Neurochemical Systems and Signaling: From Molecules to Networks (2023)

Cover
Half Title
Title Page
Copyright Page
Table of Contents
Preface
Editor Biography
List of Contributors
Section I Transmitters and Systems
	1 Adrenergic Neurotransmission
		1.1 Introduction
		1.2 Intercellular Communication in the Nervous System
			1.2.1 Electrical Synapses
			1.2.2 Chemical Synapses
				1.2.2.1 Neuromuscular Junction
				1.2.2.2 Chemical Synapses in the Central Nervous System
		1.3 Adrenergic Neurotransmission
			1.3.1 Synthesis and Storage of Catecholamines
			1.3.2 Release of Catecholamines
			1.3.3 Termination of the Action of Catecholamines
		1.4 Adrenergic Receptors and Signal Transduction Pathways
		1.5 Catecholamines and Adrenoceptors
		1.6 Possible Roles of Catecholamines in Various Diseases
			1.6.1 Pheochromocytoma
			1.6.2 Alzheimer’s Disease
			1.6.3 Parkinson’s Disease
			1.6.4 Autoimmune Diseases
			1.6.5 Familial Dysautonomia
		1.7 Future Directions in Catecholamine Research
		1.8 Conclusion
		References
	2 Cholinergic Neurotransmission
		2.1 Introduction
		2.2 Basic Steps in Neurochemical Transmission
		2.3 Steps in Cholinergic Neurotransmission
			2.3.1 Biosynthesis of Acetylcholine
			2.3.2 Storage of Acetylcholine
			2.3.3 Release of Acetylcholine
			2.3.4 Receptor Binding
			2.3.5 Degradation of Acetylcholine
			2.3.6 Recycling of Choline
		2.4 Acetylcholine Receptors
			2.4.1 Nicotinic Receptors
			2.4.2 Muscarinic Receptors
		2.5 Effects of Cholinergic Nervous Stimulation on Effector Organs
			2.5.1 Muscarinic Effects
				2.5.1.1 Cardiovascular Effects
				2.5.1.2 The Eye
				2.5.1.3 Gastrointestinal Tract
				2.5.1.4 Respiratory System
				2.5.1.5 Urinary System
				2.5.1.6 Glands
			2.5.2 Nicotinic Actions
				2.5.2.1 Cardiovascular System
				2.5.2.2 Respiratory System
				2.5.2.3 Central Nervous System
				2.5.2.4 Digestive System
				2.5.2.5 Skeletal Muscles
		2.6 Drugs Affecting Cholinergic Neurotransmission
			2.6.1 Cholinergic Agonists
			2.6.2 Cholinergic Antagonists
		2.7 Role of Cholinergic Transmission in Pathophysiology and Disease Management
			2.7.1 Myasthenia Gravis
			2.7.2 Alzheimer’s Disease
			2.7.3 Parkinson’s Disease
			2.7.4 Epilepsy
			2.7.5 Cholinergic Anti-Inflammatory Pathway
			2.7.6 Huntington’s Disease
			2.7.7 Schizophrenia
			2.7.8 Motion Sickness
			2.7.9 Glaucoma
			2.7.10 Bradycardia
			2.7.11 Peptic Ulcers
		2.8 Recent Developments and Challenges
		2.9 Conclusion
		References
	3 Dopamine Signaling
		3.1 Introduction
		3.2 Dopamine Receptors: Classification, Genes, Structure, Expression, and Functions
		3.3 General Principles of Dopamine Receptor Signal Transduction and Regulation
		3.4 Dopamine Receptor Signaling
			3.4.1 Camp, Protein Kinase A, Darpp-32, and Associated Proteins
			3.4.2 Alternative G Protein Mechanisms
			3.4.3 Regulation of G Protein Activity
			3.4.4 Direct Interactions With Ion Channels and Associated Proteins
			3.4.5 β-Arrestins/G Protein-Coupled Receptor Kinases: From Dopamine Receptor Desensitization to Signaling
			3.4.6 β-Arrestin-Mediated Signaling and the Regulation of Akt By Dopamine
		3.5 Pharmacology of Dopamine Receptors
		3.6 Recent Developments and Challenges
		3.7 Conclusion
		References
Section II Neurochemical Signaling and Pathologies
	4 Neurochemical Signaling in Alzheimer’s Disease
		4.1 Introduction
		4.2 Genetics of Alzheimer’s Disease
		4.3 Neurobiology of Alzheimer’s Disease
			4.3.1 The Beta Amyloid Hypothesis
			4.3.2 The Tau Hypothesis
			4.3.3 The Mitochondrial Hypothesis and Oxidative Stress
			4.3.4 Neuroinflammation
		4.4 Neurotransmission and Neurochemical Alterations in Alzheimer’s Disease
			4.4.1 Cholinergic Transmission in Alzheimer’s Disease
			4.4.2 Glutaminergic Transmission in Alzheimer’s Disease
			4.4.3 Serotonergic Transmission in Alzheimer’s Disease
			4.4.4 Dopaminergic Transmission in Alzheimer’s Disease
			4.4.5 Adrenergic Transmission and Alzheimer’s Disease
		4.5 Molecular Signaling Mechanisms and Alzheimer’s disease
			4.5.1 Fyn Kinases and Alzheimer’s Disease
			4.5.2 Wnt Signaling and Alzheimer’s Disease
			4.5.3 Cdk5 and Alzheimer’s Disease
			4.5.4 Pi3k/Akt/Mtor Signaling and Alzheimer’s Disease
			4.5.5 Ampk Signaling and Alzheimer’s Disease
			4.5.6 Sirt1, Pgc-1a, and Alzheimer’s Disease
		4.6 Future Opportunities and Challenges
		4.7 Conclusion
		Acknowledgements
		References
	5 Alzheimer’s Disease: Pathogenesis and Therapeutics Advancements Targeting Potential Neurotransmitters and Neuronal Peptides
		5.1 Introduction
		5.2 Human Brain
		5.3 Alzheimer’s Disease
		5.4 Genetics of Alzheimer’s Disease
		5.5 Neurochemical Involvement in Alzheimer’s Disease
			5.5.1 Acetylcholine in Alzheimer’s Disease
			5.5.2 Dopamine in Alzheimer’s Disease
			5.5.3 Glutamate in Alzheimer’s Disease
			5.5.4 γ-Aminobutyric Acid in Alzheimer’s Disease
			5.5.5 Serotonin and Monoamine Signaling in Alzheimer’s Disease
			5.5.6 Noradrenaline in Alzheimer’s Disease
			5.5.7 Histamine and Alzheimer’s Disease
			5.5.8 Adenosine and Alzheimer’s Disease
			5.5.9 Cannabinoids in Alzheimer’s Disease
		5.6 Pathological Alterations in Alzheimer’s Disease
			5.6.1 Amyloid β and Alzheimer’s Disease
			5.6.2 Tau and Alzheimer’s Disease
			5.6.3 Inflammation and Alzheimer’s Disease
			5.6.4 Impaired Glucose Metabolism and Alzheimer’s Disease
		5.7 Advances in the Pharmacologic Approach to Alzheimer’s Disease
			5.7.1 Therapies Targeted at the Acetylcholine Receptor and Acetylcholinesterase
			5.7.2 Therapies Targeted at the Serotonin Receptor and Monoamine Oxidase Inhibitors
			5.7.3 Therapies Targeted at the Dopamine Receptor
			5.7.4 Therapies Targeted at the Glutamate Receptor
			5.7.5 Therapies Targeted at G-Aminobutyric Acid
			5.7.6 Therapies Targeted at Noradrenaline-Related Neurotransmission
			5.7.7 Therapies Targeted at Cannabinoid Receptors
			5.7.8 Therapies Targeted at Amyloid β Synthesis and Clearance
			5.7.9 Therapies Targeted at Tau Stabilizations, Aggregation, and Post-Translational Modifications
			5.7.10 Therapies Targeted at Anti-Tau Immunotherapy
			5.7.11 Therapies Targeted at Apolipoprotein E
			5.7.12 Therapies Targeted at Neurotrophins
			5.7.13 Therapies Targeted at Oxidative Stress, Inflammation, and Neuroprotection
		5.8 Recent Developments and Challenges
		5.9 Conclusion
		References
	6 Cholinergic Neurotransmission System: Signaling Pathways and Their Role in Parkinson’s Disease
		6.1 Introduction
		6.2 Acetylcholine: A Cholinergic Neurotransmitter
			6.2.1 Acetylcholine Biosynthesis and Storage
			6.2.2 Acetylcholine Catabolism
		6.3 Cholinergic or Acetylcholine Receptors
			6.3.1 Nicotinic Acetylcholine Receptors
				6.3.1.1 Mechanism of NAChR Activation and Neurotransmission
			6.3.2 Muscarinic Acetylcholine Receptors
				6.3.2.1 Mechanism of MAChR Activation and Neurotransmission
		6.4 Molecular and Cellular Mechanisms of the Cholinergic Signaling Pathway
			6.4.1 Ultra-Fast Cholinergic Neurotransmission
			6.4.2 Rapid Cholinergic Neurotransmission
			6.4.3 Slow Cholinergic Processes in the Nervous Systems
				6.4.3.1 Adenylate Cyclase Inhibition
				6.4.3.2 Activation of Phospholipase C
				6.4.3.3 Activation of K+ Channels
		6.5 Deficit of Cholinergic Neurotransmission in Parkinson’s Disease
			6.5.1 Cholinergic Deficit and Impairment in Parkinson’s Disease
				6.5.1.1 Motor Function
				6.5.1.2 Gait Impairment
				6.5.1.3 Levodopa-Induced Dyskinesias
				6.5.1.4 Cognitive Impairment and Mood
				6.5.1.5 Lewy Body Dementia and Delirium
				6.5.1.6 REM Sleep Behavior Disorder
				6.5.1.7 Olfactory Dysfunction
		6.6 Recent Developments and Challenges
		6.7 Conclusion
		References
	7 Neurochemical Alterations in Parkinson’s Disease
		7.1 Introduction
		7.2 Synthesis of Dopamine
		7.3 Transporters of Dopamine
			7.3.1 Regulation of Dopamine Transporter
				7.3.1.1 Post-Translation Modification
				7.3.1.2 Protein–Protein Interactions
				7.3.1.3 Transporter Localization
			7.3.2 Regulation of Vesicular Monoamine Transporter-2
		7.4 Dopamine Receptors
			7.4.1 D1 Receptors
			7.4.2 D2 Receptors
			7.4.3 D3 Receptors
			7.4.4 D4 Receptors
			7.4.5 D5 Receptors
		7.5 Metabolism of Dopamine
		7.6 The Dopaminergic Pathways in the Brain
			7.6.1 Nigrostriatal Pathway
			7.6.2 Mesolimbic Pathway
			7.6.3 Mesocortical Pathway
			7.6.4 Tuberoinfundibular Pathway
		7.7 The Basic Structures and Projections of Basal Ganglia
		7.8 The Effect of Dopamine on the Basal Ganglia Circuitry
		7.9 Non-​Dopaminergic Direct Neurotransmitter Pathways in Basal Nuclei
		7.10 Non-​Dopaminergic Indirect Neurotransmitter Pathways in Basal Nuclei
		7.11 The Effect of Dopamine on the Direct and Indirect Pathways in the Brain
		7.12 The Imbalance of Dopamine in Parkinson’s Disease
		7.13 Neurochemistry of Other Neurotransmitters in Parkinson’s Disease
			7.13.1 Classification of Neurotransmitters
				7.13.1.1 GABA
				7.13.1.2 Glutamate
				7.13.1.3 Acetylcholine
				7.13.1.4 Serotonin
				7.13.1.5 Adenosine
				7.13.1.6 Noradrenaline
				7.13.1.7 Histamine
		7.14 Pathophysiology of Motor Symptoms in Parkinson’s Disease
			7.14.1 Bradykinesia
			7.14.2 Rigidity
			7.14.3 Tremor
			7.14.4 Motor Fluctuations
			7.14.5 Gait Disturbance and Balance
			7.14.6 Postural Instability
		7.15 Stages of Parkinson’s Disease
		7.16 Recent Developments and Challenges in the Treatment of Parkinson’s Disease
		7.17 Conclusion
		References
	8 Therapeutic Targets and Neurochemical Signaling in Huntington’s Disease
		8.1 Introduction
		8.2 Signs and Symptoms of Huntington’s Disease
			8.2.1 Motor Disorders
			8.2.2 Cognitive and Behavioral Disorders
			8.2.3 Other Symptoms and Cause of Mortality
		8.3 Pathophysiologic Mechanism of Huntington’s Disease
			8.3.1 The Role of Mutant Huntingtin and Huntington’s Disease Genes
			8.3.2 Dopamine Signaling in Huntington’s Disease
			8.3.3 Glutamate Signaling in Huntington’s Disease
			8.3.4 Dopamine and Glutamate Receptor Interactions in Huntington’s Disease
			8.3.5 Gamma-Aminobutyric Acid
			8.3.6 Brain-Derived Neurotrophic Factor
			8.3.7 Endocannabinoids
			8.3.8 Adenosine
			8.3.9 Impaired Autophagy
			8.3.10 Mitochondrial Dysfunction
			8.3.11 Alpha-Synuclein and Huntington’s Disease
		8.4 Diagnosis of Huntington’s Disease
			8.4.1 Genetic Testing
			8.4.2 Imaging
			8.4.3 Other Biomarkers
			8.4.4 Oxidative Stress and Neuroinflammation in Huntington’s Disease
		8.5 Differentiating Huntington’s Disease-​Like 2 from Huntington’s Disease
		8.6 Parkinsonism in Huntington’s Disease
		8.7 Management of Huntington’s Disease
			8.7.1 Pharmacologic Management
				8.7.1.1 Managing Motor Features
				8.7.1.2 Management of Cognitive Dysfunction
				8.7.1.3 Management of Affective Disorders
				8.7.1.4 Management of Other Features of Huntington’s Disease
			8.7.2 Gene Therapy
		8.8 Recent Developments and Challenges
		8.9 Conclusion
		References
	9 Schizophrenia: Neurochemical Insight Into a Mind’s Faulty Dimension
		9.1 Introduction
		9.2 Neurochemistry of Schizophrenia
			9.2.1 Altered Dopaminergic Neurotransmission (Dopamine Hypothesis)
			9.2.2 Abnormal Gabaergic Neurotransmission in Schizophrenia (Gaba Hypothesis)
			9.2.3 Serotonergic Dysfunction in Schizophrenia (Serotonin Hypothesis)
			9.2.4 Flawed Glutamatergic Neurotransmission in Schizophrenia (Glutamate Hypothesis)
		9.3 Diagnosis
		9.4 Pharmacologic Treatments of Schizophrenia
			9.4.1 Drugs Targeting the Dopamine System
				9.4.1.1 Chlorpromazine
				9.4.1.2 Phosphodiesterase 10A Inhibitors
				9.4.1.3 Cariprazine
				9.4.1.4 Stepholidine
				9.4.1.5 L-DOPA
			9.4.2 Drugs Targeting the Glutamate System
				9.4.2.1 Bitopertin
				9.4.2.2 D-Amino Acid Oxidase Inhibitors
			9.4.3 Drugs Targeting the Serotonin System
				9.4.3.1 Clozapine
				9.4.3.2 Ondansetron
				9.4.3.3 Tropisetron
			9.4.4 Drugs Targeting the Gabaergic System
		9.5 Recent Developments and Challenges
		9.6 Conclusion
		References
	10 Role of Endocannabinoids in Neurocognitive Dysfunctions
		10.1 Introduction
		10.2 Composition and Synthesis of the Endocannabinoid System
			10.2.1 Endogenous Ligands
			10.2.2 Receptors
				10.2.2.1 CB1
				10.2.2.2 CB2
			10.2.3 Enzymes
		10.3 Endocannabinoids in Neurocognitive Dysfunction
			10.3.1 Alzheimer’s Disease
			10.3.2 Parkinson’s Disease
			10.3.3 Cognition
			10.3.4 Huntington’s Disease
			10.3.5 Psychosis and Anxiety
			10.3.6 Depression
			10.3.7 Aging
		10.4 Preclinical and Clinical Interventions with Endocannabinoids
			10.4.1 Preclinical Studies
			10.4.2 Clinical Studies (Table 10.1)
		10.5 Future Trends and Challenges
		10.6 Conclusion
		References
	11 Role of the Glutaminergic System in Schizophrenia
		11.1 Introduction
		11.2 Glutamate Biosynthesis
		11.3 Glutamate Receptors
			11.3.1 Inotropic Glutamate Receptors
			11.3.2 Metabotropic Glutamate Receptors
		11.4 Glutamate Receptor Function and Distribution
		11.5 Glutamate Release
		11.6 Glutamate Transporters
		11.7 Glutamate in the Healthy Brain
			11.7.1 Normal Functions of the Glutamate Neurotransmitter in the Brain
			11.7.2 Glutamate in the Schizophrenic Brain
		11.8 Schizophrenia and the Glutamate Hypothesis
			11.8.1 Nmdar Antagonists and Schizophrenia
				11.8.1.1 Reduced NMDAR and Hyperglutamate Basis of Schizophrenia
				11.8.1.2 Role of NMDAR Antagonists in the Firing of Cortical Neurons
		11.9 Abnormality of the Glutamate Transporter in Schizophrenia
		11.10 Genetic Abnormalities of Receptors in Schizophrenia
			11.10.1 Chromosomal Abnormalities in Schizophrenia
		11.11 Animal Models of Schizophrenia Based on Glutamate
		11.12 Interaction Between Glutamate and Dopamine in Schizophrenia
		11.13 Possible Glutamate-​Based Treatment
		11.14 Recent Developments and Challenges
			11.14.1 Drugs Targeting Glutamate Under Development in Schizophrenia
		11.15 Conclusion
		References
	12 Myasthenia Gravis: Molecular Pathogenesis and Therapeutic Advances
		12.1 Introduction
		12.2 Classification of Myasthenia Gravis
			12.2.1 Osserman’s Classification, Based on Disease Severity
				12.2.1.1 Generalized Myasthenia Gravis
				12.2.1.2 Ocular Myasthenia
				12.2.1.3 Paraneoplastic Myasthenia Gravis
				12.2.1.4 Neonatal Myasthenia Gravis
			12.2.2 Osserman’s Classification, Based on Causative Agents
				12.2.2.1 Muscle-​Specific Kinase Antibody Myasthenia Gravis
				12.2.2.2 Lipoprotein-​Related Protein 4-​Associated Myasthenia Gravis
				12.2.2.3 Drug-​Induced Myasthenia Gravis
			12.2.3 Clinical Classification of Myasthenia Gravis
		12.3 Molecular Mechanisms/​Pathophysiology
			12.3.1 Neurochemical Aspects of Myasthenia Gravis
			12.3.2 Immune Pathogenesis of Myasthenia Gravis (Role of the Thymus in Autoantibodies Against
			12.3.3 Extracellular or Transmembrane Proteins
				12.3.3.1 AChR
				12.3.3.2 MuSK
				12.3.3.3 LRP4
			12.3.4 Intracellular Proteins
				12.3.4.1 Titin
				12.3.4.2 Ryanodine Receptor
		12.4 Ongoing Therapeutic Management of Myasthenia Gravis
			12.4.1 Pyridostigmine
			12.4.2 Prednisone
			12.4.3 Azathioprine
			12.4.4 Intravenous Immunoglobulin and Plasma Exchange
		12.5 Therapeutic Advancements and Future Perspectives in Myasthenia Gravis
			12.5.1 Thymectomy
			12.5.2 Robotic-​Assisted Thoracoscopic Surgery
			12.5.3 Eculizumab
			12.5.4 Ravulizumab (ALXN1210)
			12.5.5 Neonatal Fc Receptor Antibodies
				12.5.5.1 Efgartigimod (ARGX-​113)
				12.5.5.2 Rozanolixizumab (UCB7665)
			12.5.6 Rituximab
			12.5.7 Monarsen (EN101)
			12.5.8 Autologous Hemopoietic Stem Cell Transplantation
		12.6 Recent Developments and Challenges
		12.7 Conclusion
		References
Section III Typical Neurochemical Processes
	Chapter 13 Neurogenesis in the Embryonic and Adult Brain
		13.1 Introduction
		13.2 Neurogenesis in Embryonic Brain
		13.3 Neurogenesis in Somatosensory Plasticity
		13.4 Neurogenesis in Adult Brain
		13.5 Neurochemistry of Adult Neurogenesis
			13.5.1 Dopamine
			13.5.2 Glutamate
			13.5.3 Gaba
			13.5.4 Other Neurochemicals
		13.6 Role of microRNAs in Neurogenesis
			13.6.1 Micrornas and Embryonic Neurogenesis
			13.6.2 Micrornas and Adult Neurogenesis
		13.7 Hippocampal Neurogenesis
			13.7.1 The Role of Omega-3 Fatty Acids
		13.8 Neurogenesis in Olfactory and Vomeronasal Sensory Epithelia
		13.9 Neurogenesis and Human Pathologies
			13.9.1 Epilepsy
			13.9.2 Cerebrovascular Disease
		13.10 Neurogenesis and the Molecular Mechanism of Memory
			13.10.1 Neurogenesis in the Adult Hippocampus
		13.11 Recent Developments and Future Research Directions
		13.12 Conclusion
		References
	14 Neuronal Proliferation and Associated Diseases
		14.1 Introduction
		14.2 Neuronal Proliferation Under Normal Conditions/​Normal Development
		14.3 Aberrant Development of the Brain and Related Disorders
			14.3.1 Disorders Linked to Aberrant Neuronal Proliferation
				14.3.1.1 Macrocephaly
				14.3.1.2 Hemimegalencephaly
				14.3.1.3 Microcephaly
		14.4 Genetics of Megalencephaly and Related Disorders
		14.5 Future Prospects
		14.6 Conclusion
		References
	15 Neurobiology in Correlation With Romantic Attraction
		15.1 Introduction
		15.2 Neurobiological Basis of Romantic Attraction
		15.3 Neurochemical and Hormonal Balance in Romantic Attraction
			15.3.1 Adrenaline and Noradrenaline
			15.3.2 Serotonin
			15.3.3 Dopamine
			15.3.4 Oxytocin
			15.3.5 Vasopressin
			15.3.6 Testosterone
			15.3.7 Endorphins
			15.3.8 Nerve Growth Factor
		15.4 Investigational Studies
			15.4.1 Preclinical Studies
			15.4.2 Clinical Studies
		15.5 Recent Developments and Challenges
		15.6 Conclusions
		References
	16 Neurobiology of Love: A Comprehensive Analysis
		16.1 Introduction
		16.2 Evolution of Love
		16.3 The Scientific Perspective of Love
		16.4 Parts of the Brain Involved in Love and Relevant Biomolecules
			16.4.1 Parts of the Brain Involved in Love
			16.4.2 Biochemicals Involved in Communication in Various Parts of the Brain
				16.4.2.1 Role of Oxytocin and Vasopressin
				16.4.2.2 Role of Luteinizing Hormone, Nitric Oxide, and Other Chemicals
		16.5 The Phenomenon of ‘Rewards vs Punishment’ in Strengthening Attachments
		16.6 Mechanism of Love: At a Glance
			16.6.1 A Detailed Mechanism of Parental Love
				16.6.1.1 Parental Attachment
				16.6.1.2 Specific Role of Biomolecules Involved in Parental Behavior
				16.6.1.3 Evolutionary Genetics of Caregiving
		16.7 Romantic Love
			16.7.1 Classification of Romantic Love
				16.7.1.1 Lust
				16.7.1.2 Attraction
				16.7.1.3 Attachment
			16.7.2 Principles of Attraction
				16.7.2.1 The Similarity Principle
				16.7.2.2 Reciprocity
				16.7.2.3 Beauty (Physical Attractiveness)
				16.7.2.4 Security
			16.7.3 Initiators of Attraction
				16.7.3.1 Sight
				16.7.3.2 Masculinity
				16.7.3.3 Positive Personality
				16.7.3.4 Smell
				16.7.3.5 Fertility
				16.7.3.6 Stress
		16.8 Sexual Behavioral Changes
			16.8.1 Sex Behavior in Males
			16.8.2 Sex Behavior in Females
		16.9 Opportunities and Challenges
		16.10 Conclusion
		Acknowledgement
		References
Index