and glutamate systems cross-talk at multiple levels, such as at the postsynaptic density (PSD). The PSD is a structural and functional protein mesh implicated in dopamine and glutamate-mediated synaptic plasticity. Proteins at PSD have been demonstrated to be involved in mood disorders pathophysiology and to be modulated by antipsychotics and mood stabilizers. On the other side, post-receptor effectors such as protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3) and the extracellular signal-regulated kinase (Erk), which are implicated in both molecular abnormalities and treatment of BD, may interact with PSD proteins, and participate in the interplay of the dopamine-glutamate signalling pathway. In this review, we describe emerging evidence on the molecular cross-talk between dopamine and glutamate signalling in BD pathophysiology and pharmacological treatment, mainly focusing on dysfunctions in PSD molecules. We also aim to discuss future therapeutic strategies that could selectively target the PSD-mediated signalling cascade at the crossroads of dopamine-glutamate neurotransmission
Targeting glutamate system for novel antipsychotic approaches: relevance for residual psychotic symptoms and treatment resistant schizophrenia.
No full textAntipsychotics are the mainstay of schizophrenia treatment. However, approximately one third of schizophrenic patients do not respond or respond poorly to antipsychotics. Therefore, there is a need for new approaches that can improve schizophrenia treatment significantly. Promising strategies arise from the modulation of glutamatergic system, according to its proposed involvement in schizophrenia pathogenesis. In this review, we critically updated preclinical and clinical data on the modulation of glutamate N-methyl-D-aspartate (NMDA) receptor activity by NMDA-Rs co-agonists, glycine transporters inhibitors, AMPAkines, mGluR5 agonists, NMDA-Rs partial agonists. We focused on: 1) preclinical results in animal models mimicking the pathophysiology of psychosis, mainly believed to be responsible of negative and cognitive symptoms, and predicting antipsychotic-like activity of these compounds; and 2) clinical efficacy in open-label and double-blind trials. Albeit promising preclinical findings for virtually all compounds, clinical efficacy has not been confirmed for D-cycloserine. Contrasting evidence has been reported for glycine and D-serine, that may however have a role as add-on agents. More promising results in humans have been found for glycine transporter inhibitors. AMPAkines appear to be beneficial as pro-cognitive agents, while positive allosteric modulators of mGluR5 have not been tested in humans. Memantine has been proposed in early stages of schizophrenia, as it may counteract the effects of glutamate excitotoxicity correlated to high glutamate levels, slowing the progression of negative symptoms associated to more advanced stages of the illness
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