1,721,062 research outputs found
The stress impact on glutamate transmission: a key to mood and anxiety disorders
No full textDysfunction of the glutamate system is increasingly considered a core feature of neuropsychiatric disorders, including mood and anxiety disorders. Neuroimaging studies have shown consistent volumetric changes in brain areas where glutamate neurons predominate. In parallel, preclinical studies with rodent stress/depression models found dendritic remodeling/reduction of synapses in the same areas, suggesting these changes are major factors in psychopathology. Additional studies have shown that antidepressants may partly reverse maladaptive changes in synapses/circuitry of rodent models. Destabilization of glutamate release/transmission in cortical/limbic areas, in turn induced by stress and glucocorticoids, seems to be crucial for these structural/functional changes [1].
We have previously shown that acute stress induces rapid enhancement of depolarization-evoked glutamate release/transmission in prefrontal and frontal cortex (PFC/FC), by increasing corticosterone levels and stimulation of synaptic glucocorticoid/mineralocorticoid receptors (GR/MR). In addition, we have shown that chronic antidepressants are able to prevent the enhancement of glutamate release induced by acute stressors [2]. We have now evidence that acute stress rapidly enhances glutamate vesicles mobilization and increases the readily releasable pool size, through activation of synaptic GR/MR-mediated non-genomic mechanisms. In vitro application of corticosterone to purified PFC/FC synaptosomes mimics vesicles mobilization, but does not enhance depolarization-dependent glutamate release and transmission. Our results suggest that rapid (non-genomic) synaptic action of corticosterone on the RRP size is necessary, but not sufficient, to increase glutamate release/transmission in PFC/FC. Enhancement of glutamate release/transmission likely needs the activation of delayed, possibly genomic, mechanisms. These studies may help defining new targets for pharmacological treatments of mood and anxiety disorders
Stress Response and Perinatal Reprogramming: Unraveling (Mal)adaptive Strategies
Full text linkEnvironmental stressors induce coping strategies in the majority of individuals. The stress response, involving the activation of the hypothalamic-pituitary-adrenocortical axis and the consequent release of corticosteroid hormones, is indeed aimed at promoting metabolic, functional, and behavioral adaptations. However, behavioral stress is also associated with fast and long-lasting neurochemical, structural, and behavioral changes, leading to long-term remodeling of glutamate transmission, and increased susceptibility to neuropsychiatric disorders. Of note, early-life events, both in utero and during the early postnatal life, trigger reprogramming of the stress response, which is often associated with loss of stress resilience and ensuing neurobehavioral (mal)adaptations. Indeed, adverse experiences in early life are known to induce long-term stress-related neuropsychiatric disorders in vulnerable individuals. Here, we discuss recent findings about stress remodeling of excitatory neurotransmission and brain morphology in animal models of behavioral stress. These changes are likely driven by epigenetic factors that lie at the core of the stress-response reprogramming in individuals with a history of perinatal stress. We propose that reprogramming mechanisms may underlie the reorganization of excitatory neurotransmission in the short- and long-term response to stressful stimuli
The Role of the Glutamate System in Posttraumatic Stress Disorder and Glutamate-Based Treatments
No full textPosttraumatic Stress Disorder (PTSD) is a chronic mental illness with limited options for treatment, characterized by intrusive memory of trauma, avoidance, hyperarousal, emotional numbing, and anhedonia. PTSD is often triggered by exposure to a single traumatic experience, with high prevalence among war veterans. PTSD, together with other neuropsychiatric disorders, involves long-term changes in the structure and function of brain areas, synaptic disconnection, and changes in large-scale brain networks.
Trauma-focused psychotherapy is considered first-line treatment, with greater and more persistent efficacy than pharmacotherapeutic approaches. Pharmacological treatments include SSRI, particularly paroxetine and sertraline, and other traditional antidepressants. The effect size of efficacy for these drugs is often small, with high treatment resistance in certain populations. In recent years a major shift in the conceptual framework of neuropsychiatric disorders has occurred, from the monoamine hypothesis to a neuroplasticity hypothesis, in which the glutamate system is conceived as a primary mediator of pathology and a straight target for antidepressant drugs. Novel potential treatment options have emerged in recent years, in particular several modulators of the glutamate system, including ketamine, riluzole, d-cycloserine, N-acetylcysteine. Ketamine, the prototypical rapid-acting antidepressant, has received much attention for its complex mechanism of action (including clinical trials), and has been proposed as a prophylactic agent against the onset of PTSD after exposure to traumatic stress.
This chapter will explore new pharmacological approaches to the therapy of PTSD, based on the modulation of the glutamate system
The action of antidepressants on the glutamate system : regulation of glutamate release and glutamate receptors
No full textRecent compelling evidence has suggested that the glutamate system is a primary mediator of psychiatric pathology and also a target for rapid-acting antidepressants. Clinical research in mood and anxiety disorders has shown alterations in levels, clearance, and metabolism of glutamate and consistent volumetric changes in brain areas where glutamate neurons predominate. In parallel, preclinical studies with rodent stress and depression models have found dendritic remodeling and synaptic spines reduction in corresponding areas, suggesting these as major factors in psychopathology. Enhancement of glutamate release/transmission, in turn induced by stress/glucocorticoids, seems crucial for structural/functional changes. Understanding mechanisms of maladaptive plasticity may allow identification of new targets for drugs and therapies. Interestingly, traditional monoaminergic-based antidepressants have been repeatedly shown to interfere with glutamate system function, starting with modulation of N-methyl-D-aspartate (NMDA) receptors. Subsequently, it has been shown that antidepressants reduce glutamate release and synaptic transmission; in particular, it was found antidepressants prevent the acute stress-induced enhancement of glutamate release. Additional studies have shown that antidepressants may partly reverse the maladaptive changes in synapses/circuitry in stress and depression models. Finally, a number of studies over the years have shown that these drugs regulate glutamate receptors, reducing the function of NMDA receptors, potentiating the function of α-amino-3-hydroxy-5- methyl-4-isoxazole-propionic acid receptors, and, more recently, exerting variable effects on different subtypes of metabotropic glutamate receptors. The development of NMDA receptor antagonists has opened new avenues for glutamatergic, rapid acting, antidepressants, while additional targets in the glutamate synapse await development of new compounds for better, faster antidepressant action
Acute stress is not acute : sustained enhancement of glutamate release after acute stress involves readily releasable pool size and synapsin I activation
No full textStress, glucocorticoids and glutamate release : effects of antidepressant drugs
No full textStressful life events impact on memory, cognition and emotional responses, and are known to precipitate mood/anxiety disorders. It is increasingly recognized that stress and its neurochemical and endocrine mediators induce changes in glutamate synapses and circuitry, and this in turn modify mental states. Half a century after the monoamine hypothesis, it is widely accepted that maladaptive changes in excitatory/inhibitory circuitry have a primary role in the pathophysiology of mood/anxiety disorders. 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. A considerable body of work, carried out with in vivo microdialysis as well as alternative methodologies, has shown that both stress and corticosterone treatment induce enhancement of activity-dependent glutamate release. Accordingly, results from preclinical studies suggest that stress- and glucocorticoid-induced enhancement of glutamate release and transmission plays a main role in the induction of maladaptive cellular effects, in turn responsible for dendritic remodeling. Additional recent work has showed that drugs employed for therapy of mood/anxiety disorders (antidepressants) prevent the enhancement of glutamate release induced by stress. Understanding the action of traditional drugs on glutamate transmission could be of great help in developing drugs that may work directly at this level
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