Handbook of Neurotoxicity

Description

This handbook is a reference source for identifying, characterizing, instructing on use, and describing outcomes of neurotoxin treatments – to understand mechanisms associated with toxin use; to project outcomes of neurotoxin treatments; to gauge neurotoxins as predictors of events leading to neurodegenerative disorders and as aids to rational use of neurotoxins to model disease entities. Neuroprotection is approached in different manners including those 1) afforded by therapeutic agents – clinical and preclinical; or 2) by non-drug means, such as exercise. The amorphous term ‘neurotoxin’ is discussed in terms of the possible eventuality of a neuroprotectant producing an outcome of excess neuronal survival and a behavioral spectrum that might produce a dysfunction – akin to a neurotoxin’s effect. This new edition significantly expands on the information provided in the first edition, providing the latest research in neurotoxicity and highlighting the relationship between specific neurotoxins and the neurodegenerative disorders they can cause. It also includes new sections on the neurotoxicity of heavy metals, fungi, and snake venom. The Handbook of Neurotoxicity is thus an instructive and valuable guide towards understanding the role of neurotoxins/neurotoxicity in the expansive field of Neuroscience, and is an indispensable tool for laboratory investigators, neuroscientists, and clinical researchers. Preface Contents About the Editor Contributors Part I: Principles of Neurotoxicity Neurotoxicity: A Complex Multistage Process Involving Different Mechanisms 1 Introduction 2 Intrinsic Factors Engaged in Neurotoxicity 2.1 Neurotoxicity Induced by Glutamate 2.2 Neurotoxicity Induced by Calcium Ions 2.3 Neurotoxicity Induced by RS 2.4 Neurotoxicity Induced by Apoptosis 2.5 Neurotoxicity Induced by Glial Cell Activation 2.6 Neurotoxicity Induced by DNA Damage 2.7 Neurotoxicity Induced by Epigenetic Mechanisms 3 Conclusion 4 Cross-References References Targeting Necroptosis as Therapeutic Potential in Central Nervous System Diseases 1 Introduction 2 The Cellular Signal Transduction of Necroptosis 2.1 The Central Signals for Necroptosis: RIP1 and RIP3 2.2 The Upstream Positive and Negative Regulators of Necroptosis 2.2.1 RIP1-TRADD-cIAP2-LUBAC Signal Pathway 2.2.2 RIP1-TRADD-FADD-Caspase-8 Signal Pathway 2.3 Downstream Signals of Necroptosis 2.3.1 Mixed Lineage Kinase Domain-Like Protein (MLKL) 2.3.2 Poly (ADP-Ribose) Polymerase-1/Apoptosis-Inducing Factor (PARP-1/AIF) 3 Inhibitors and Interventions for Necroptotic Cell Death 3.1 Nec-1 and Its Analogs 3.2 HS-1371 3.3 Necrosulfonamide 4 Necroptotic Cell Death in Neurological Diseases 4.1 Stroke 4.2 Neonatal Hypoxic-Ischemic Encephalopathy (HIE) 4.3 Trauma 4.4 Huntington´s Disease 4.5 Amyotrophic Lateral Sclerosis (ALS) 4.6 Alzheimer Disease (AD) 5 Conclusion References Microglia: A Critical Cell for Neurodevelopment 1 Introduction 2 Mature Microglia Morphology 3 Microglia Colonization and Development 4 Influence of Gut Microbiome on Developing Microglia 5 Microglia and Neurovascularization 6 Microglia Influence on Neurogenesis 7 Microglia Influence on Synaptogenesis 8 Microglia Influence on Gliogenesis and Myelination 9 Signaling Mechanisms 10 Pro-inflammatory Cytokines 11 Conclusions 12 Cross-References References Microglial Cell Dysregulation in the Aged Brain and Neurodegeneration 1 Introduction 2 The Microglia-Neuron Interaction 3 Microglia and the Complement 4 The Aging Microglia 5 The Aged Microglia in Neurodegenerative Diseases 6 Conclusion 7 Cross-References References Mechanisms Underlying Long-Latency Neurodegenerative Diseases of Environmental Origin 1 Introduction 2 Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex 2.1 Clinical Phenotypes 2.2 History and Epidemiology 2.3 Disease Hallmarks 2.4 Disease Etiology 2.4.1 Cycasin/MAM 2.4.2 L-BMAA 3 Application to Other Sporadic Neurodegenerative Disorders 3.1 Chemical Exposome 3.1.1 Organophosphates 4 Conclusion 5 Cross-References References BDNF-TrkB Signaling in Lifelong Central Nervous System Myelination and Myelin Repair 1 Introduction 2 Postnatal CNS Myelin Development 2.1 Activity-Dependent Myelin Plasticity 2.2 CNS Myelination in Adulthood and Healthy Brain Aging 3 The Role of BDNF in Postnatal CNS Myelination 3.1 BDNF in Activity-Dependent Myelination 3.2 BDNF-TrkB Signaling in Oligodendrocytes 3.3 The Influence of Neuronal TrkB Signaling in CNS Myelination 4 TrkB Activation as a Target for Myelin Repair 5 Conclusions References Necrostatin-1 as a Neuroprotectant 1 Introduction 2 Characterization of Necrostatin-1 2.1 Mechanisms of Necrostatin-1 Action 2.2 Pharmacokinetics of Necrostatin-1 3 Neuroprotection by Necrostatin-1 in Animal Models 3.1 Brain Ischemia 3.2 Neonatal Hypoxia-Ischemia 3.3 Intracranial Hemorrhages 3.4 Traumatic Brain and Spinal Cord Injuries 3.5 Retina Injuries 3.6 Neurodegenerative Diseases 3.6.1 Alzheimer´s Disease 3.6.2 Parkinson´s Disease 3.6.3 ALS and Other Neuropathies 3.6.4 Other Neurodegenerative Diseases 4 Conclusions 5 Cross-References References Part II: Selective Neurotoxins: Overview Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons 1 Introduction 2 Terminology 3 Early History of Selective Neurotoxins 4 The Era of Synthetic and Small Molecule Selective Neurotoxins 5 Survey of Individual Selective Monoaminergic Neurotoxins 5.1 6-Hydroxydopamine (6-OHDA) 5.1.1 Historical Perspective 5.1.2 6-OHDA Selectivity of Action 5.1.3 6-OHDA Mechanism of Action 5.1.4 Effects of 6-OHDA Treatment of Adult Rodents 5.1.5 Intraparenchymal 6-OHDA Treatments in Rat Brain 5.1.6 Intracisternal and Intraventricular 6-OHDA Treatment of Rats 5.1.7 Effects of 6-OHDA Treatment of Neonatal Rodents 5.2 6-OHDA Analogs 5.3 6-Hydroxydopa (6-OHDOPA) 5.3.1 Historical Background 5.3.2 Advantages of 6-OHDOPA Versus 6-OHDA 5.3.3 Disadvantages of 6-OHDOPA Versus 6-OHDA 5.3.4 Effects in the Periphery and Brain of Rodents Lesioned as Adults with 6-OHDOPA 5.3.5 Long-Lived Effects in the Brain of Rodents Lesioned as Neonates with 6-OHDOPA 5.4 DSP-4 and Xylamine 5.4.1 Overview 5.4.2 Mechanism of Action of DSP-4 and Xylamine 5.4.3 Specificity of DSP-4 5.4.4 Long-Lived Effects of DSP-4 Treatment 5.4.5 Summary on DSP-4 5.5 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 5.5.1 Historical Perspective 5.5.2 MPTP Mechanism and Selectivity of Action 5.5.3 Interspecies Effects of MPTP 5.6 Haloperidol-Related Chemical Species 5.7 2′-Amino-MPTP 5.8 5,6- and 5,7-Dihydroxytryptamine (5,6-DHT, 5,7-DHT) 5.8.1 Mechanisms of Action of 5,6- and 5,7-DHT 5.8.2 Limitations of 5,6-DHT 5.8.3 Effects of 5,7-DHT in Adults 5.9 Amphetamines 5.9.1 Amphetamine (AMPH) 5.9.2 Methamphetamine (METH, Speed, Crank) 5.9.3 Methylenedioxymethamphetamine (MDMA, Ecstasy) 5.9.4 Parachloroamphetamine (PCA) 5.9.5 Fenfluramine 5.9.6 Rotenone 5.9.7 Quinpirole Induction of Long-Lived DA D2-R Supersensitivity 6 Conclusion 7 Cross-References References Survey of the Spectrum of Classic Selective Neurotoxins 1 Introduction 2 Excitatory Amino Acids 2.1 Historical Perspective 2.2 Mechanisms of GLU Excitotoxicity 2.3 Excitotoxicity in Neurological and Neurodegenerative Disorders 2.3.1 Ischemia, Anoxia, and Traumatic Brain Injury 2.3.2 Neurodegenerative Disorders 3 3-Nitropropionic Acid (3-NP) 3.1 3-NP Mechanism of Action 4 NMDA-R Antagonists 5 Cocaine 6 AF64A (Ethylcholine Aziridinium Ion) 7 IgG-Saporin 7.1 Selectivity of IgG-Saporin 7.2 Effect of IgG-Saporin Lesioning 8 Toxic Vanilloids, TRPV1 Receptor Agonists 8.1 Overview 8.2 Mechanism of Vanilloid Action 9 Botulinum Neurotoxin 10 Other Neurotoxins 11 The Future of Neurotoxins in Biomedicine References Part III: Neurotoxins: Dopaminergic, Noradrenergic, and Serotoninergic Neurons Biomarkers of Neurotoxicity Inform Mechanisms of Vulnerability and Resilience in Dopaminergic Neurons 1 Causes of Neurodegenerative Disease 2 In Vitro Models for Neuronal Toxicity 3 Why Are Dopaminergic Neurons Sensitive to Mitochondrial Inhibitors? 4 Rotenone, MPP+, and 6HD Selectively Kill Dopaminergic Neurons 5 Does Neuromelanin Contribute to PD or Protect Neurons from Iron? 6 ``ToxMatrix´´ Screen Reveals Vulnerable Toxicity Pathways in Neurons 7 Biomarkers Reveal Resilience Pathways in Neurons 8 Further Questions 9 Conclusion 10 Cross-References References RCSN Cell System for Identifying Dopaminergic Neurotoxicity 1 Neurons in Culture: What Can They Do for Us? 2 Parkinson´s Disease: Where We Stand 3 Ex Vivo Dopaminergic Cells: What Can They Do to Help? 4 RCSN-3: A Permanent In Vitro Neuronal Dopaminergic Model 5 Can Dopamine Be Harmful? How? 6 Cell Transplantation in PD: The Final Frontier? 7 Cell Therapy: RCSN-3 Contribution and the Use of Induced Pluripotent Stem Cells (iPSCs) 8 Conclusion 9 Cross-References References Dopamine and L-Dopa as Selective Endogenous Neurotoxins 1 Synthesis of L-Dopa and Dopamine 1.1 Dopamine Degradation 2 Dopamine Neurotoxicity 3 Dopamine Oxidation to Orthoquinones 4 Aminochrome Metabolism 5 Aminochrome and Parkinson´s Disease 6 L-Dopa Metabolism 7 L-Dopa Neurotoxicity in Vitro 8 L-Dopa-Induced Dyskinesia 9 L-Dopa, Parkinson´s Disease, and Melanoma 10 Dopamine and L-Dopa as Selective Neurotoxins 11 Conclusion 12 Cross-References References Dopamine Homeostasis and Role of VMAT2 in Neurodegeneration 1 Introduction 2 DA-Mediated Toxicity 3 DA Metabolism 3.1 Synthesis 3.2 Cleavage 3.3 Synaptic Vesicle Sequestration 3.4 Reuptake 3.5 Spatial Considerations 3.6 Duration of Exposure 4 VMAT Expression and DA-Mediated Neurotoxicity 4.1 Less VMAT, More Toxicity 4.2 More VMAT, Less Toxicity 5 Conclusions 6 Cross-References References Neuroprotection and Neurorestoration of Nigra Striatal Dopamine Neurons by Novel Multitarget Drugs, M30 1 Introduction 1.1 Parkinson´s Disease 1.2 Iron and Neurodegeneration 1.3 MAO Inhibition 1.4 Development of Novel Multifunctional Molecules with Various CNS Targets 1.5 Ex Vivo Characterization of the Novel Multifunctional Iron Chelator- MAO Inhibitor Drugs 1.6 Effects of the Novel Iron Chelators on Iron-Induced Lipid Peroxidation Ex Vivo 1.7 Assessment of MAO Inhibitory Activity of the Novel Multifunctional Iron Chelators-MAO Inhibitor Drugs Ex Vivo 1.8 In Vivo Characterization of the MAO Inhibitory Activity of the Novel Multifunctional Iron Chelators 1.9 Effect of Chronic M30 Treatment on Brain and Systemic MAO-A and MAO-B Activities 1.10 Chronic Effect of M30 on Brain Regional Neurotransmitters 1.11 Effect of M30 on Blood Pressure Potentiation in Response to Oral Tyramine in the Rat Model 1.12 Neuroprotective Effect of M30 in the MPTP Mouse Model of Parkinsonism 1.13 Neurorescue-Neurorestoration Effect of M30 in MPTP-Induced Neurotoxicity in Mice 1.14 Effect of M30 on TfR Cell Count in the MPTP Neurorescue Paradigm in Mice 1.15 Effect of M30 on Cell Division in the MPTP Neurorescue Paradigm in Mice 2 Discussion 3 Conclusion References 6-Hydroxydopa: A Precursor-Neurotoxin with Relative Selectivity for Noradrenergic Neurons 1 Introduction 2 Historical Perspective 3 6-OHDOPA As an Experimental Research Tool 4 6-OHDOPA Depletion of NE in the Periphery 5 6-OHDOPA Central Effects 6 Ontogenetic Effects of 6-OHDOPA 7 Phenotypic Specificity of 6-OHDOPA 7.1 Dopaminergic Neurons and 6-OHDOPA 7.2 Cholinergic Phenotype and 6-OHDOPA 7.3 Serotoninergic Phenotype and 6-OHDOPA 7.4 Summary on 6-OHDOPA Phenotypic Selectivity 8 Mechanisms Attending 6-OHDOPA Destruction of Noradrenergic Neurons 9 Summation of 6-OHDOPA Effects and Limitations to 6-OHDOPA 10 6-OHDOPA and Excitotoxicity 11 Conclusion 12 Cross-References References 6-Hydroxydopamine Lesioning of Dopamine Neurons in Neonatal and Adult Rats Induces Age-Dependent Consequences 1 Introduction 2 The 6-OHDA-Lesioned Rat Model 2.1 Mechanism of Action of 6-OHDA 2.2 Microinjections of 6-OHDA into the Brain to Lesion Nigrostriatal DA Neurons in Adult Rats 2.3 Intracisternal Injection of 6-OHDA to Lesion CA-Containing Neurons in Adult Rats 2.4 Intracisternal Injection of 6-OHDA to Lesion CA-Containing Neurons in Neonatal Rats 3 Behavioral Responses After 6-OHDA Lesions 3.1 Behavioral Impairment and Recovery of Function in Rats Lesioned as Adults 3.2 Sparing of Behavioral Impairment and Recovery of Function in Rats Lesioned as Neonates 4 Compensatory Neural Responses After 6-OHDA Lesions 4.1 Adaptations in the DA System of Adult Lesioned Rats 4.2 Adaptations in the DA System of Neonatal Lesioned Rats 4.3 Adaptations in the 5-HT System by 6-OHDA Lesions 4.4 Adaptations in GABA and Other Amino Acid Transmitter Systems by 6-OHDA 4.5 Altered Cholinergic Function 4.6 Altered Expression of Neuropeptides 5 Behavioral Supersensitivity After 6-OHDA Lesions 5.1 Hyperlocomotor and Stereotyped Responses to DA Agonists 5.2 Priming of D1 Agonist-Induced Supersensitivity 5.3 Functional Uncoupling of D1 and D2 Receptors by 6-OHDA 5.4 Hyperlocomotor Responses to NMDA Antagonists 5.5 NMDA Antagonist Inhibition of D1 Agonist-Induced Supersensitivity 5.6 IEG and Signal Transduction Pathway Involvement in D1 Agonist-Induced Supersensitivity 5.7 Hyperlocomotor and Oral Responses to 5-HT Receptor Agonists 5.8 Increased Stereotyped Responses to GABA Agonists 6 Modeling Specific Brain Disorders Using Rats with 6-OHDA Lesions 6.1 Parkinson´s Disease 6.2 Lesch-Nyhan Syndrome 6.3 Other Psychiatric Conditions 7 Conclusion References MPTP Neurotoxicity: Actions, Mechanisms, and Animal Modeling of Parkinson´s Disease 1 Introduction 2 MPTP Metabolism 3 MPP+ and Mitochondria 4 MPP+ and Free Radicals 5 MPTP, Protein Clearing Mechanisms, and Apoptosis 6 MPTP and Glutamate 7 MPTP and Dopamine 8 MPTP Toxicity and Norepinephrine 9 Acute, Chronic, and Continuous MPTP Administration 10 Spinal Cord and MPTP 11 MPTP, the Heart, the Gut, and Other Peripheral Organs 12 MPTP and Thalamic Toxicity 13 MPTP and microRNAs 14 Species Differences in MPTP Toxicity 15 MPTP in Nonhuman Primates 16 MPTP in Mice 17 MPTP in Rats 18 Conclusion 19 Cross-References References MPTP: Advances from an Evergreen Neurotoxin 1 Introduction 2 PD Symptoms and Neuropathology 3 MPTP Neurotoxicity 4 Animal Species and Strand Sensitivity to MPTP Neurotoxicity 4.1 Rodents 4.2 Primates 5 Currently Available In Vivo MPTP Models 5.1 Rodents 5.2 Primates 6 Motor and Nonmotor Symptoms 6.1 Rodents 6.2 Primates 7 Neuropathological Markers of PD in MPTP Models 7.1 Neurodegeneration in Rodents 7.2 Neurodegeneration in Primates 7.3 Alpha-Synuclein/Lewy Body Deposits in Rodents 7.4 Alpha-Synuclein/Lewy Body Deposits in Primates 7.5 Neuroinflammation in Rodents 7.6 Neuroinflammation in Primates 8 Conclusion References Neurotoxicity: Calpain and 1-Methyl-4-phenylpyridinium (MPP+) 1 Role of Calpain in Parkinsonian Models 2 Calcium Homeostasis 3 Mitochondria 4 T Cell Activation and Neurodegeneration 5 Calpain Activation and Neuroinflammation 6 Cell Death 7 Extranigral Neuronal Degeneration 8 Endocrine Effects in MPP+/Calpain Toxicity 9 Conclusion 10 Cross-References References Neurotoxicity of Methamphetamine 1 Introduction 1.1 Background, Medical Use, and Epidemiology 1.2 Administration Routes and Patterns of Methamphetamine Use 1.3 Methamphetamine: Mechanism of Action and Effects 2 Methamphetamine Induces Neurotoxicity 3 Mechanisms of Methamphetamine-Induced Neurotoxicity 3.1 Role of Dopamine 3.2 Implications of Oxidative Stress 3.3 Role of Hyperthermia 3.4 Role of Dopamine Receptors and Dopaminergic System 3.5 Role of Glutamate and Nitric Oxide 3.6 Role of Astroglial and Microglial Activation 3.7 Nrf2 and Inflammation Play a Role in Methamphetamine-Induced Neurotoxicity 3.8 Role of Mitochondrial Dysfunction and DNA Damage 3.9 Autophagy and Methamphetamine 3.10 Role of α-Synuclein 4 Neuroprotective Strategies Against Methamphetamine-Induced Neurotoxicity 5 Conclusion 6 Cross-References References Methamphetamine and MDMA Neurotoxicity: Biochemical and Molecular Mechanisms 1 Introduction 2 Methamphetamine Toxicity and Underlying Mechanisms 2.1 Dopamine and Oxidative Stress 2.2 Role of DAT and VMAT-2 in METH Toxicity 2.3 Role of Dopamine Receptors in METH Toxicity 2.4 Role of Microglia on METH-Induced Toxicity 3 METH Preconditioning Protects aAgainst METH Toxicity 4 METH Self-Administration Animal Model with Extended Access 5 Cognition in Human METH Subjects 6 Summary: METH Toxicity and Risk of Parkinsonism 7 MDMA Neurotoxicity 8 Protective Mechanisms aAgainst MDMA-Induced Toxicity 9 Cognition in Human MDMA Subjects 10 Conclusion 11 Cross-References References On the Disbalance and Impairment of Serotonin Heteroreceptor Complexes in the Rat Brain After MDMA and Hallucinogens Administr... 1 GPCR Heteroreceptor Complexes and Their Receptor-Receptor Interactions 2 Serotonin Homo- and Heteroreceptor Complexes: Understanding Their Balance 2.1 5-HT Iso-receptor Complexes 2.2 D2R-5-HT2AR Heteroreceptor Complexes and the Action of Hallucinogenic Drugs 2.3 mGluR2-5-HT2A Heteromers and Their Receptor-Receptor Interactions in Relation to Schizophrenia and as Targets for Antipsyc... 2.4 5-HT2AR-Oxytocin (OXTR) and 5-HT2CR-OXTR Heterocomplexes 3 MDMA Potentially Alters the Balance and Induces Changes in Serotonin Heteroreceptor Complexes in the Brain: An Hypothesis 4 Conclusions 5 Cross-References References Models of Methamphetamine-Induced Neurotoxicity 1 Introduction 2 Methamphetamine and Striatal Dopamine Neurotoxicity in Humans 3 Methamphetamine and Deficits in Cognitive Functions Mediated by Corticostriatal Circuitry in Humans 4 Animal Models of METH-Induced Neurotoxicity 4.1 Contingent Models of METH Exposure in Rodents 4.2 Non-contingent Models of METH Exposure in Rodents 4.3 Long-Term Consequences of METH-Induced Dopamine Toxicity on Striatal Function 4.3.1 Striatal Dopamine 4.3.2 Striatally Based Behavior 5 Conclusion 6 Cross-References References Cocaine as a Neurotoxin 1 Introduction 2 Pharmacology of Cocaine 3 Neurologic Dysfunction in Cocaine Abusers 4 Impairment of Neurotransmission 4.1 Cocaine Effects on Dopamine and Glutamate Signaling 5 Mechanisms of Neurotoxicity 5.1 Cocaine Toxicity and Oxidative Stress 5.2 Cocaine Toxicity and Mitochondrial Dysfunction 6 Combinations of Cocaine and Other Substances 6.1 Effects of Speedball 6.2 Cocaine and Ethanol 7 Conclusion 8 Cross-References References Enteric Neurotoxicity and Salsolinol 1 Introduction 2 The Enteric Nervous System 2.1 Enteric Neurogenesis in Healthy Adult Gut 2.2 Enteric Neurodegeneration 3 Salsolinol: A Double-Faced Molecule 3.1 Neurotoxic Potential of Salsolinol 3.2 Neuroprotective Potential of Salsolinol 4 Salsolinol and the Gut 4.1 Is There Any Evidence of Salsolinol Production in the Gastrointestinal Tract? 4.2 Should Salsolinol Play Any Role in the Gastrointestinal Tract? 5 Conclusions 6 Cross-References References Nature of DSP-4-Induced Neurotoxicity 1 Introduction 2 Molecular Mechanism of Action 3 DSP-4 Neurotoxic Effects 3.1 DSP-4 Specificity and Monoamine Reuptake 3.2 Synaptic Norepinephrine Levels and Noradrenergic Receptors 3.3 Norepinephrine Synthesizing and Metabolizing Enzymes 3.4 Oxidative Stress and Inflammation-Related Neurodegeneration 3.5 Electrophysiological Responsiveness 4 DSP-4 Doses and Routes of Administration 5 The Nature and Extension of DSP-4-Induced Neurotoxicity in Adulthood 5.1 DSP-4 Treatment of Adult Rats 5.1.1 Noradrenergic System 5.1.2 Serotoninergic System 5.1.3 Dopaminergic System 5.1.4 Other Neuronal Phenotypic Systems 5.1.5 Peripheral Sympathetic Neurons 5.2 DSP-4 Treatment of Newborn Rats 5.2.1 Noradrenergic System 5.2.2 Serotoninergic System 5.2.3 Dopaminergic System 5.2.4 GABAergic System 5.2.5 Peripheral Sympathetic Neurons 5.3 Prenatal DSP-4 Treatment 6 Rodent and Gender Differences in the Susceptibility to DSP-4 7 Conclusion 8 Cross-References References 5,6- and 5,7-Dihydroxytryptamines as Serotoninergic Neurotoxins 1 Introduction 1.1 The Significance of Serotonin and Serotonergic Neurons 1.2 From the First Neurotoxins to the Discovery of Dihydroxytryptamines 2 Dihydroxytryptamines 2.1 Chemical Structure 2.2 The Mode of Administration 2.3 Cytochrome-c Oxidase and the Neurotoxicity of Dihydroxytryptamines 3 Dose-Dependent Action of Dihydroxytryptamines 3.1 5,6-Dihydroxytryptamine 3.2 5,7-Dihydroxytryptamine 4 Dihydroxytryptamines: Differences 4.1 Neurotoxicity 4.2 IC50 for 5-HT Uptake Inhibition 4.3 Selectivity for Catecholamine Uptake 4.4 Half-Life and Stability 4.5 The Rate of Oxygen Consumption 4.6 Diffusion 5 Factors That Affect the Action of 5-HT Neurotoxins 5.1 The Site of Injection 5.2 The Speed and the Volume of Injection 5.3 The Influence of Anesthesia 6 Mechanism of 5,6- and 5,7-Dihydroxytryptamine Neurotoxicity 6.1 Mechanism of 5,7-DHT Action 6.2 Mechanism of 5,6-DHT Action 7 Behavioral Effects 7.1 Adult Animal Studies 7.1.1 Changes in Locomotor Activity 7.1.2 Prepulse Inhibition 7.1.3 Seizure Susceptibility 7.1.4 Serotonin Syndrome 7.1.5 Feeding and Drinking Behavior 7.1.6 Body Temperature 7.1.7 Sexual Behavior 7.1.8 Aggressive Behavior 7.1.9 Response to Novel and Noxious Stimuli 7.1.10 Learning and Memory Functions 7.1.11 Effect of Dihydroxytryptamines on the Antinociceptive Actions of Drugs 7.1.12 Sleeping Behavior 7.1.13 Neuroendocrine Consequences of Dihydroxytryptamine Administration 7.1.14 Effect of 5,7-DHT on the Dopaminergic System 7.2 Neonatal Animal Studies 7.2.1 Locomotor Activity 7.2.2 Seizure Susceptibility 7.2.3 Serotonin Syndrome 7.2.4 Body Weights 7.2.5 Learning and Memory Function 7.2.6 Emotional and Exploratory Behaviors 7.2.7 Prepulse Inhibition 7.2.8 Developmental Plasticity 7.2.9 Effect of 5,7-DHT on Dopaminergic, Noradrenergic, and Histaminergic Systems 8 Conclusion References Long-Lived Dopamine D2-Receptor Supersensitivity: Neurotoxicity in the Presence and Absence of Neuronal Damage 1 Introduction 2 DA Receptor Supersensitization (DA RSS) Following Dopaminergic Denervation in Adulthood 3 DA RSS in Neonates 3.1 DA D1 Receptor Latent and Overt Supersensitization Following Dopaminergic Denervation in Early Postnatal Ontogeny 4 5-HT-R ANTAGONISTS and D1-RSS 4.1 Overt DA D1 Receptor Supersensitization Following Dopaminergic Denervation in Early Postnatal Ontogeny 4.1.1 D1R Supersensitization 4.1.2 5-HT-R Supersensitization 4.1.3 Cholinergic/Muscarinic-R Supersensitization 4.1.4 Intricacies of Neural Phenotypes and Receptor Supersensitization (RSS) 4.2 Overt DA D2 Receptor Supersensitization Following Dopaminergic Denervation in Early Postnatal Ontogeny 5 DA D2-R Agonist Induction of Long-Lived Dopamine D2-R Supersensitivity - Neurotoxicity in the Absence of Overt Neuropathology 6 Conclusion 7 Cross-References References Consequences of Neurotoxin-Induced Dopamine Loss on Striatal Synaptic Plasticity 1 Introduction 1.1 Tonic and Phasic Dopamine Signaling 1.2 Evidence of D1-MSN Impairment Following METH-Induced Neurotoxicity 1.3 Dopamine-Dependent Striatal Plasticity 1.4 Targeting Phasic Dopamine Signaling and Striatal Plasticity as an Approach for Treating METH Abuse and Addiction 2 Conclusions 3 Cross-References References Part IV: Excitotoxicity, Excitotoxins, and Excitoprotectants Ionotropic Receptors in the Central Nervous System and Neurodegenerative Disease 1 Introduction 2 Structural Features of Ionotropic Glutamate Receptors 2.1 NMDA Receptors 2.2 AMPA Receptors 2.3 Kainate Receptors 3 Pharmacology of Ionotropic Glutamate Receptors 3.1 NMDA Receptors 3.2 AMPA Receptors 3.3 Kainate Receptors 4 Molecular Mechanisms in Neurodegenerative Diseases 4.1 Alzheimer´s Disease 4.2 Parkinson´s Disease 4.3 Huntington´s Disease 4.4 Amyotrophic Lateral Sclerosis 5 Conclusion 6 Cross-References References Glutamate as a Neurotoxin 1 Introduction 2 Glutamate Receptors 2.1 NMDA Receptors 2.2 AMPA/Kainate Receptors 2.3 Metabotropic Glutamate Receptors 3 The Neurotoxin Glutamate 4 Mechanisms of Excitotoxicity 4.1 Calcium 4.2 Nitric Oxide, Peroxynitrite, and Free Radicals 4.3 Zinc 4.4 Caspases and Calpains 5 Excitotoxicity in Ischemia and Trauma 6 Excitotoxicity and Chronic Neurodegenerative Diseases 7 Clinical Experience with Drugs Targeting Excitotoxicity in Stroke and Traumatic Brain Injury 8 Clinical Trials with Free Radical Scavengers 9 Conclusion References Glutamate Neurotoxicity Related to Energy Failure 1 Introduction 2 Glutamate Receptors 2.1 Ionotropic Receptors 2.2 Metabotropic Glutamate Receptors 3 Glutamate Transporters 3.1 GLAST and GLT-1 3.2 Energy Requirements of Glutamate Transport 4 Glutamate Metabolism 4.1 Astrocytes 4.2 Neurons 5 Consequences of Energy Failure in Glutamatergic Neurotransmission 5.1 Glycogen, Glucose, and Lactate as Energy Substrates 5.2 Energy Failure and Glutamatergic Neurotransmission 5.3 Energy Failure and Excitotoxicity 6 Possible Interaction Between Excitatory and Inhibitory Neurotransmission 7 Conclusion 8 Cross-References References Glutamate Neurotoxicity, Transport and Alternate Splicing of Transporters 1 Introduction 1.1 Neurotransmission: A Regulated Process of Neurotransmitter Release and Removal 2 Splicing of Glutamate Transporters 2.1 Mechanism of Splicing 2.2 Splicing of 5′-Untranslated Region 2.3 Splicing of 3′-Untranslated Region 2.4 Alternative Splicing and Generation of PDZ-Binding Motifs 2.5 Alternative Splicing and Generation of Exon-Skipping EAAT Variants 2.6 Splicing of N- and C-Termini 3 Are the EAAT Variants Generated by Alternative Splicing Functional? 4 Disease Association of EAAT Splice Variants 5 Conclusion References Quinolinic Acid and Related Excitotoxins: Mechanisms of Neurotoxicity and Disease Relevance 1 Introduction 2 Components of the Kynurenine Pathway 2.1 Tryptophan Cleavage and Immune System 2.2 Formation of 3-Hydroxykynurenine, 3-Hydroxyanthranilic Acid, and QUIN 2.3 Formation of KYNA 2.4 Gut-Brain Axis 3 Neurodegeneration and Kynurenine Metabolites 4 Neuroprotective Kynurenine Metabolites and Their Control 5 Diseases Associated with Kynurenines 5.1 HIV-1-Associated Neurocognitive Disorder (HAND) 5.2 Alzheimer´s Disease 5.3 Huntington´s Disease 5.4 Parkinson´s Disease 5.5 Schizophrenia 5.6 Depression 5.7 Stroke 5.8 Multiple Sclerosis 6 Therapeutic Possibilities 6.1 Diet and Exercise 7 Conclusion 8 Cross-References References The NMDA Receptor System and Developmental Neurotoxicity 1 Introduction 2 NMDA Receptor Structure and Function in the Developing Brain 3 NMDA Receptor Expression or Distribution Pattern and Toxicology in the Developing Brain 4 NMDA Receptor Composition/Regulation and Neurotoxicology in the Developing Brain 5 Conclusion 6 Cross-References References Domoic Acid as a Neurotoxin 1 Chemistry, Physicochemical Properties, and Mechanism(s) of Action 2 DOM Toxicity In Vitro 3 DOM Toxicity In Vivo 3.1 Absorption, Distribution, and Elimination 3.2 Acute Behavioral Toxicity 3.3 Histopathology 3.3.1 Central Nervous System 3.3.2 Peripheral Tissues 3.4 DOM as a Developmental Neurotoxin 3.4.1 Prenatal Studies 3.4.2 Neonatal Studies 4 Clinical Toxicity 4.1 Toxicity in Wildlife 4.2 Toxicity in Humans 5 Conclusion 6 Cross-References References BMAA Neurotoxicity 1 BMAA and Its Isomers 2 Detection of BMAA 3 Sources of BMAA in the Environment 4 Biomagnification of BMAA 5 Human Exposures to BMAA 6 Modes of Action 7 Conclusion 8 Cross-References References The Mechanisms and Modes of BMAA Neurotoxicity 1 Introduction 1.1 Clinical Features of BMAA-Linked Neurodegenerative Diseases 2 Do Animal Models Support a Role for BMAA in ALS/PDC? 3 Proposed Mechanisms of Neurotoxicity 3.1 Excitotoxicity 3.2 Misincorporation 3.3 Protein Association and Enzyme Inhibition 3.4 Other Proposed Mechanisms and Modes of BMAA Toxicity 4 In Vivo Evidence for Mechanisms and Modes 5 Conclusion 6 Cross-References References Glutaric Acid Neurotoxicity: Mechanisms and Actions 1 Key Points 2 Glutaric Acid in Inherited Metabolic Disorders 2.1 Glutaric Acidemia Type 1: Glutaryl-CoA Dehydrogenase Expression, Biochemical and Clinical Phenotypes 2.1.1 Glutaryl-CoA Dehydrogenase Expression in Rodents and Humans 2.1.2 Biochemical Findings 2.1.3 Clinical Manifestations 2.2 Glutaric Acidemia Type 2: Expression of Mitochondrial Electron Transfer Flavoprotein Dehydrogenase and Electron Transfer F... 2.3 Glutaric Acidemia Type 3: Expression of Succinate-Hydroxymethylglutarate CoA-Transferase - Biochemical and Clinical Phenot... 3 Glutaric Acid Transport Across Membranes. Blood-Brain Barrier - Glutaric Acid Accumulation in the Central Nervous System (Tr... 3.1 Glutaric Acid Transport Across Membranes 3.2 Blood-Brain Barrier 3.3 Glutaric Acid Accumulation in the Central Nervous System (Trapping Theory) 4 Human Evidence of Glutaric Acid Neurotoxicity in Glutaric Acidemia Type 1 5 In Vitro and In Vivo Animal Evidence of Glutaric Acid Neurotoxicity 5.1 Chemically Induced and Genetic Models of Glutaric Acidemia Type 1 5.2 Neurobehavioral Disturbances Caused by In Vivo Administration of Glutaric Acid 6 Pathomechanisms of Glutaric Acid Neurotoxicity 6.1 Disruption of Glutamatergic and GABAergic Neurotransmission 6.2 Oxidative Stress 6.3 Reactive Astrogliosis and Astrocyte Dysfunction 6.4 Neuroinflammation 6.5 Bioenergetics Disruption 6.6 Blood-Brain Barrier Breakdown and Vascular Alterations 6.7 Myelination Disturbance 7 Conclusion 8 Cross-References References Glutaric Acidemia Type 1: An Inherited Neurometabolic Disorder of Intoxication 1 Key Points 2 Molecular Defect and General Features 3 Prevalence 4 Accumulating Metabolites and Biochemical Subgroups 5 Clinical Features and Classification 5.1 Clinical Manifestations 5.2 Classification 5.2.1 Infantile- or Early-Onset Glutaric Acidemia Type 1 5.2.2 Insidious-Onset Glutaric Acidemia Type 1 5.2.3 Late-Onset Glutaric Acidemia Type 1 6 Neuroradiological Findings 6.1 Striatum Neuroradiological Findings in Infantile-Onset and Insidious-Onset Glutaric Acidemia Type 1 6.2 Subependymal Lesions and Extensive White Matter Changes in Late-Onset Glutaric Acidemia Type 1 7 Diagnosis 7.1 Asymptomatic Individuals 7.1.1 Newborn Screening 7.1.2 Suggestive Cerebral Magnetic Resonance Imaging Findings 7.1.3 Positive Glutaric Acidemia Type 1 Sibling 7.2 Symptomatic Patients 7.3 Prenatal Testing 8 Treatment 8.1 Maternal Glutaric Acidemia Type 1 9 Neurological and Systemic Outcome: Prevention of Secondary Complications 10 Pathogenesis of Brain Damage 11 Conclusion 12 Cross-References References Neurotoxic Cyanobacterial Toxins 1 Introduction 2 Cyanobacterial Neurotoxins and Mechanisms 2.1 -N-Methylamino-L-Alanine (BMAA) 2.2 Microcystin (MC) 2.3 Anatoxins (ATXs) and ATX-a(s) 2.4 Saxitoxin (STX) 3 Potential and/or Emerging Cyanobacterial Neurotoxins 3.1 Nodularin (NOD) 3.2 Cylindrospermopsin (CYN) 3.3 Neurotoxic Lipopeptides 4 Routes of Human Exposure 4.1 Ingestion 4.2 Aerosolization/Inhalation 4.3 Dermal Contact 5 Underexplored Chronic and Synergistic Effects of Neurotoxins 5.1 Neurotoxic Cyanotoxin Treatment Options 6 Conclusion 7 Cross-References References Endogenous Kynurenic Acid and Neurotoxicity 1 Introduction 2 Formation of KYNA 3 Regulation of KYNA Synthesis 4 Biological Targets of KYNA 5 Experimental KYNA Deficiency 6 KYNA and Brain Disorders 6.1 Parkinson´s Disease 6.2 Huntington´s Disease 6.3 Alzheimer´s Disease 6.4 Cerebral Ischemia 6.5 Seizures and Epilepsy 7 Conclusion 8 Cross-References References Neuroprotection by Kynurenine Metabolites 1 Introduction 2 Glutamatergic Excitotoxicity 3 The Kynurenine Pathway and Its Metabolites 3.1 The Kynurenine Pathway 3.2 Quinolinic Acid and Other Kynurenines with Neurotoxic Properties 3.3 The Endogenous Neuroprotectant Kynurenic Acid 4 Conclusion References Part V: Cholinergic Neurotoxins Botulinum Neurotoxin History 1 Introduction 2 Initial Discovery 3 Isolation of the Toxin and the Canning Industry 4 Biological Warfare 5 First Therapeutic Use 6 From FDA Approval to Therapy 7 Cosmetics 8 Current Therapeutic Indications and ``Off-Label´´ Uses: Historical Aspects 9 Off-Label Uses in Cardiology 10 Off-Label Uses in Psychiatry 11 Other Uses of Botulinum Toxin 12 Future Uses of Botulinum Toxin 13 Conclusion 14 Cross-References References Botulinum Neurotoxins as a Therapeutic 1 Introduction 2 Mechanism of Action of BoNT 2.1 Different and Unique Properties of Various Serotypes of BoNT 2.2 Antigenicity and Immunoresistance 2.3 Adverse Effects 3 Clinical Application 3.1 Neurological Disorders 3.1.1 Blepharospasm 3.1.2 Other Cranial Dystonias 3.1.3 Laryngeal Dystonia (Spasmodic Dysphonia) 3.1.4 Cervical Dystonia 3.1.5 Writer´s Cramps, Other Limb Dystonias, and Axial Dystonia 3.1.6 Hemifacial Spasm 3.1.7 Tremor 3.1.8 Tics Spasticity and Other Hypertonic Disorders 3.2 Painful Disorders 3.2.1 Headache 3.2.2 Chronic Knee Pain 3.2.3 Neuropathic Pain 3.2.4 Restless Legs Syndrome, Painful Limbs/Moving Extremities 3.2.5 Other Pain Syndromes 3.3 Hyperhidrosis 3.4 Autonomic and Gastrointestinal Conditions 3.4.1 Sialorrhea 3.4.2 Achalasia 3.4.3 Constipation and Fecal Incontinence 3.4.4 Anal Fissure 3.5 Overactive Bladder and Other Urologic Problems 3.6 Allergic Rhinitis 3.7 Cosmetic 4 Conclusion 5 Cross-References References Light Chain Role in Action of Botulinum Toxins/Clostridial Neurotoxins 1 Introduction 2 CNT Structure-Function 3 CNT Entry into a Neuron 4 BT Subtypes Possess Unique Biological Properties 4.1 Light Chain Potency and Substrate Specificity 5 CNTs as Therapeutic Agents 5.1 CNT Therapies and Vaccines 6 Conclusions 7 Cross-References References Molecular Mechanism and Effects of Clostridial Neurotoxins 1 Toxins 2 Clostridium Family 3 The Clostridium Botulinum 3.1 Botulism 4 Clostridium Neurotoxins 4.1 Neurotoxin-Associated Proteins 5 Mechanism of Action of Clostridial Neurotoxin 5.1 Receptor Binding and Internalization 5.2 Pore Formation and Translocation 5.3 Blockage of Neurotransmitter Release 5.3.1 SNAREs and Neurotransmission 5.3.2 Motifs and Conformations Involved in Unique Substrate Recognition of BoNT Endopeptidase 5.3.3 Static Versus Dynamic Structure: Role of PRIME Conformation 5.3.4 Chemical Mechanism of Substrate Cleavage 6 Effects and Consequences of Botulinum Neurotoxin Exposure 7 Medical Applications of Clostridial Neurotoxins 8 Potential Future Applications References Part VI: Spectrum of Alternate Neurotoxins Cellular and Molecular Mechanisms of PCB Developmental Neurotoxicity 1 Introduction 2 Human Exposures to PCBs 3 Neurobehavioral Effects of PCBs 4 Neurodevelopmental Processes Altered by PCBs 4.1 PCB Effects on Neuronal Apoptosis 4.2 PCB Effects on Axonal and Dendritic Morphogenesis 5 Molecular Targets of PCBs 5.1 Thyroid Hormone (TH) Homeostasis and Signaling 5.2 Neurotransmitters 5.3 Calcium Signaling 5.4 Oxidative Stress 6 Relevance of PCB DNT to NDDs 7 Conclusion References Ethanol Neurotoxicity 1 Introduction 2 Ethanol 2.1 Dose Dependency 2.2 Alcohol Use Disorder (AUD) 2.3 Risk Factors for AUD 3 Neurotoxicity 3.1 Brain Regions 3.2 Neurotransmitters 3.3 Neurotrophic and Neuroinflammatory Markers 3.4 Cellular and Molecular Mechanisms 4 Comorbid Conditions 4.1 Neuropsychiatric Disorders 4.1.1 Anxiety and Depression 4.1.2 Schizoaffective Disorder 4.1.3 Antisocial Personality Disorder 4.1.4 Panic Disorder 4.1.5 Sleep Disorder 4.2 Neurodegenerative Disorders 4.2.1 Alzheimer´s Disease (AD), Parkinson´s Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) 4.2.2 Multiple Sclerosis (MS) 4.2.3 Dementia 5 Treatment Modalities 5.1 Current Treatments 5.2 Novel Targets 5.2.1 Neurosteroids, Polyphenols, Etc. 5.2.2 Neuropeptides 5.2.3 Neurotransmitters and Receptors Nicotinic Acetylcholine Receptors (nAChRs) Muscarinic Acetylcholine Receptors (mAChRs) Glutamate Receptors GABA Receptors Cannabinoid Receptors G Protein-Coupled Receptors (GPCRs) Tyrosine-Kinase Receptors 5.2.4 Nutrients Carnitine Folic Acid and Selenium Omega-3 Fatty Acids Zinc 6 Conclusion References Neurotoxic Effects, Mechanisms, and Outcome of 192 IgG-Saporin Lesions 1 Introduction 2 Immunolesioning Techniques 3 192 IgG-Saporin 4 Organization of the Basal Forebrain Cholinergic System 5 Selectivity and Effectiveness of 192 IgG-Saporin 6 Structural and Biochemical Effects of 192 IgG-Saporin 7 Behavioral and Cognitive Outcomes of 192 IgG-Saporin Lesions 7.1 Mnesic Functions 7.2 Spatial/Object Novelty Discrimination 7.3 Attentional Functions 8 Neonatal Lesions 9 Conclusion 10 Cross-References References Neurotoxicity in Psychostimulant and Opiate Addiction 1 Introduction 2 Psychostimulants and Opiates 3 In vivo Evidences of Neurotoxicity 3.1 Human Studies 3.1.1 Psychostimulants Neurological and Psychiatric Impairments Morphological Changes Microglia Changes Metabolic Changes Changes in Neurotransmission Manifestations of Genomic Mechanisms 3.1.2 Opiates Neurological and Psychiatric Impairments Morphological Changes Metabolic Changes Manifestation of Oxidative Stress Manifestations of Genomic and Epigenetic Mechanisms 3.2 Animal Studies 3.2.1 Psychostimulants Behavioral Manifestation of Neurotoxicity Changes in Neurotransmission Metabolic Changes Manifestation of Oxidative Stress Manifestations of Epigenetic Mechanisms 3.2.2 Opiates Behavioral Manifestation of Neurotoxicity Changes in Neurotransmission 4 Postmortem Evidences of Neurotoxicity 4.1 Human Studies 4.1.1 Psychostimulants Changes in Neurotransmission Activation of Microglia Manifestation of Oxidative Stress Manifestations of Apoptosis Manifestations of Genomic and Epigenetic Mechanisms 4.1.2 Opiates Changes in Neurotransmission Changes in Protein Levels Manifestation of Oxidative Stress Manifestations of Epigenetic Mechanisms 4.2 Animal Studies 4.2.1 Psychostimulants Changes in Neurotransmission Metabolic Changes Morphological Changes Glia and Microglia Activation Manifestations of Oxidative Stress Manifestation of Apoptosis Manifestations of Genomic and Epigenomic Actions 4.2.2 Opiates Metabolic Changes Morphological Changes Glia and Microglia Activation Manifestation of Oxidative Stress Manifestation of Apoptosis Manifestation of Genetic and Epigenetic Actions 5 Conclusion 6 Cross References References Neurotoxicity of Exogenous Cannabinoids 1 Introduction 2 The Endocannabinoid System 2.1 2-Arachidonoylglycerol and N-Arachidonoylethanolamine: Two Major Endocannabinoids 2.2 Cannabinoid CB1 and CB2 Receptors 3 Cannabis and Phytocannabinoids 3.1 Cannabis: The Most Used Illicit Drug Worldwide 3.2 Effects of Δ9-THC, the Primary Psychoactive Component of Cannabis 3.2.1 Preclinical Studies 3.2.2 Human Studies Positive and Adverse Effects of Cannabis Use Effects of Cannabis on Cognitive Function and Brain Morphology 3.3 Why Are the Concentration of Δ9-THC and the Δ9-THC:CBD Ratio in Cannabis Products so Important for Human Health? 4 Synthetic Cannabinoids 4.1 Synthetic Cannabinoids: The Largest and Most Diverse Group of New Psychoactive Substances 4.2 Synthetic Cannabinoids and Their Products 4.3 Who Uses Synthetic Cannabinoids and Why? 4.4 Synthetic Cannabinoids Are Potent Agonists of Cannabinoid Receptors 4.5 Effects of Synthetic Cannabinoids 4.5.1 Preclinical Studies 4.5.2 Human Data 5 Cannabinoids Use in Pregnancy 6 Conclusion 7 Cross-References References Heteroreceptor Complexes in Substance Use Disorders 1 Introduction 2 Heteroreceptor Complexes, Their Allosteric Interactions and Functions 3 Heteroreceptor Complexes in the Ventral and Dorsal Striatum 3.1 Dopamine D1 Homo- and Heteroreceptor Complexes 3.2 D1R-D2R Heteroreceptor Complexes 3.3 D1R-D3R Heteroreceptor Complexes 3.4 A1R-D1R Heteroreceptor Complexes 3.5 A2AR-D2R Heteroreceptor Complexes 3.6 D2R-Metabotropic Glutamate 5 Receptor (mGluR5), A2AR-mGluR5, and A2AR-D2R-mGlu5 Heteroreceptor Complexes 3.7 A2AR-D2R-Sigma1R Heteroreceptor Complexes 3.8 D3R-Acetylcholine Nicotinic R (nAChR) 3.9 A2AR-Cannabinoid CB1 Receptor (CB1R), CB1R-D2R, and A2AR-CB1R-D2R Heteroreceptor Complexes 3.10 GABAB Receptor Heterodimers 3.11 Serotonin 2A Receptor (5-HT2AR)-Metabotropic Glutamate 2 Receptor (mGluR2) Heteroreceptor Complexes 3.12 5-HT2AR-5-HT2CR and 5-HT2BR-5-HT2CR Heteroreceptor Complexes 3.13 MOR-DOR Heteroreceptor Complexes 3.14 Sigma1R-Ghrelin Receptor 1a (GHS-R1a) Heteroreceptor Complexes 3.15 Corticotropin-Releasing Hormone Receptor 1 (CRF1R)-Orexin 1 Receptor (OX1R) Heteroreceptor Complexes 4 Heteroreceptor Complexes in SUD 4.1 Heteroreceptor Complexes in Alcohol Use Disorder 4.1.1 Ex Vivo 4.1.2 In Vivo 4.2 Heteroreceptor Complexes in Hallucinogen Use Disorder 4.2.1 In Vitro 4.2.2 In Vivo 4.3 Receptor Heteromers in Nicotine Use Disorder 4.3.1 Ex Vivo 4.3.2 In Vivo 4.4 Heteroreceptor Complexes in Opioid Use Disorder 4.4.1 Ex Vivo 4.4.2 In Vivo 4.5 Heteroreceptor Complexes in Psychostimulant Use Disorder 4.5.1 In Vitro 4.5.2 Ex Vivo 4.5.3 In Vivo 4.6 Heteroreceptor Complexes in THC Use Disorder 4.6.1 Ex Vivo 4.6.2 In Vivo 5 Conclusion 6 Cross-References References 3-Hydroxyglutaric Acid as a Neurotoxin 1 3-Hydroxyglutaric Acid Synthesis 2 3-Hydroxyglutaric Acid in Glutaric Acidemia Type 1 (GA 1), Carnitine Palmitoyltransferase 1 Deficiency, and Ketosis 3 3-Hydroxyglutaric Acid in Glutaryl-CoA Dehydrogenase Deficient Mice 4 3-Hydroxyglutaric Acid Transport Through Cellular Membranes 5 3-Hydroxyglutaric Acid Neurotoxicity: Implications for GA 1 Neuropathology 5.1 3-Hydroxyglutaric Acid Behaves as an Excitotoxin 5.2 3-Hydroxyglutaric Acid Induces Oxidative Stress in the Brain 5.3 3-Hydroxyglutaric Acid Disrupts Bioenergetics Homeostasis in the Brain 5.4 3-Hydroxyglutaric Acid Induces Reactive Astrogliosis 5.5 3-Hydroxyglutaric Acid Causes Blood-Brain Barrier Breakdown and Cerebral Vascular Alterations 6 Conclusion 7 Cross-References References Pharmacology and Neurotoxicity of 5-MeO-DIPT 1 Introduction 2 Pharmacology and Metabolic Pathways of 5-MeO-DIPT 3 Neurotoxicity of 5-MeO-DIPT 4 Conclusions 5 Cross-References References Salicylate Ototoxicity, Tinnitus, and Hyperacusis 1 Introduction 1.1 Cellular Mechanisms 2 Salicylate-Induced Hearing Loss 2.1 Salicylate-Induced Outer Hair Cell Impairment 2.2 Effects of Salicylate on Spiral Ganglion Neurons (SGNs) 3 Salicylate-Induced Tinnitus 3.1 Animal Models of Tinnitus 4 Animal Model of Salicylate-Induced Hyperacusis 5 Salicylate-Induced Increases in Stress Hormones 6 Salicylate-Induced Brain Hyperactivity 7 Salicylate-Induced Hyperactivity in AMY and AC 8 Brain Imaging of Salicylate-Induced Tinnitus and Hyperacusis 9 Model of Salicylate-Induced Hearing Loss, Tinnitus, and Hyperacusis 10 Conclusion 11 Cross-References References Part VII: Neurotoxin Models of Human Neurodegenerative Disorders Mechanisms of Dopamine Oxidation and Parkinson´s Disease 1 Dopamine 1.1 Dopamine Synthesis 1.2 Regulation of Dopamine Synthesis 2 Dopamine Degradation 2.1 The Oxidative Deamination of Dopamine 2.2 Ortho-Methylation of Dopamine 3 Dopamine Oxidation to Ortho-Quinones 3.1 Dopamine Oxidation to Aminochrome 3.2 Aminochrome Tautomerization 4 Aminochrome Metabolism 4.1 Aminochrome Polymerization to Neuromelanin 4.2 Aminochrome Adducts with Proteins 4.3 Aminochrome One-Electron Reduction 4.4 Aminochrome-Induced Adduct Formation 4.5 Aminochrome Two-Electron Reduction 4.6 Aminochrome Conjugation with Glutathione 4.7 Neuroprotection Against Aminochrome-Induced Neurotoxicity 5 Aminochrome and Parkinson´s Disease 6 Conclusion 7 Cross-References References Links Between Paraquat and Parkinson´s Disease 1 Introduction 2 Epidemiologic Evidence 3 Relation Between Environmental and Genetic Factors in Parkinson´s Disease: The Paraquat and PARK Genes Connection 4 Cellular Models in Paraquat Neurotoxicity 5 Animal Models in Paraquat Neurotoxicity 5.1 Rat Animal Model 5.2 Mouse Animal Model 5.3 Fruit Fly Animal Model 5.4 Nematode Animal Model 5.5 Zebrafish Animal Model 5.6 Dog Animal Model 5.7 Rabbit Animal Model 5.8 Pig Animal Model 6 Conclusion References Alpha-Synuclein Toxicity: An Insight on Controversial Issues 1 Introduction 2 α-Syn Structure and Functions Within the CNS 2.1 A Summary on the Current Knowledge of the Specific Role of α-Syn in the Dopamine (DA) System 3 α-Synuclein and Neurodegenerative Disorders 4 Potential Detrimental Roles of α-Syn 5 α-Syn and Tau Interaction 6 Potential Beneficial Roles of Endogenous α-Syn 7 Conclusions 8 Cross-References References Autophagy and Parkinson´s Disease 1 Introduction 2 The Autophagic Machinery 3 Autophagy and Neurodegeneration 4 Autophagy in Parkinson´s Disease 5 Autophagy-Related Monogenic PD-Causative Genes 5.1 WT, A53T, A30P, and E46K a-Synuclein 5.1.1 Trafficking Defects 5.2 VPS35 5.2.1 Lysosomal Defects 5.3 LRRK2 5.4 GBA 5.5 ATP13A2α 5.6 PARK2 and PINK1 6 Autophagy and Sporadic PD (WT a-Syn and Autophagy) 7 Autophagy Modulators as PD Therapeutics 7.1 mTOR-Dependent Compounds 7.2 mTOR-Independent Compounds 8 Neuroinflammatory Processes Related to PD and Autophagy 8.1 Neuroinflammation 8.2 Autophagy and Inflammation 8.3 Autophagy and Innate Immune Receptors 8.4 Inflammasome Regulation 8.5 Unconventional Secretion 8.6 Cytokines and Autophagy 9 Conclusion 10 Cross-References References Doxycycline Therapeutic Approach in Parkinson´s Disease and L-DOPA-Induced Dyskinesia 1 Introduction 2 Neuroinflammation in Parkinson´s Disease and L-DOPA-Induced Dyskinesia: An Innovative Intervention 3 The Tetracycline Second Generation and Anti-Inflammatory Action 4 The Tetracycline Derivatives and Parkinson´s Disease 5 L-DOPA-Induced Dyskinesia 5.1 Doxycycline and L-DOPA-Induced Dyskinesia 6 Bonus Effect: Tetracycline Anti-aggregation Activity 7 We Got DOXY! Some Anecdotic Clinical Observation 8 Conclusion 9 Cross-References References Iron-Induced Dopaminergic Cell Death In Vivo as a Model of Parkinson´s Disease 1 Introduction 2 Evidence for an Increased Iron Content in Parkinson´s Disease 3 Neuromelanin as an Intraneuronal Iron Source 4 Effects of Unilateral Intranigral Injections of Ferric Iron 5 Effects of Unilateral Injections of Human NM-Bound Ferric Iron into the SN 6 Conclusion 7 Cross-References References N-Methyl-(R)salsolinol and Enzymes Involved in Enantioselective Biosynthesis, Bioactivation, and Toxicity in Parkinson´s Disea... 1 Introduction 2 Chemical Structure and Occurrence of Isoquinoline Derivatives in Human Control and Parkinsonian Brains 3 Biosynthesis and Bioactivation of (R)salsolinol and Other Isoquinoline Derivatives in the Human Brain: Enzymes in Parkinson´... 3.1 (R)Salsolinol Synthase Catalyzing the Enantio-Specific Synthesis of (R)salsolinol 3.2 N-Methyltransferases and Their Role in Parkinson´s Disease 3.3 Oxidases Producing Toxic Isoquinoline Cations 4 Neurotoxicity of Isoquinolines 4.1 Animal Models of Parkinson´s Disease 4.2 Molecular Mechanisms Underlying Neurotoxicity of Isoquinolines 5 Conclusion 6 Cross-References References Neuromelanin and Parkinson´s Disease 1 Introduction 2 Distribution and Appearance of Neuromelanin (NM) 3 Structure of NM 3.1 The Melanin Pigment 3.2 Peptide Component in NM 3.3 Lipid Component in NM 4 Biosynthesis of NM 5 Developmental Stages of NM 6 Dual Role of NM 7 Implication of NM Architecture in Parkinson´s Disease 8 Conclusion References Protective Agents in Parkinson´s Disease: Caffeine and Adenosine A2A Receptor Antagonists 1 Introduction 2 Neuromodulatory Role of Adenosine 3 Adenosine A2A Receptors 4 Pharmacological Properties of Caffeine 5 Epidemiological Studies on the Neuroprotective Role of Caffeine in Parkinson´s Disease 6 Mechanisms of Dopaminergic Neuroprotection by Caffeine and A2A Receptor Antagonists 7 Potential Neuroprotective Properties of Urate in Parkinson´s Disease 8 Conclusion 9 Cross-References References Novel Pharmacotherapies for L-DOPA-Induced Dyskinesia 1 Introduction 2 Parkinson´s Disease (PD) 2.1 Treatment Modalities for PD 2.2 L-DOPA-Induced Dyskinesia (LID) 2.3 Neurobiological Hypotheses of LID 2.4 Current Management of LID 3 Novel Interventions for LID 3.1 Nicotinic Cholinergic Receptors (nAChRs) 3.2 nAChRs and PD 3.3 Nicotine/nAChR Use in LID 3.4 Ionotropic Glutamatergic Receptors 3.5 Ketamine 3.6 Ketamine Use in LID 3.7 Cannabinoid (CB) Receptors 3.8 Cannabinoids and PD 3.9 Cannabinoid Use in LID 4 Conclusion 5 Cross-References References Experimental Approach to Alzheimer´s Disease with Emphasis on Insulin Resistance in the Brain 1 Introduction 2 Relevant Animal Models 2.1 Corticosterone Model 2.2 Streptozotocin Model 2.3 Streptozotocin-icv + Transgenic Mice Model 2.4 Cholinotoxin Model 2.5 β-Amyloid-icv Model 3 Conclusion 4 Cross-References References Pathogenesis of Alzheimer´s Disease 1 Introduction 2 Amyloidosis Linked to Neurodegeneration 2.1 Does Aβ Correlate with Clinical and Anatomic Indices of Disease? 3 Phosphorylated Tau 3.1 Does Phospho-Tau Correlate with Clinical and Anatomic Indices of Disease? 4 Apolipoprotein E 5 Genetic Aspects Associated with Alzheimer´s Disease Risk 6 Influence of Lifestyle Factors in Alzheimer´s Disease 7 Alternative Hypothesis for Pathogenesis of Alzheimer´s Disease 8 Conclusion 9 Cross-References References p75NTR: A Molecule with Multiple Functions in Amyloid-β Metabolism and Neurotoxicity 1 Introduction 1.1 Molecular Biology, Structure, Distribution, and Expression Pattern 1.2 Expression Location of p75NTR 1.3 Physiological Roles of p75NTR and Its Metabolism 1.4 Signal Pathway of p75NTR Action 2 Pathological Roles of p75NTR in the Nervous System 3 Roles of p75NTR in Pathogenesis of Alzheimer´s Disease 3.1 P75NTR Is a Receptor of Aβ: Expression of p75NTR in Alzheimer´s Disease 3.2 p75NTR and Aβ Production 3.3 p75NTR and Aβ Deposition and Clearance 3.4 P75NTR and tau Phosphorylation 3.5 p75NTR and Neuronal Death 3.6 p75NTR and Neurite Degeneration 3.7 p75NTR and Neuronal Cell Cycle Reentry 3.8 p75NTR and Cognition 4 Potential Use of p75NTR as a Therapeutic Target for Alzheimer´s Disease 5 Conclusion 6 Cross-References References Neurotoxicity in Huntington Disease 1 Neurotoxicity at RNA and Protein Levels 1.1 Toxic Gain of Function 1.1.1 Altered Conformation 1.1.2 Aberrant Post-translational Modifications 1.1.3 Impaired Clearance 1.1.4 Toxic Proteolytic Cleavage Products 1.1.5 Increased Propensity to Aggregate 1.2 Loss of Normal Function 1.3 Altered Transcription of Other Genes 2 Neurotoxicity on an Intracellular Level 2.1 Role of Intranuclear Inclusion Bodies 2.2 Mitochondrial Dysfunction 2.3 Impaired Cytoskeleton and Intracellular Trafficking 3 Neurotoxicity on an Intercellular Level 3.1 Impaired Synaptic Transmission 3.2 Excitotoxicity and the Kynurenine Pathway 3.3 Inflammatory Response 4 Neurotoxicity on an Organ Level 4.1 Brain 4.2 Peripheral Tissues 5 Conclusions 6 Cross-References References Huntington´s Disease and Neurodegeneration 1 Introduction 2 Clinical Features 3 Neuropathology 4 Molecular Mechanisms of Neurodegeneration 4.1 Polyglutamine Protein-Mediated Mechanisms 4.2 Protein Aggregation 4.3 Proteolytic Cleavage: A Probably Rate-Limiting Step 4.4 Transcriptional Deregulation 4.5 Mitochondrial Dysfunction 4.6 Decreased Neurotrophic Factor Expression 4.7 ER Stress 4.8 Axonal Transport Defects 4.9 Deregulated Protein Degradation 5 CAG Repeat RNA-Mediated Mechanisms 5.1 Deregulated Splicing 5.2 Aberrant Translation 5.3 siRNA Machinery 6 Therapeutic Approaches 7 Conclusion 8 Cross-References References Excitotoxicity and Amyotrophic Lateral Sclerosis 1 Introduction of ALS 1.1 Basics 1.2 ALS Genetics 1.3 ALS Models 1.4 Non-cell Autonomous 1.5 Excitotoxicity in ALS 1.6 Non-glutamate Excitotoxins 1.7 Poor Calcium Buffering 2 AMPA Receptors in Excitotoxicity in ALS 2.1 Basic Excitotoxicity 2.2 AMPA Receptor-Mediated Cell Death 2.3 GluR2 Subunit of the AMPA Receptor 2.4 GluR2 Editing 3 Glutamate Transporters in ALS 3.1 Glutamate Transporter Levels in ALS 3.2 Reducing Glutamate Transporters in ALS 3.3 Increasing Glutamate Transporters in ALS 4 Conclusion References Neurotoxicity and ALS: Insights into Pathogenesis 1 Introduction 2 Cortical Hyperexcitability, Glutamate-Mediated Neurotoxicity, and ALS Pathogenesis 3 Glutamate-Mediated Neurotoxicity 4 Mitochondrial Dysfunction 5 Oxidative Stress 6 Protein Aggregation and Neurotoxicity 7 Conclusion 8 Cross-References References Excitotoxicity and the Kynurenine Pathway in Multiple Sclerosis 1 Introduction 2 Multiple Sclerosis, an Autoimmune Disease or Neurodegenerative Disease? 3 Clinical Evidence of Glutamate-Induced Excitotoxicity in MS 4 Cell-Specific Glutamate-Induced Excitotoxicity in MS 4.1 Oligodendrocytes 4.2 Microglia and Astrocytes 5 Potential Endogenous Culprit in Excitotoxicity of MS 6 Clinical Evidence of Quinolinic Acid-induced Excitotoxicity in MS 7 Cell-Specific QUIN-induced Excitotoxicity in MS 7.1 Quinolinic Acid and Oligodendrocytes 7.2 Quinolinic Acid and Astrocytes 7.3 Quinolinic Acid and Microglia 8 Conclusion 9 Cross-References References Multiple System Atrophy 1 Introduction 2 Pathological Aspects of MSA 2.1 Neurodegeneration and Clinic-Pathological Correlations 2.2 Inclusion Pathology 2.3 Neuroinflammation 2.4 Other Disease Processes in MSA 3 Lessons from Preclinical Models of MSA and Potential Therapeutic Strategies 3.1 α-Syn Amyloidogenesis and Propagation Models of MSA 3.2 α-Syn Overexpression Models of MSA 3.3 Potential Effects of α-Syn Aggregation and Accumulation with Contribution to MSA Pathogenesis 3.4 MSA Therapeutic Strategies 3.4.1 Targeting α-Syn as a Potential Strategy for Disease Modification 3.4.2 Targeting Microglial Activation and Neuroinflammation in MSA 3.4.3 Other Possible Therapies for MSA 4 Futures Directions in MSA Research and Therapy 5 Conclusion 6 Cross-References References Neurodegenerative Aspects of Multiple System Atrophy 1 Introduction 1.1 Glial Cytoplasmic Inclusions and the Aggresome Model 2 α-Synuclein 2.1 Alpha-Synuclein Aggregation and p25α 2.2 Posttranslational Modifications of Alpha-Synuclein 3 Heat Shock Proteins 3.1 αB-Crystallin and Small Heat Shock Proteins 3.2 Heat Shock Protein 90 4 Inflammation and Inflammatory Markers 4.1 Microglia and Astroglia 4.2 Metallothionein 5 Calcium Homeostasis 6 Ubiquitin and Ubiquitin Homologues 6.1 SUMO-1 7 Autophagy 8 Oxidative Stress 9 Conclusion References Neurotrophic Therapy for ALS/MND 1 Introduction: What Are the Neurotrophic Factors and How Do They Relate to Neurotoxicity in ALS? 2 Searches for the Cause and Pathophysiology of ALS 3 Treatments for ALS Targeted at Neurotoxicity 3.1 Treatments Targeted at Downregulation of Genetic Mutations 3.2 Treatments Targeted at Excitotoxicity 3.3 Treatments Targeted at Mitochondria 4 Neurotrophic Factor Withdrawals and Neurotrophic Factors as Treatments 4.1 Rationale 4.2 Glial Cell-Derived Neurotrophic Factor 4.3 Brain-Derived Neurotrophic Factor (BDNF) 4.4 Neurotrophin-3 4.5 Ciliary Neurotrophic Factor 4.6 Insulin-Like Growth Factor-1 4.7 Vascular Endothelial Growth Factor 4.8 Fibroblast Growth Factors 4.9 Hepatocyte Growth Factor 4.10 The Future of Neurotrophic Therapy for ALS 5 Conclusion 6 Cross-References References Epilepsy 1 Introduction 2 Neuronal Cell Death in Epilepsy 3 NMDA Receptors and Seizure-Induced Cell Death 4 AMPA Receptors and Seizure-Induced Cell Death 5 Seizure-Induced Cell Death, Epilepsy, and Mitochondria 6 Seizure-Induced Cell Death and Reactive Oxygen Species (ROS) 7 Conclusion References Excitotoxicity in the Pathogenesis of Autism 1 Introduction 2 Evidence for Excitotoxicity in Autistic Patients 3 Conclusion References Glutamate and Neurodegeneration in the Retina 1 Introduction 2 Glutamate Receptors in the Retinal Circuitry 3 Glutamate Receptors in Neurodegenerative Mechanisms 4 Glutamate Transporters in Neurodegenerative Mechanisms 5 Glutamate Mechanisms in Retinal Diseases 6 Neuroprotection via Activation of mGlu Receptors 7 Concluding Remarks 8 Cross-References References Role of Ionotropic Glutamate Receptors in Neurodegenerative and Other Disorders 1 CNS Disorders: A Complex Multifactorial Etiology 2 Dementia and Its Classification 3 Risk Factors for Dementia 4 Prevalence of Neurodegenerative Disorders 5 Societal Cost of Neurodegenerative Disorders 6 The History of L-Glutamate 7 Ionotropic L-Glutamate Receptors 8 NMDA Receptors 9 AMPA Receptors 10 Kainate Receptors 11 Metabotropic L-Glutamate Receptors 12 L-Glu-Mediated Neuronal Excitotoxicity 13 Is Excitotoxicity the Cause of Neurodegenerative Disorders? 14 Alzheimer´s Disease 15 Alzheimer´s Disease and iGluRs 15.1 AMPA Receptors in AD 15.2 NMDA Receptors in AD 16 Interplay of Aβ with NMDARs in Alzheimer´s Disease 17 Parkinson´s Disease 18 Involvement of iGluRs in Parkinson´s Disease 19 NMDA Receptors in PD 20 AMPA Receptors in PD 21 Traumatic Brain Injury 21.1 NMDA Receptors in TBI 21.2 AMPA Receptors in TBI 22 Involvement of iGluRs in Epilepsy 22.1 AMPA Receptors in Epilepsy 22.2 NMDA Receptors in Epilepsy 22.3 Kainate Receptors in Epilepsy 23 Conclusion 24 Cross-References References Neurodegeneration Associated with HIV-1 in the Era of cART 1 Introduction 2 HIV-1 Infection and Viral Life Cycle 3 Mechanisms of HIV Neuroinvasion 4 Clinical Presentation and Histopathological Features of HAND 5 Neuropathology of HIV-1 Infection Before and After Introduction of cART 6 Pathological Mechanisms of HIV-1-Associated Injury in the CNS 7 The Role of Chemokines and Their Receptors in HIV-Induced Brain Injury 8 Effects of HIV-1 on Neurogenesis 9 Potential Links Between HAND and AD 10 AD Neuropathology in HAND Patients 11 Mitogen-Activated Protein Kinase Signaling: Overlap and Differences Between AD and HAND 12 Conclusions 13 Cross-References References Glutamate in the Pathogenesis of Gliomas 1 Introduction 2 Glutaminergic System in the CNS 3 Glutamate Release from Gliomas 4 Effect of Released Glutamate on Neighboring Brain Cells 4.1 Neuron 4.2 Astrocyte 4.3 Glioma 5 Targeting the Glutaminergic System as Anti-Tumoral Agents 5.1 Antagonism of the AMPA Receptor 5.2 Antagonism of Other Glutaminergic Receptors 5.3 Blockade of System xc- in Gliomas 5.4 Inhibition of Glutamate Reuptake 6 Conclusion 7 Cross-References References Neuronal Cytoskeleton and HIV-Mediated Neurodegeneration 1 Introduction 2 HIV Infection 2.1 HIV Genome 2.2 HIV Tropism 2.3 HIV in the CNS 3 HIV Proteins and Neurodegeneration 3.1 Transactivator of Transcription 3.2 Envelope Glycoprotein gp120 4 The Neuronal Cytoskeleton and Neurodegeneration 4.1 The Cytoskeleton 4.2 Axonal Trafficking 4.3 Stability of MTs 5 HAND and Cytoskeleton 5.1 gp120 and Synaptic Pathology 5.2 gp120 Is ``Toxic´´ to Axonal Transport 6 Conclusion 7 Cross-References References Molecular, Cellular, and Behavioural Effects Produced by Perinatal Asphyxia: Protection by Poly (ADP-Ribose) Polymerase 1 (PAR... 1 Introduction 2 Reoxygenation 3 Sentinel Proteins 4 Apoptosis 5 Neuroinflammation 6 Epigenetics 7 A Therapeutic Target 8 An Experimental Model for Perinatal Asphyxia 9 Effect of Nicotinamide on the Long-Term Functional Consequences Elicited by Perinatal Asphyxia 10 Pharmacodynamics and Pharmacokinetics of Nicotinamide 11 Conclusion References Part VIII: Neurotoxicity and Psychiatric Disorders Neurotoxicity in Depression 1 Introduction 2 The Evidence for Brain Structures Changes in Depression: Clinical Data 3 The Evidence for Changes in Brain Structures in Depression: Experimental Data 4 The Involvement of the HPA Axis in Neurodegenerative Processes in Depression 5 The Involvement of Enhanced Glutamate Transmission in Neurodegenerative Processes in Depression 6 The Involvement of the Immune System in Neurodegenerative Processes in Depression 7 The Disturbed Glucose Metabolism in Depression 8 The Role of Glial Cells in Neurodegenerative Processes in Depression 9 Effects of Antidepressant Drugs on Neurodegenerative Processes in Depression 9.1 Effects of Antidepressants on Proinflammatory Cytokines 9.2 Effects of Antidepressant Drugs on Neurogenesis 9.3 Effects of Antidepressant Drugs on the Brain-Derived Neurotrophic Factor 9.4 Effects of Antidepressant Drugs on the Atrophy of Hippocampal Neurons 10 Zinc Deficiency-Induced Neurodegeneration in Depression 11 Conclusion 12 Cross-References References Psychiatric Disorders in Animal Models of Depression 1 Introduction 2 The Toxicological Research of 1MeTIQ: In Silico, In Vitro, and In Vivo Studies 2.1 Histopathological Analysis 2.2 In Silico Prediction (ADMET Predictor Software) 3 The Forced Swimming Test (FST) as an Animal Model of Depression and Its Biochemical Correlates: The Effect of 1,2,3,4-Tetrah... 4 Repeated Administration of a Low Dose of Reserpine as an Animal Model of Depressive Disorder: The Effect of Tetrahydroisoqui... 5 Clonidine-Induced Depression: The Effect of 1MeTIQ 6 Conclusions 7 Cross-References References Psychiatric Disorders in Animal Models of Schizophrenia 1 Introduction 2 CNS Dysfunction in Schizophrenia 3 Animal Models of Schizophrenia 3.1 Glutamatergic Hypofunction Models 3.2 Neurodevelopmental Models 3.3 Genetic Model 4 Searching for New Drugs: The Antipsychotic Potential of 1MeTIQ 5 Conclusion 6 Cross-References References Susceptibility of GPCR Heteroreceptor Complexes to Neurotoxins. Relevance for Neurodegenerative and Psychiatric Disorders 1 Susceptibility of GPCR Heteroreceptor Complexes to Neurotoxins (Misfolded Alpha-Synuclein) 2 Folding of Adenosine A2A Receptor (A2AR) 3 How Can Misfolding in the A2AR Alter A2AR Homo- and Heterocomplexes and Their Formation and Allosteric Receptor-Receptor Int... 4 A2AR and Their Homo and Heteroreceptor Complexes Can Interact with Alpha Synuclein 4.1 Fibrillar Alpha Synuclein and Its Interactions with the A2AR and Its Complexes 5 Conclusion 6 Cross-References References Tardive Dyskinesia: Outcome of Antipsychotic Treatment and Brain Damage? 1 Introduction 2 Multineuronal Associations with Tardive Dyskinesia 3 Oral Dyskinesia Arising in Rodents from Acute Dopamine Receptor Agonist or Antagonist Treatments 3.1 Experimental Induction of Oral Dyskinesia in Rodents by Acute Dopamine D1 R Agonist Treatment or D2 R Antagonist Treatment 3.2 Effect of Neonatal Dopaminergic Denervation on Induction of Oral Dyskinesia in Rodents by Dopamine D1R Agonists or D2R Ant... 4 Oral Dyskinesia Arising in Rodents from Acute Serotonin Agonist Treatment 5 Abatement of Oral Dyskinesia in a Rodent Model of Tardive Dyskinesia 6 Tardive Dyskinesia Arising in Rodents from Chronic Dopamine Receptor Antagonist Treatment 7 Neural Mechanisms Attending Animal Modeling of Tardive Dyskinesia: Relevance to Human Tardive Dyskinesia 8 Conclusion 9 Cross-References References Dopamine Receptor Supersensitivity and Schizophrenia 1 Introduction 2 The Dopamine D2 Receptor and Schizophrenia 3 Rodent Models of Schizophrenia 4 GPCRs and the D2High State 5 G-protein-Dependent Signaling and RGS9 6 G-protein-Independent Signaling 7 DAD2 Receptor Heteromers: Alternative Treatment Options? 8 Antipsychotic-Induced Supersensitization and Relapse Psychosis 9 Implications for Addiction 10 Conclusion 11 Cross-References References TAARs and Neurodegenerative and Psychiatric Disorders 1 Introduction 2 Metabolism of Trace Amines 3 Molecular and Cellular Biology of TAARs 4 TAARs as a Therapeutic Target in Psychiatry 4.1 Schizophrenia 4.2 Parkinson´s Disease Psychosis 4.3 ADHD 4.4 Addictions 4.5 Stimulant Addiction 4.6 Nicotine Addiction 4.7 Opiate Addiction 4.8 Alcohol Addiction 4.9 Obsessive-Compulsive Disorder 4.10 Binge Eating 4.11 Anxiety Spectrum Disorders 5 Drug-Induced Neurotoxicity 5.1 Psychotropic Drugs of Misuse as TAAR1 Agonists 5.2 MDMA 5.3 Methamphetamine 5.4 NBOMe Derivatives of 2C Drugs 5.5 Synthetic Cathinones 6 TAARs in Neurodegenerative Disorders 7 Conclusion 8 Cross-References References Pathophysiology of Obsessive-Compulsive Disorder: Insights from Normal Function and Neurotoxic Effects of Drugs, Infection, an... 1 Introduction 2 Description of OCD 3 Security Motivation System as the Framework to Explain OCD 4 Neurobiology of the SMS and Substrate of OCD Pathophysiology 5 Pathophysiology of OCD 6 Evidence for Overactive SMS Circuit in OCD 7 Neurotoxic Effects Producing OCD Pathophysiology 7.1 Drugs 7.2 Brain Injury 7.3 Infection 8 Conclusion 9 Cross-References References Part IX: Metals and Neurotoxicity Iron Neurotoxicity in Parkinson´s Disease 1 Introduction 2 Iron Homeostasis and Dyshomeostasis in Parkinson´s Disease 2.1 The Iron Responsive Element - Iron Regulatory Protein (IRE/IRP) System: A Brief Description 2.2 Molecular Components of Neuronal Iron Homeostasis 2.2.1 Iron Uptake Systems 2.2.2 The Iron Exporter FPN1 2.2.3 TfR1 2.2.4 Ferritin 2.2.5 The Ferrireductases and Ferroxidases 2.2.6 Neuromelanin 2.3 Iron Accumulation and Iron Chelation Therapy in PD 3 Fe-S Clusters and PD 4 A Role for Ferroptosis in the Execution Step of Dopaminergic Neuronal Death 5 Mitochondrial Dysfunction in PD 6 Inflammation, Hepcidin, and PD 6.1 Hepcidin: The Master Regulator of Iron Homeostasis 6.2 Hepcidin Expression in the CNS 6.3 FPN1-Hepcidin Interactions in the CNS 6.4 Hepcidin: A Nexus Between Inflammation and Iron Accumulation in PD 6.5 Hepcidin-Independent Relationships Between Iron Accumulation and the Inflammatory Response 7 A Positive Feedback Loop in the Death of SN Dopaminergic Neurons 8 Conclusion 9 Cross-References References Lead and Excitotoxicity 1 Introduction 2 Neurotoxicity of Lead 3 Hippocampal Plasticity, NMDA Receptor, and Learning 4 Overview of Glutamate Receptors 5 Activity-Dependent Expression of NMDA Receptor Subunit 6 Lead and Synaptic Transmission 7 Lead and LTP 8 Lead, Calcium, and Glutamate Release 9 Lead and NMDA Receptor 10 Lead and NMDA Signalling 11 Lead and BDNF Signalling 12 Lead and Other Brain Cells 13 Lead and Metabotropic Glutamate Receptors 14 Protein Phosphatases and Lead-Induced NMDAR-Dependent Neurotoxicity 15 Metallothionein and Lead-Induced Excitotoxicity 16 Quinolinic Acid in Lead-Induced Excitotoxicity 17 Conclusion 18 Cross-References References Aluminum and Neurodegenerative Disease 1 Introduction 2 Growing Bioavailability of Aluminum in the Environment 3 Acute Exposure to High Levels of Aluminum Can Lead to Adverse Neurological Consequences 4 Basal Inflammation Within the Brain Increases with Aging. Most Neurodegenerative Diseases Are Characterized by an Even Great... 5 Epidemiological Studies Suggest a Relationship Between Aluminum Exposure and the Incidence of Neurodegenerative Disease 5.1 Alzheimer´s Disease 5.2 Association Between Al Exposure and Neurological Disorders Other than Alzheimer´s Disease 6 Research from Animal Models and In Vitro Systems Implies That High Levels of Aluminum Can Further the Evolution of Age-Relat... 6.1 Immunomodulation and Neuroinflammation 6.2 Oxidative Stress 7 The Neurotoxicity of Aluminum in Amounts Encountered in the Human Environment Continues to Be Contentious 8 Conclusion 9 Cross-References References Manganese Neurotoxicity 1 Introduction 2 Manganese Essentiality 3 Manganese Toxicity 3.1 Sources of Manganese Exposure 3.2 Main Routes of Manganese Exposure 3.2.1 Pulmonary Tract 3.2.2 Gastrointestinal (GI) Tract 3.3 Manganese Pharmacokinetics 3.3.1 Absorption 3.3.2 Transport 3.3.3 Distribution 3.3.4 Excretion 4 Manganese Neurotoxicity 4.1 Manganese and Mitochondria 4.2 Dopaminergic System 4.3 Manganese and Autophagy 5 Manganese and Parkinson´s Disease 5.1 Studies in Drosophila melanogaster 5.2 Studies in Caenorhabditis elegans 5.3 Studies in Rodents 5.4 Studies in Nonhuman Primates 5.5 Studies in Humans 6 Conclusion 7 Cross-References References Thallium Neurotoxicity 1 Introduction 2 Environmental Pollution 2.1 Air 2.2 Soil 2.3 Water 2.4 Food 2.5 Animal and Plant Exposures 2.6 Technologies for Tl+ Remediation 3 Human Reports 4 Mechanisms and Clinical Symptoms 5 Clinical Cases 6 Biochemical Findings in Experimental Models 7 Conclusion 8 Cross-References References Trimethyltin as a Model to Explore Mechanisms of Selective Neuronal Death, Glial Reactivity, and Repair 1 Introduction 2 Trimethyltin as an Experimental Model 3 Human Poisonings 4 Neuropathology in Animal Models 4.1 Non-Human Primates 4.2 Rodents 4.2.1 Rat Model 4.2.2 Mouse Model 4.3 Sensory Systems 5 Glia Involvement 6 Pro-Inflammatory Response 7 Mechanisms of Cell Responses 8 Repair Processes 8.1 Injury-Induced Hippocampal Neurogenesis 9 Gene Expression Pathway Analysis 10 Biomarkers of Neurodegeneration 11 Conclusion 12 Cross-References References Mercury´s Neurotoxic Effects on Brain Selenoenzymes 1 Introduction 2 Selenium Physiology 2.1 Selenoenzymes in Brain Development and Functions 2.2 Selenocysteine Synthesis and Selenoprotein Activities 3 Mercury Toxicity 3.1 Dose-Dependent Effects of Mercury Toxicity 3.2 Dietary Selenium Counteracting Mercury Toxicity 3.3 The Mechanisms of Mercury Toxicity 3.3.1 Synthesis of Suicide Substrates (SOS-1) 3.3.2 Silencing of Selenoenzymes (SOS-2) 3.3.3 Sequestration of Selenium (SOS-3) 3.3.4 Suicide of Selenium-Deprived Cells (SOS-4) 3.3.5 Sustained Oblivion of Sec Synthesis (SOS-5) 3.4 Brain Specificity of Mercury-Dependent Oxidative Damage 3.5 Enhanced Fetal Vulnerability to Mercury 3.6 The ``Silent´´ Latency of Mercury Toxicity 4 Future Directions 5 Conclusion 6 Cross-References References Methylmercury and Cellular Signal Transduction Systems 1 Introduction 2 Redox Signaling 3 MAPK Cascade 4 Rho/ROCK Signaling Pathway 5 Nfr2 Signaling Pathway 6 Conclusion 7 Cross-References References Methylmercury Exposure and Developmental Neurotoxicity: New Insights from Neural Stem Cells 1 Introduction 2 In Vitro Models for Developmental Neurotoxicity Studies 2.1 Neural Stem Cells 2.2 Cell Lines and Primary Cultures of Mouse, Rat, and Human-Derived Neural Stem Cells 3 MeHg Exposure Affects NSCs by Dysregulation of Developmental Processes 3.1 Levels of MeHg Exposure Reported in Humans During Development 3.2 Relevant Endpoints for Assessing Neurotoxic Effects in NSCs 3.2.1 Apoptosis 3.2.2 Proliferation 3.2.3 Differentiation 3.2.4 Migration and Neurite Outgrowth 3.3 Inheritable Effects 4 Critical Mechanisms Behind NSC Dysregulation Induced by MeHg 4.1 Mitochondria Impairment and Oxidative Stress 4.2 Epigenetic Changes 4.2.1 DNA Methylation 4.2.2 Modification of Histones 4.2.3 Noncoding RNAs 5 Conclusion 6 Cross-References References Neurotoxic Electrophile Interactions with Brain Selenoenzymes 1 Introduction 2 Biochemistry of Chalcogen Amino Acids 3 Brain Selenoenzymes and Selenium Interactive Proteins 3.1 Proteins Involved in Selenocysteine Formation, Degradation, and Transport 3.1.1 Selenophosphate Synthetase and Selenocysteine Lyase 3.1.2 Selenoprotein P and the Selenoprotein P Receptor 3.2 Selenoproteins Involved in Prevention, Reversal, and Regulation of Oxidation 3.2.1 Glutathione Peroxidases 3.2.2 Thioredoxin Reductases 3.2.3 Methionine R-Sulfoxide Reductase 3.2.4 Selenoproteins M, F, N, W, T, H, and K 3.3 Selenoprotein S, I, O, and V 3.4 Iodothyronine Deiodinases 4 Reactive Oxygen, Nitrogen, and Electrophile Species 4.1 Metallic Electrophiles 4.2 Organic Electrophiles 4.3 Kinetic and Thermodynamic Considerations 5 Conclusion 6 Cross-References References Selenium Neuroprotection in Neurodegenerative Disorders 1 Introduction 2 Sources of Se 2.1 Dietary Recommendation of Se Intake 3 Chemistry of Se: From the Diet to the Selenoproteins 3.1 Sec Synthesis 3.2 tRNA[Ser]Sec 3.3 Selenoproteins Translation 3.4 Hierarchy of Selenoprotein Expression 3.5 Selenoproteins and the Brain 4 Neurodegenerative Diseases 4.1 Alzheimer´s Disease (AD) 4.2 Parkinson´s Disease (PD) 4.3 Amyotrophic Lateral Sclerosis (ALS) 5 Selenium and Neurodegenerative Diseases 5.1 Evidence that Overexposure to Se Can Trigger Neurodegenerative Diseases 5.2 Evidence that Se Can Protect from Neurodegenerative Diseases Development 6 Loss of Se from Selenoproteins and Its Influence on Neurodegenerative Diseases 6.1 Synthetic Organoselenium Compounds: Small Molecules with Weak Selenoprotein-Like Activity 7 Conclusion 8 Cross-References References Index