1,721,182 research outputs found
The impact of stress on the glutamate system: relevance for psychopathology and treatment
No full textStressful life events impact on memory and cognition and are known to precipitate mood and anxiety disorders. The outcome of stress may range from plasticity enhancing effects, associated with improved cognition, to noxious effects, associated with impaired function or triggering of neuropsychiatric disorders. Half a century after the monoamine hypothesis, it has become increasingly acknowledged that maladaptive changes in the structure and function of excitatory/inhibitory circuitry (representing the vast majority of neurons and synapses in brain) have a primary role in the pathophysiology of mood and anxiety disorders, particularly major depression.
Clinical neuroimaging studies showed consistent volumetric changes in brain areas where glutamate neurons and synapses predominate. In parallel, rodent studies have shown that stressors induce dendritic atrophy, reduction of synapses number and volumetric reductions resembling those observed in patients with mood and anxiety disorders. A major role in this process is attributed to elevation of glucocorticoid hormones by stressors, which enhance glutamate release/transmission, in turn inducing retraction of dendrites. Converging evidence from various groups, including ours, has shown that enhancement of glutamate release/transmission in cortical/limbic areas, in turn induced by stress and glucocorticoids, is crucial for these structural/functional changes (1). We have shown that acute stress rapidly enhances glutamate release/transmission in prefrontal and frontal cortex (PFC/FC), mediated by glucocorticoid/mineralocorticoid receptors (GR/MR) (2). We have now evidence that acute stress rapidly enhances glutamate vesicles mobilization, through activation of synaptic GR/MR-mediated non-genomic mechanisms. Our results suggest that rapid (non-genomic) synaptic action of corticosterone is necessary, but not sufficient, to increase glutamate release/transmission in PFC/FC, which requires activation of delayed, genomic, mechanisms.
Additional support for the role of glutamate in mood and anxiety disorders comes from studies showing that antidepressants prevent the enhancement of glutamate release induced by acute stressors, and may partly reverse the maladaptive changes in synapses/circuitry of chronically stressed rodents. Furthermore, recent compelling evidence showed rapid and sustained antidepressant action of glutamate receptor antagonists (e.g., ketamine) whose rapid action has been linked to a burst of glutamate release/transmission (3). However, the nature and direction of changes in the glutamate system, in pathophysiology and during treatment, is not clear. While acute stressors enhance glutamate release and transmission, repeated stressors seem to bring about destabilization of neuronal architecture and loss of synaptic connections in some pathways, with diffuse alterations in areas and circuits mediating cognitive and emotional behaviors (e.g., hippocampus, prefrontal cortex). A main target for research is the identification of specific effectors mediating the destabilizing effects of repeated stress.
References
1. M. Popoli, Z. Yan, B.S. McEwen, G. Sanacora, Nat. Rev. Neurosci. 13, 22 (2012).
2. L. Musazzi et al., PLoS ONE. 18, 1413 (2012).
3. R.S. Duman, G.K. Aghajanian, Science 338, 68 (2012)
The central role of the glutamate system in stress response and anxiety
No full textThe 9th symposium on ‘Systems Neuropsychiatry’, we will discuss integrative concepts
of ‘Stress, Anxiety and Addiction’. Here, we would like to present integrated functional knowledge of circuits of stress and anxiety which are interconnected with circuits of addiction. Risk factors are key factors to be discussed from an interdisciplinary
perspective. Concepts like ‘regulation’, ‘dysbalance’, ‘adaptation’ are crucial in
this macro-structural context. Additionally, the intracellular molecular signaling network, connected to dopamine and glutamate signaling pathways, is analysed by exploratory computational models. Finally, the interplay between the genome, the proteome, the transcriptome and the epigenome is being explored. The symposium aims to find a better understanding of the pathways from stress and anxiety to addiction, as one of the most important public health issues
The glutamate system as a primary mediator of psychiatric pathology and a pathway for antidepressant action. New biomarkers and targets for treatment
No full textGlutamate neurotransmission dysfunction is increasingly considered a core feature of mental illnesses. For over half a century the conceptual framework of research on these disorders has been dominated by the monoamine hypothesis, on which most of the drugs developed for clinical therapy are based. Although it was not acknowledged as a neurotransmitter until the early 1980s, glutamate has been later recognized as the major excitatory neurotransmitter in the brain, with glutamatergic neurons representing about 80% of total neurons in neocortex. In the past decade it has become increasingly acknowledged that maladaptive changes in the structure and function of excitatory/inhibitory circuitry (representing the vast majority of neurons and synapses in brain) have a primary role in the pathophysiology of mood and anxiety disorders, particularly major depression.
Indeed, clinical research has shown alterations in levels, clearance and metabolism of glutamate in mood and anxiety disorders, and consistent volumetric changes in brain areas where glutamate neurons and synapses predominate. In parallel, preclinical studies with rodent stress and depression models have found dendritic remodeling and synaptic spines reduction in corresponding areas, suggesting these changes are major factors in psychopathology. Converging evidence from various groups, including ours, has shown that enhancement of glutamate release/transmission in cortical/limbic areas, in turn induced by stress and glucocorticoids, is crucial for these structural/functional changes. In addition, antidepressants are able to prevent the enhancement of glutamate release induced by acute stressors. Additional studies have shown that antidepressants may partly reverse the maladaptive changes in synapses/circuitry in stress and depression animal models. Furthermore, recent compelling evidence has shown that the glutamate system is also a target for rapid acting antidepressants, such as NMDA receptor antagonists.
Building up on this large body of evidence, it will be shown how recent preclinical and clinical works can suggest novel biomarkers for pathology and targets for pharmacological intervention at the level of glutamate synapses and circuitry
Agomelatine : innovative pharmacological approach in depression
No full textCurrently available antidepressant agents such as tricyclic antidepressants (TCAs) act primarily through monoaminergic systems in the brain, and have proved to be suboptimal for the management of major depressive disorder (MDD). Such agents are also active at non-target receptor sites, contributing to the development of often serious adverse events. Even the newer selective serotonin reuptake inhibitors (SSRIs), which also act through monoaminergic systems, have suboptimal antidepressant efficacy, and the adverse events that do occur often negatively influence adherence. Although the pathophysiology of depression is not completely understood, it is increasingly recognized that monoamine deficiency/disruption is not the only pathway involved. Recognition that circadian rhythm desynchronization also plays a key role in mood disorders has led to the development of agomelatine, which is endowed with a novel mechanism of action distinct from that of currently available antidepressants. Agomelatine is an agonist of the melatonergic MT(1) and MT(2) receptors, as well as a 5-HT(2C) receptor antagonist. The antidepressant activity of agomelatine is proposed to stem from the synergy between these sets of receptors, which are key components of the circadian timing system. Agomelatine has shown antidepressant-like activity in a number of animal models of depression, such as the learned helplessness model, the chronic mild stress model, the forced swim test and the chronic psychosocial stress test. Moreover, agomelatine has been found to restore normal circadian rhythms in animal models of a disrupted circadian system, and has proved beneficial in an animal model of delayed sleep phase syndrome. Likewise, it has been shown to improve disturbed sleep-wake rhythms in depressed patients. Moreover, current pharmacological and clinical data strongly support the use of agomelatine in the management of MDD
A GLUTAMATERGIC HYPOTHESIS OF MOOD/ANXIETY DISORDERS
No full textHalf a century after the monoamine hypothesis of mood/anxiety disorders, it is widely accepted that maladaptive changes in brain excitatory/inhibitory circuitry have a primary role in pathophysiology of mood/anxiety disorders. However, although most of what we allude to as “neuroplasticity changes” has been detected in glutamatergic neurons and circuitry, by far predominant in the brain, we still refer by default to a “monoamine hypothesis”, without having a clearly defined “glutamate hypothesis” of depression.
The neuroplasticity hypothesis posits that volumetric changes consistently found in limbic and cortical areas of depressed subjects are in good part due to remodeling of neuronal dendritic arbors and loss of synaptic spines. Concurrently, a wealth of data from animal models of stress have shown that different types of behavioral stress enhance glutamate release and transmission in limbic/cortical areas and have powerful effects on structure/morphology, inducing dendritic remodeling, reduction of synaptic spines and global volumetric reductions resembling those observed in depressed patients. Therefore, although monoaminergic transmission has a primary role in the modulation of emotion and cognition, we believe it is time to recognize and posit that mainly excitatory transmission mediates the complex emotional/cognitive changes associated with depression, and also likely represents the actual final common pathway of therapeutic treatments (both psychotherapy and antidepressants) for depression and other mood/anxiety disorders.
Importantly, while all antidepressant drugs available have a monoamine-based mechanism or at least a monoamine-based component in their mechanism, only 50-60% of depressed patients respond to first treatment. This means there is a large space for improvement in antidepressant treatments if non-monoamine targets are taken into account and new compounds are developed that target directly glutamate transmission and related pathways
The impact of stress on glutamate transmission and neuronal architecture. A key to pathophysiology and treatment of mood and anxiety disorders
No full textIn the past decade it has become increasingly acknowledged that maladaptive changes in the structure and function of excitatory/inhibitory circuitry (representing the vast majority of neurons and synapses in brain) have a primary role in the pathophysiology of mood and anxiety disorders, particularly major depression. Indeed, clinical research has shown alterations in levels, clearance and metabolism of glutamate in mood and anxiety disorders, and neuroimaging studies showed consistent volumetric changes in brain areas where glutamate neurons and synapses predominate. In parallel, rodent studies have shown that stressors induce dendritic atrophy, reduction of synapses number and volumetric reductions resembling those observed in patients with mood disorders. A major role in this process is attributed to elevation of glucocorticoid hormones by stressors, which enhance glutamate release/transmission, in turn inducing retraction of dendrites. Converging evidence from various groups, including ours, has shown that enhancement of glutamate release/transmission in cortical/limbic areas, in turn induced by stress and glucocorticoids, is crucial for these structural/functional changes. We have shown that acute stress rapidly enhances glutamate release/transmission in prefrontal and frontal cortex (PFC/FC), mediated by glucocorticoid/mineralocorticoid receptors (GR/MR). We have now evidence that acute stress rapidly enhances glutamate vesicles mobilization, through activation of synaptic GR/MR-mediated non-genomic mechanisms. Our results suggest that rapid (non-genomic) synaptic action of corticosterone is necessary, but not sufficient, to increase glutamate release/transmission in PFC/FC, which requires activation of delayed, genomic, mechanisms.
In addition, antidepressants are able to prevent the enhancement of glutamate release induced by acute stressors. Additional studies have shown that antidepressants may partly reverse the maladaptive changes in synapses/circuitry in stress and depression animal models. Furthermore, recent compelling evidence has shown that the glutamate system is also a target for rapid acting antidepressants, such as NMDA receptor antagonists.
A comprehensive, integrated analysis of the stress- and drug-induced changes in excitatory transmission (representing over 80% of circuitry in cortical and limbic brain areas) may supply crucial information as to how adaptive/maladaptive changes may determine the fate of cognition and affect at the boundary between normal function and mental illness
The pharmacological properties of antidepressants
No full textAntidepressant drugs represent one of the main forms of effective treatment for the amelioration of depressive symptoms. Most available antidepressants increase extracellular levels of monoamines. However, it is now recognized that monoamine levels and availability are only part of the story, and that antidepressants whose mechanism of action is mainly based on the modulation of monoaminergic systems may not be able to satisfy the unmet needs of depression. Therefore, a number of compounds, developed for their potential antidepressant activity, are endowed with putative mechanisms of action not affecting traditional monoamine targets. This article briefly reviews, within a mechanistic perspective, the pharmacological profiles of representative antidepressants from each class, including monoamine oxidase inhibitors, tricyclics, norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, norepinephrine and serotonin reuptake inhibitors, antidepressants interacting with dopaminergic, melatonergic, glutamatergic, or neuropeptide systems. The undesirable side effects of currently used antidepressants, which can often be a reason for lack of compliance, are also considered
Cellular and molecular mechanisms in the long-term action of antidepressants
No full textThe hypotheses on the pathophysiology of depression/mood disorders and on antidepressant mechanisms have greatly changed in recent years. The classical monoamine hypothesis was revealed to be simplistic, in that it could not explain the temporal delay in the therapeutic action of antidepressants. Converging lines of evidence have shown that adaptive changes in the several mechanisms of neuroplasticity are likely to be the cellular and molecular correlates of therapeutic effect. In this article, several mechanisms of neuroplasticity are analyzed in relation to the mechanism of antidepressants, ranging from changes in gene expression (including neurotrophic mechanisms), to synaptic transmission and plasticity, and neurogenesis. We propose that the current version of the hypothesis of antidepressant mechanism simply be called the "hypothesis of neuroplasticity." In the final section, we also briefly review the main current novel strategies in the pharmacology of depression and the new putative targets for antidepressants, with particular emphasis on non-monoaminergic mechanisms. Copyrigh
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