Glutamate And Neuropsychiatric Disorders

This volume provides a comprehensive overview of recent advances in targeting glutamate signaling for the treatment of major psychiatric and neurological disorders. It draws on the latest findings in glutamate neurobiology and offers valuable insights into the application of translational principles in neuroscience drug discovery and development. In each chapter, glutamate as a neurotransmitter, its receptors and transporters, and their interplay with other neurotransmitters and neurotrophic factors, are discussed in the context of a specific, highly prevalent and disabling CNS disease. Most recent and detailed information is provided on Ischemic Stroke, Chronic Stress, Major Depressive Disorder, Bipolar Disorder, Autism Spectrum Disorders (ASD), Posttraumatic Stress Disorder (PTSD), Alzheimer’s Dementia, Schizophrenia, Impulsive Aggression, Substance Use Disorders (SUD), Amyotrophic Lateral Sclerosis (ALS), Chronic Pain, Multiple Sclerosis, Parkinson’s Disease, Attention Deficit Hyperactivity Disorder (ADHD), Migraine, Epilepsy and Anxiety disorders. Moreover, the book includes an extensive overview of glutamatergic treatments already available on the market, and those which are currently in pharmaceutical drug development pipelines. The primary beneficiaries will be neurology and psychiatry specialists and residents, neuroscientists, neuropharmacologists, pharmaceutical industry and clinical research organization professionals, academics, and clinicians working with psychiatric and neurological patients with comorbidities such as cardiologists, pulmonologists, and endocrinologists. This book will also appeal to psychiatry and neurology subspecialists and clinicians working in neuroscience labs seeking an easy-to-understand yet comprehensive overview of contemporary evidence-based clinical insights backed by basic science (preclinical) research evidence. Given its scope, the book is also a unique and indispensable resource for both preclinical and clinical neuroscientists, medical advisors, and clinical research specialists in the pharmaceutical industry. In addition, it will appeal to neuroscience and neuropsychopharmacology students and guide them through the complexities of glutamate involvement in the pathophysiology of the most common debilitating brain diseases with high unmet medical needs.

Considering that neurological and psychiatric illnesses do not still have efficient therapies and are becoming increasingly widespread, the search for novel targets appears fundamental. Neuroinflammation, alterations in adult neurogenesis and excitotoxicity, all associated with glutamate transmission dysfunction, are key components of the pathogenetic mechanisms underlying neuropsychiatric illnesses. Counteracting the neurotoxic actions of glutamate through the modulatory actions of metabotropic glutamate receptors (mGluRs), represents a rational intervention that offers tolerability compatible with clinical therapy. Their suitability as targets for developing novel therapies is also based on the fact that mGluRs are found abundantly expressed in synapses of the central nervous system (CNS) that are considered critical in certain neurological and psychiatric disorders. Moreover, recently there has been an exponential development of selective ligands, especially positive and negative allosteric modulators, which by binding to less conserved transmembrane domain sequences ensure, besides a good permeability in the CNS, an adequate selectivity for each mGluR subtype. The eBook “Metabotropic Glutamate Receptors and Neurological/Psychiatric Disorders”, collects contributes (original and review articles) on the beneficial effects of positive and negative allosteric modulators of mGluRs in animal models of neurological and psychiatric diseases from renown experts in the field. The hope is that the effort of both Editors and Contributors of this eBook confirms the unlimited potential of mGluRs in CNS diseases and generate a collaborative discussion on the state of art, overall trends, novel strategies, and future direction of this attractive field of research.

Recent studies show that changes in Glutamate/GABA synapses and related pathways may determine whether the synaptic plasticity that occurs as a response to stress is adaptive or maladaptive. Findings have shed new light on the mechanisms that determine the effects of stress on cognitive and affective function. Researchers have brought a wide range of techniques to bear on the study of this problem, including cutting-edge live imaging techniques, electrophysiology, glutamate release from isolated live synaptic terminals, development of transgenic and animal models and new behavioral methods. This book provides an overview of these recent findings and of the techniques used as well as a discussion of how the molecular, cellular, and functional effects of stress may trigger or precipitate neuropsychiatric disorders such as depression, schizophrenia, anxiety and PTSD.

Mounting evidence from preclinical and clinical research suggests that the glutamatergic system is highly involved in the pathophysiology of major neuropsychiatric disorders. All of these scientific activities are a necessary first step, which translates into opportunities in terms of development of new and improved treatment strategies. Glutamate-based research over the last couple of decades has provided novel insights into the pathogenesis of both psychiatric disorders such as treatment resistant depression, bipolar disorder, schizophrenia, PTSD, ADHD and neurological disorders including Alzheimer's dementia, migraine, epilepsy, ALS and neuropathic pain. Recent news developments also indicate glutamate involvement in neurodevelopmental disorders such as autism. In addition to the above, recent discoveries that several novel therapeutic agents like riluzole, memantine, ketamine, topiramate and lamotrigine possess glutamatergic properties as part of their mechanism of action, further boosted the interest of drug development companies and academic research centers to put more effort into investigating novel therapeutically efficacious compounds. Moreover, recent large "real life" clinical studies, such as STAR*D, also looked into disease-associated glutamate genetics and paved the way for the future creation of first individualised pharmacogenetic treatments. The overall purpose of this book is to provide the reader with expert opinions relating to the most up-to-date information on glutamate's role in pathophysiology of neuropsychiatric disorders and current and future glutamatergic treatment strategies. The authors' hope that this contribution will foster future research activities, which are all ultimately aiming to improve quality of life in patients with chronic, psychiatric and neurological disorders, thus enhancing their contribution to society.

Neuropsychiatric disorders, covering both psychotic and depressive disorders, but also autism and attention-deficit hyperactivity disorder (ADHD), are characterized by abnormal behavior and brain structure. Accumulating evidence suggests that altered neurochemistry plays a role in these disorders and may have a causal relationship with the observed behavioral and structural abnormalities. To improve the understanding of neurochemical anomalies and (patho)physiological changes in psychiatric conditions, in vivo assessment of the affected tissue, the brain, is wanted and needed. Magnetic resonance spectroscopy (MRS) is a non-invasive technique which allows in vivo assessment of the molecular composition of brain tissues and identification of metabolites involved in physiological and pathological processes, which is otherwise virtually impossible. Only in the last decade with the development of high field MR methodologies, MRS has become sensitive enough for broader use in clinical studies. The implications are many, but proper guidance and elucidation of the pros and cons for the specific methods is needed to optimally exploit the potential. This Research Topic updates the reader on the possibilities and pitfalls of MRS today and highlights methodologies and applications for the future.

The brain is the most complex organ in our body. Indeed, it is perhaps the most complex structure we have ever encountered in nature. Both structurally and functionally, there are many peculiarities that differentiate the brain from all other organs. The brain is our connection to the world around us and by governing nervous system and higher function, any disturbance induces severe neurological and psychiatric disorders that can have a devastating effect on quality of life. Our understanding of the physiology and biochemistry of the brain has improved dramatically in the last two decades. In particular, the critical role of cations, including magnesium, has become evident, even if incompletely understood at a mechanistic level. The exact role and regulation of magnesium, in particular, remains elusive, largely because intracellular levels are so difficult to routinely quantify. Nonetheless, the importance of magnesium to normal central nervous system activity is self-evident given the complicated homeostatic mechanisms that maintain the concentration of this cation within strict limits essential for normal physiology and metabolism. There is also considerable accumulating evidence to suggest alterations to some brain functions in both normal and pathological conditions may be linked to alterations in local magnesium concentration. This book, containing chapters written by some of the foremost experts in the field of magnesium research, brings together the latest in experimental and clinical magnesium research as it relates to the central nervous system. It offers a complete and updated view of magnesiums involvement in central nervous system function and in so doing, brings together two main pillars of contemporary neuroscience research, namely providing an explanation for the molecular mechanisms involved in brain function, and emphasizing the connections between the molecular changes and behavior. It is the untiring efforts of those magnesium researchers who have dedicated their lives to unraveling the mysteries of magnesiums role in biological systems that has inspired the collation of this volume of work.

Neuropsychiatric diseases, such as schizophrenia, Alzheimer's disease, and etc., represent a serious medical and socioeconomic problems. These diseases are often accompanied by impairments of cognitive function, e.g., abstract thinking, decision-making, attention, and several types of memory. Such deficits significantly disrupt quality of life and daily functioning of patients. Cognitive deficits in neuropsychiatric diseases are associated with alterations of brain morphology and function, and are often resistant to therapeutic interventions. In schizophrenia and related disorders, cognitive deficits are also defined as endophenotypes, i.e. measurable phenotypes linking these disaeses with discrete heritable and reproducible traits. This points to the importance of elucidating these endophenotypes in translational studies. Animal models may not mimic the full spectrum of clinical symptoms, but may act as analogies of particular behaviors or other pathological outcomes. They are useful to search for the etiology of particular psychiatric illnesses and novel therapeutics. Moreover, several behavioral tests to measure cognitive performance in rodents and other species have been implemented. The primary focus of the present topic is to provide up-to-date information on cognitive deficits of neuropsychiatric disorders, such as schizophrenia. This Research Topic also delineates future directions for translational studies aimed at developing novel treatments/interventions of cognitive disturbances.