GABA (eBook)

Cover Page 1
Contents 6
Abbreviations 12
Contributors 14
Chapter 1: The Role of GABA in the Mediation and Perception of Pain 17
I. Chapter Overview 17
II. Introduction 18
III. Molecular and Anatomical Considerations 19
IV. Pharmacological Studies 25
V. Summary and Conclusions 34
Acknowledgments 35
References 35
Chapter 2: Distribution of GABA Receptors in the Thalamus and Their Involvement in Nociception 45
I. Chapter Overview 45
II. Introduction 46
III. GABA Receptors in the Thalamus 48
IV. Role of GABA Receptors in Nociception Within the Thalamus 56
References 59
Chapter 3: GABAA Agonists and Partial Agonists: THIP (Gaboxadol) as a Non-Opioid Analgesic and a Novel Type of Hypnotic 69
I. Chapter Overview 69
II. GABA Receptors: Multiplicity, Structure, and Function 70
III. GABAA Agonists 72
IV. Partial GABAA Agonists 76
V. 4-PIOL Analogs as GABAA Antagonists 77
VI. Behavioral and Clinical Effects of the Partial GABAA Agonist THIP (Gaboxadol) 79
VII. Conclusions 82
Acknowledgments 82
References 83
Chapter 4: Rat Modeling for GABA Defects in.Schizophrenia 89
I. Chapter Overview 89
II. Introduction 90
III. Rodent Model for Postmortem Findings in Schizophrenia 97
IV. Commentary 102
Acknowledgments 104
References 105
Chapter 5: Epigenetic Targets in GABAergic Neurons to Treat Schizophrenia 111
I. Chapter Overview 111
II. Introduction 112
III. Regulation of Histone Acetylation 114
IV. Chromatin Remodeling at Neuromuscular Junction 114
V. Chromatin Remodeling During Memory Formation 115
VI. Role of Reelin and Apolipoprotein E Receptors in Hippocampal Plasticity and Learning 117
VII. Is Reelin Expressed Only in a Selective Subpopulation of GABAergic Neurons? 119
VIII. RELN and GAD67 CpG Island Promoter Hypermethylation and Reelin and GAD67 Expression Downregulation in SZ Patients 120
IX. Increased DNA-Methyltransferase-1 Expression in Cortical GABAergic Neurons of SZ Patients 121
X. Relationship Between DNMT1 Overexpression and Reelin and GAD67 Downregulation in GABAergic Neurons of SZ Patients 122
XI. Pharmacological Strategies to Reduce Reelin and GAD67 Promoter Hypermethylation in SZ Patients 123
XII. The MET-Induced Epigenetic Mouse Model to Evaluate Prospective HDAC Inhibitors to be Used to Influence Epigenetic Mechanisms in Cortical GABAergic Neurons 126
XIII. Conclusions 127
References 128
Chapter 6: GABAAergic Malfunction in the Limbic System Resulting from an Aboriginal Genetic Defect in Voltage-Gated Na+-Channel SCN5A is Proposed to Give Rise to Susceptibility to Schizophrenia 135
I. Chapter Overview 135
II. Introduction 136
III. Levels of Concern 139
IV. The Hypothalamo-Hypophyseal System 145
V. The Cybernins 146
VI. A Failed Therapeutic Adventure 148
VII. Linkage of Propranolol Cognitive Effects with Correction of a Limbic System Defect that Results in Failure of Habituation in Schizophrenia (See Gruzelier, 1978) 151
VIII. Susceptibility to Schizophrenia may Result from Mutation of the Na+ Channel-Coding SCN5A Gene, Which Occurs at Uniquely High Levels in Neural Components of the Limbic System 153
IX. Recyberneticizing Substances and Mechanisms of Their Action 155
X. Problems in Therapy with Racemic Propranolol 157
XI. The GABA System and Schizophrenia 157
Acknowledgments 159
References 160
Chapter 7: GABAA Receptpor Mutations Associated with Generalized Epilepsies 163
I. Chapter Overview 163
II. GABAA Receptors 164
III. GABAA Receptor Epilepsy Genes 165
IV. Conclusions 181
References 183
Chapter 8: From Gene to Behavior and Back Again: New Perspectives on GABAA Receptor Subunit Selectivity of Alcohol Actions 187
I. Abstract 187
II. Chapter Overview 188
III. alpha-Subunit Knockout Mice 189
IV. beta-Subunit Knockout Mice 195
V. gamma-2-Subunit Knockout and Transgenic Mice 197
VI. delta-Subunit Knockout Mice 198
VII. GABAA Receptor Subunit Knock-in Mice 200
VIII. Functional Compensation in Genetically Altered Mice: Gene-Behavior Associations Put into Context 201
IX. GABAA Receptor Subunit-Associated Quantitative Trait Loci 202
X. GABAA Receptor Subunit-Associated Gene Expression Patterns 209
XI. Conclusions 211
References 212
Chapter 9: A Role for GABA in Alcohol Dependence 221
I. Chapter Overview 221
II. Alcohol and GABA 222
III. Targets Within the Addiction Cycle Relevant for Actions of GABA 225
IV. Extended Amygdala: A Basal Forebrain Macrostructure as a Focal Point for GABAergic Actions on Alcohol Reinforcement 226
V. Role for GABA in Acute Alcohol Reinforcement 227
VI. Effects of GABAergic Agents on Self-Administration of Alcohol in Nondependent Rats 227
VII. Effects of GABAergic Agents on Self-Administration of Alcohol in Dependent Rats 231
Acknowledgments 239
References 240
Chapter 10: Structure, Pharmacology, and Function of GABAA Receptor Subtypes 247
I. Chapter Overview 247
II. Introduction 248
III. Heterogeneity of GABAA Receptors 248
IV. Pharmacology of GABAA Receptors 250
V. Function of GABAA Receptor Subtypes in the Brain 264
VI. GABAA Receptor Structure 266
Acknowledgments 270
References 270
Chapter 11: Structure-Activity Relationship and Pharmacology of alpha-Aminobutyric Acid (GABA) Transport Inhibitors 281
I. Chapter Overview 281
II. The GABAergic Synapses 282
III. Transporter Heterogeneity, Nomenclature, and Function 283
IV. Structure-Activity Relationship of GABA Uptake Inhibitors 284
V. Kinetics of GABA Uptake Inhibitors 289
VI. Reevaluation of Lipophilic Aromatic GABA Uptake Inhibitors 291
VII. Conclusions 296
Acknowledgments 296
References 297
Chapter 12: Modulation of Ionotropic GABA Receptors by Natural Products of Plant Origin 301
I. Chapter Overview 301
II. Introduction 302
III. Ionotropic GABA Receptors 303
IV. Flavonoids 305
V. Terpenoids 312
VI. Other Phenolic Compounds 316
VII. Polyacetylenic Alcohols 319
VIII. Alcoholic Beverages Containing GABA Receptor Modulators 321
IX. GABA Receptor Modulators in Tea and Coffee 323
X. Plant Sources of GABA Receptor Modulating Substances: Implications for Herbal Medicines 323
Acknowledgments 325
References 325
Index 333
Contents of Previous Volumes 345