GABA and Sleep (eBook)

Foreword 7
Preface 9
About the Editors 13
Credits and Acknowledgements 15
Contents 17
List of Contributors 21
Part I Basic Physiology and Pharmacology 25
Physiology and Pharmacology of the GABA System: Focus on GABA Receptors 26
1 Neural Oscillations and GABA 27
2 Role of GABA Receptors 28
3 GABAA Receptors and their Multiplicity 29
4 Benzodiazepine-Sensitive GABAA Receptors 30
5 The Benzodiazepine Site, a Servo Mechanism for Inhibition 33
6 Diazepam-Insensitive GABAA Receptors 33
7 GABAA Receptors and Sleep Promotion 33
8 GABAA Receptor Subtypes and EEG Patterns 34
9 Role of a3GABAA Receptor Subtypes in the Arousal Systems 35
10 Role of delta GABAA Receptors and Gaboxadol (THIP) 35
11 Anxiolytic Activity Without Sedation 36
12 Pain Suppression via Spinal a2/a3 GABAA Receptors 37
13 Targeting Cognitive Impairment Through a5GABAA Receptors 37
14 Cognitive Enhancement Through a2 and a3 GABAA Receptors 38
15 Dependence Liability of GABAA Receptor Drugs 38
16 GABAB Receptors 39
16.1 Structure and Physiology of GABAB Receptors 39
16.2 GABAB Receptors and Orexin Neurons 40
16.3 GABAB Receptors as Target for Gamma-Hydroxybutyrate 41
16.4 Pharmacology of GABAB Receptors Beyond Narcolepsy 41
References 42
Development of Subtype-Selective GABAA Receptor Compounds for the Treatment of Anxiety, Sleep Disorders 47
1 Introduction 48
1.1 GABAA Receptor Structure and Function 48
1.2 GABAA Receptor Pharmacology 49
1.2.1 GABA Binding Site 49
1.2.2 Benzodiazepine Binding Site 51
1.2.3 Neurosteroid Binding Site 53
1.2.4 Convulsant Binding Site 54
1.2.5 Barbiturate Binding Site 55
1.2.6 beta Subunit Binding Site(s) 55
1.3 Subtype-Selective Affinity and Subtype-Selective Efficacy 56
2 GABAA Receptor Compounds for Anxiety 56
2.1 Anxiety Disorders and Benzodiazepines 56
2.2 Benzodiazepine Site Modulators: Pre-clinical Compounds 58
2.3 Benzodiazepine Site Modulators: Clinical Compounds 59
2.3.1 Ocinaplon 60
2.3.2 SL65.1498 61
2.3.3 Pagoclone 62
2.3.4 ELB-139 63
2.3.5 Merck Compounds 64
2.4 Additional Properties Of Non-Sedating Anxiolytics 65
2.5 Summary of GABAA Receptors as a Target for Anxiety Disorders 66
3 GABAA Receptor Compounds for Sleep Disorders 66
3.1 Insomnia 66
3.2 Marketed Non-Benzodiazepine GABAA-Modulating Hypnotics: The ``Z-Drugs´´ 69
3.3 Non-Benzodiazepine GABAA-Modulating Hypnotics in Clinical Development 70
3.3.1 Adipiplon 70
3.3.2 Indiplon 71
3.3.3 EVT-201 72
3.3.4 Gaboxadol 73
3.4 Summary of GABAA Receptors as a Target for Hypnotics 74
4 Epilepsy 75
4.1 Use of Benzodiazepines in the Treatment of Epilepsy 76
4.2 Novel Pre-clinical Benzodiazepine Site Modulator: ELB-138 77
4.3 Neurosteroids: Ganaxolone 78
4.4 Summary of GABAA Receptors as a Target for Epilepsy 79
5 Overall Summary 79
References 80
Distribution of GABAA Receptor Subunits in the Human Brain 95
1 Introduction 95
2 Subunit Localisation 96
2.1 Cerebral Cortex 98
2.2 Hippocampus 100
2.3 Thalamus 103
2.4 Basal Ganglia 103
2.4.1 Striatum 103
2.4.2 Globus Pallidus 104
2.4.3 Midbrain 104
2.4.4 Brainstem 105
2.4.5 Spinal Cord 107
3 Overall Distribution 107
3.1 Cellular Distribution of GABAA Receptor Subunits 108
3.2 Ultrastructure 109
3.3 Subunit Configurations 109
3.4 GABAA Receptors and Sleep 110
References 111
Pharmacokinetic Determinants of the Clinical Effects of Benzodiazepine Agonist Hypnotics 116
1 Introduction 117
2 Historic Perspective 118
3 Pharmacokinetic Determinants of Hypnotic Drug Action 121
3.1 Absorption Rate and Onset of Action 122
3.2 Elimination, Distribution, and Duration of Action 123
3.3 The Effect of Dose 124
3.4 Drug Accumulation and Discontinuation 126
4 Pharmacokinetics of Benzodiazepine Agonist Hypnotics (Table3) 128
4.1 Flurazepam and Quazepam: Precursors of Desalkylflurazepam 128
4.2 Nitrazepam 129
4.3 Temazepam 129
4.4 Triazolam 130
4.5 Zolpidem 130
4.6 Zaleplon 131
4.7 Zopiclone and Eszopiclone 131
5 Comment 132
References 132
Part II Sleep Science and Circuitry 140
Sleep and Its Modulation by Substances That Affect GABAA Receptor Function 141
1 Introduction 142
2 Synthetic Agonists 143
2.1 Barbiturates 143
2.2 Benzodiazepines 143
2.3 Nonbenzodiazepine Hypnotics 146
2.3.1 Zolpidem 147
2.3.2 Zopiclone, Eszopiclone 148
2.3.3 Zaleplone 148
2.3.4 Indiplon 149
2.4 Selective Extrasynaptic GABAA Receptor Agonist 149
2.4.1 Gaboxadol 149
2.5 GABA-Uptake Inhibitor 150
2.5.1 Tiagabine 150
3 Synthetic Partial Agonist 151
3.1 Bretazenil 151
4 Synthetic Antagonist 152
4.1 Flumazenil 152
5 beta-Carbolines 153
6 Neuroactive Steroids 154
6.1 Pregnenolone 154
6.2 3a, 5a-THDOC 154
6.3 Progesterone 156
6.4 Allopregnanolone 157
6.5 Dehydroepiandrosterone 158
7 Neuropeptides 158
7.1 Growth Hormone-Releasing Hormone 158
7.2 Neuropeptide Y 159
7.3 Galanin 160
8 Conclusions and Perspectives 160
References 161
Subcortical Neuromodulation of Feedforward and Feedback Inhibitory Microcircuits by the Reticular Activating System 167
1 Introduction 168
2 GABAergic Inhibition Originates from Distinct Subclasses of Interneuron Subtypes that Exhibit Both Pre- and Postsynaptic Spec 169
2.1 Parvalbumin-Positive Basket Cells 171
2.2 Axoaxonic Cells 173
2.3 CCK BCs and Schaeffer Collateral-Associated (SCA) Cells 173
2.4 Somatostatin-Positive Interneurons 174
2.5 Neurogliaform Cells 174
3 Cell Type-Specific Control of Feedforward and Feedback GABAergic Circuits by the Reticular Activating System 175
3.1 Cholinergic Modulation of GABAergic Circuits by the Basal Forebrain 175
3.1.1 O-LM Cells 176
3.1.2 PV BCs 177
3.1.3 CCK BCs and CCK SCA Cells 178
3.1.4 M2-Expressing Trilaminar Cells 179
3.1.5 Presynaptic Mechanisms of Cholinergic Modulation of Hippocampal GABAergic Circuits 179
3.2 Serotonergic Modulation of GABAergic Circuits by the Dorsal Raphe 180
3.3 Noradrenergic Control of GABAergic Circuits by the Locus Coeruleus 181
3.4 Histaminergic Control of GABAergic Circuits by the Tuberomammilary Nucleus 182
4 Concluding Remarks 182
References 183
Function of GABAB and rho-Containing GABAA Receptors (GABAC< /Subscr
1 Introduction 189
2 Results 190
2.1 GABAB Receptors 190
2.1.1 Thalamic and Cortical Electrophysiological Influences of GABAB Receptors 191
2.1.2 Specific Structures Involved in the Sleep-Waking Cycle 193
Brainstem Level 193
Hypothalamus 194
High Integrated Processes 196
2.2 GABAC Receptors 198
3 Conclusion 199
References 199
Interactions Between GABAergic and Serotonergic Processes in the Dorsal Raphe Nucleus in the Control of REM Sleep and Wakefulness 209
1 Introduction 210
2 The Structure of the Dorsal Raphe Nucleus 210
3 The Functional Activity of DRN Neurons During the Sleep-Wake Cycle 212
4 Operational Characteristics of the 5-HT Receptors 213
5 Serotonergic and GABAergic Neurons of the DRN and Their Involvement in the Regulation of Sleep and Wakefulness 214
6 Local Administration of 5-HT Receptor Ligands into the DRN 214
6.1 Microinjection of 5-HT1B Receptor Ligands 214
6.2 Microinjection of 5-HT2A/2C Receptor Ligands 214
6.3 Microinjection of 5-HT7 Receptor Ligands 215
7 GABAergic Inhibitory Afferents to the DRN 215
References 216
GABA-ergic Modulation of Pontine Cholinergic and Noradrenergic Neurons for REM Sleep Generation 219
1 Introduction 220
2 Noradrenergic Regulation of REMS 221
3 Cholinergic Regulation of REMS 222
4 Reciprocal Relationship Between REM-ON and REM-OFF Neurons 222
5 GABA-ergic Modulation of LC NA-ergic REM-OFF Neurons for REMS Generation 223
6 GABA-ergic Modulation of PPT Cholinergic REM-ON Neurons for REMS Generation 224
7 Regulation of REMS-Related Neurons by Wake- and Sleep-Inducing Areas for REMS Generation 225
8 A Physiological Model for REMS Regulation 226
9 Physiological Validity of the Model 228
References 229
Involvement of GABAergic Mechanisms in the Laterodorsal and Pedunculopontine Tegmental Nuclei (LDT-PPT) in the Promotion of REM Sleep 233
1 Introduction 234
2 Mesopontine GABAergic Neurons 234
3 LDT-PPT: Anatomical Overview 235
3.1 Neuronal Types 236
3.2 Colocalization of Neurotransmitters Within the LDT-PPT 236
3.3 Input and Outputs of the LDT-PPT 237
4 Dual Role of the LDT-PPT: Control of REM Sleep and Waking-Related Activities 237
5 GABA in the LDT-PPT 239
5.1 GABAergic Inputs to the LDT-PPT 239
5.2 GABAergic Receptors in the LDT-PPT 239
5.3 Local GABAergic Neurons: Interneurons or Projecting Neurons? 240
6 Activity of Putative GABAergic Neurons in the LDT-PPT During Sleep and Wakefulness 240
7 GABAA Agonists Microinjected into the LDT-PPT Promote REM Sleep 242
8 Effects on Sleep of GABAB and GABAC Agents Microinjected into the LDT-PPT 242
9 GABAergic Inputs to the LDT-PPT Regulate REM Sleep 243
10 Role of GABA in the LDT-PPT in REM Sleep Generation: Working Hypotheses 244
11 GABA in the LDT-PPT: Pathophysiology 246
12 Conclusions 246
References 247
GABAergic Mechanisms in the Ventral Oral Pontine Tegmentum: The REM Sleep-Induction Site - in the Modulation of Sleep-Wake States 252
1 Introduction 253
2 Location of GABA in the vRPO 255
3 Origin for GABA in the vRPO 257
4 Effect of GABA on vRPO 259
4.1 Intracellular Unit Recordings In Vitro 259
4.2 Studies In Vivo 260
5 Final Considerations 263
5.1 Whether GABA Inhibits vRPO REM ``on´´ Neurons Directly or Indirectly from Brain Structures Related with the Organization of NREM Sleep and Wakefulness 263
5.2 Inhibition of GABAergic Transmission in the RPO Contributes to the Generation of REM Sleep 266
5.3 Increase of GABA Release by Excitatory Afferents 267
References 268
The Role of GABAergic Modulation of Mesopontine Cholinergic Neurotransmission in Rapid Eye Movement (REM) Sleep 272
1 Introduction 273
2 Categorizing REM Sleep Mechanisms 273
3 Pontine Areas for REM Sleep Generation 275
4 REM Sleep Induction Areas in the Brainstem of the Cat 276
4.1 Short Latency Cholinergic-Sensitive REM Sleep Induction Areas 276
4.2 The Source of Cholinergic Innervation to the REM Sleep Induction Areas 278
4.3 The Interaction of REM-on and REM-off Neuronal Populations 279
4.4 Cholinergic Action in the REM Sleep Induction Areas 280
4.5 GABAergic Mechanisms in the REM Sleep Induction Areas 280
5 REM Sleep Induction Areas in the Brainstem of the Rat 282
5.1 The PnOc, a Cholinergic-Sensitive REM Sleep Induction Area 282
5.2 The Source of Cholinergic Innervation to the PnOc 283
5.3 The PnOc as an Integrator of Multiple Influences and the Role of GABA 284
5.4 The SLD, a Noncholinergically Sensitive REM Sleep Induction Area 285
5.5 GABAergic Mechanisms in the SLD 286
5.6 The Source of GABAergic Innervation to the SLD 287
5.7 SLD Neurons are Effective for Muscle Atonia 289
6 Perspectives 290
7 Conclusion 291
References 292
Melatonin and Sleep: Possible Involvement of GABAergic Mechanisms 297
1 Introduction 298
2 Regulation of Melatonin Production 298
3 Melatonin Metabolism 300
4 Melatonin Receptors 301
4.1 Identification and Regulation 301
4.2 Receptor Signaling 304
4.3 Physiological Involvement of Melatonergic Receptors in SCN Neuronal Function 305
5 Role of SCN in the Regulation of Sleep 306
5.1 Putative Neuropharmacological Mechanisms Involved in Sleep Modulation by Melatonin 308
6 Conclusions 310
References 311
GABA Involvement in the Circadian Regulation of Sleep 320
1 Introduction 321
2 Intra-SCN Communication 322
3 GABA in the SCN 322
4 Role of GABA in the SCN 323
5 GABA and Photic Entrainment 323
6 GABA and Nonphotic Entrainment 324
7 GABA and Phase Shifts 325
8 GABAA Receptor Subunits in SCN 327
9 Conclusion 332
References 334
Part III Hypnotics 339
Pathophysiology of Sleep Disorders 340
1 Insomnia 341
1.1 Key Features 341
1.1.1 Diagnostic Criteria and Subtypes of Insomnia 341
1.1.2 Comorbid Insomnia and Major Depressive Disorder 342
1.2 Pathophysiological Concepts 343
1.2.1 Neuroendocrine Parameters 343
1.2.2 Insights from Polysomnography, Actigraphy, Electroencephalography, and Multiple Sleep Latency Test 344
1.2.3 Neuroimaging 345
1.3 The Cognitive-Behavioral Model and Cognitive-Behavioral Therapy of Insomnia 347
1.4 Sleep-Wake Regulation with Regard to Insomnia and Pharmacological Treatment 348
1.5 Conclusions 351
2 Hypersomnias of Central Origin: Narcolepsy and Other Forms of Hypersomnia 352
2.1 Key Features 352
2.1.1 Narcolepsy 352
2.1.2 Other Forms of Hypersomnia 354
2.2 Pathophysiological Concepts of Narcolepsy 354
2.2.1 Changes in the Orexin/Hypocretin System 354
2.2.2 HLA Association and Immunological Aspects 355
2.2.3 Disturbed Sleep-Wake Regulation 356
2.2.4 Metabolic Aspects of Narcolepsy 356
2.2.5 GABA 356
2.3 Therapeutic Aspects 357
2.3.1 Treatment of Hypersomnia 357
2.3.2 Treatment of Cataplexy, Hypnagogic Hallucinations, Sleep Paralysis 358
2.3.3 Treatment of Disrupted Nocturnal Sleep Due to Narcolepsy 358
Sodium Oxybate 359
3 Pathophysiology of Sleep-Related Movement Disorders: Restless Legs Syndrome and Periodic Limb Movement Disorder 359
3.1 Key Features 359
3.2 Pathophysiological Concepts 361
3.3 Therapeutic Aspects 364
3.3.1 Dopaminergic Agents 365
Levodopa 365
Dopamine Agonists 365
3.3.2 Opioids 365
3.3.3 Gabapentin and Other Anticonvulsants 366
3.3.4 Benzodiazepines 366
References 366
Insomnia: Differential Diagnosis and Current Treatment Approach 377
1 Insomnia: Current Diagnostic Differential and Approach to Treatment 377
2 The Primary Insomnias Diagnosis and Treatment 378
3 Medications for Treating Insomnia: Historical Use 378
4 Current Medications Utilized in the Treatment of Insomnia 379
5 Nonprescription Sedating Agents 382
6 Antidepressants 383
7 Psychoactive Medication Effects on Sleep Stages and EEG 383
8 Nonpharmacologic Therapies for Insomnia 384
9 Secondary Insomnia 385
10 Psychiatric Disorders and Insomnia 385
11 Treatment of Secondary (Comorbid) Insomnia Associated with Psychiatric Disorders 386
11.1 Melatonin Receptor Agonists 387
12 Primary Sleep Disorders Associated with Insomnia 387
12.1 Sleep Apnea 387
12.2 Circadian Rhythm Sleep Disorders 387
12.3 Delayed Sleep Phase Syndrome 388
12.4 Advanced Sleep Phase Syndrome 389
12.5 Shift Work Sleep Disorder 389
12.6 Jet Lag Disorder 390
12.7 Restless Legs Syndrome/Periodic Leg Movement Disorder 390
13 Sleep and Medical Disorders 391
13.1 Pain and Sleep 391
13.2 Sleep in Other Medical Conditions 392
14 Insomnia and the GABA Receptor 392
References 393
Zolpidem in the Treatment of Adult and Elderly Primary Insomnia Patients 396
1 Introduction 397
2 GABAA Receptor Subtypes and the Mechanism of Action of Zolpidem 399
3 Pharmacokinetic and Metabolic Profiles 401
4 Therapeutic Efficacy 403
4.1 Efficacy Studies Performed with Zolpidem-IR in Nonelderly Insomniacs 403
4.2 Efficacy Studies Performed with Zolpidem-IR in Elderly Insomniacs 404
4.3 Comparative Studies Performed with Zolpidem-IR and Other Hypnotic Drugs 405
4.4 Intermittent and ``As-Needed´´ Studies with Zolpidem-IR 405
4.5 Studies Combining Zolpidem-IR to Cognitive Behavioral Therapy 406
4.6 Studies with New Formulations of Zolpidem 407
5 Safety and Adverse Effects 409
5.1 General Tolerance 410
5.2 Next-Day Residual Effects 410
5.3 Tolerance, Withdrawal Reaction, Abuse, and Dependence Potential 412
6 Dosage, Administration, and Place in the Management of Insomnia 414
7 Conclusions 416
Reference 416
Efficacy and Safety of Zopiclone and Eszopiclone in the Treatment of Primary and Comorbid Insomnia 425
1 Isomerism and Pharmacologic Properties 426
2 Chemical and Physical Properties of Zopiclone and Eszopiclone 427
3 Mechanism of Action 429
4 Pharmacokinetics of Zopiclone and Eszopiclone 432
5 Drug Interactions with Zopiclone and Eszopiclone 434
6 Effect on Sleep Stages 435
7 Clinical Trials 436
7.1 Drug Development History 436
8 Clinical Efficacy 438
8.1 Noncomparative Studies and Comparisons with Placebo 438
8.2 Zopiclone Data 439
8.3 Eszopiclone Data 439
8.4 Comorbid Insomnia 443
8.5 Effects on Depression 444
8.6 Effects on Anxiety 445
8.7 Effects on Perimenopausal and Menopausal Women 447
8.8 Effects on Pain (Rheumatoid Arthritis, Fibromyalgia) 448
8.9 Use in Obstructive Sleep Apnea and Pulmonary Disease 449
9 Safety Profile 450
9.1 Residual Effects and Daytime Psychomotor Function 453
9.2 Rebound Insomnia and Withdrawal Effects 454
9.3 Tolerance, Abuse, and Dependence 455
10 Conclusion 456
References 457
Indiplon 464
1 Introduction 464
2 Indiplon Chemistry 466
3 Pharmacodynamic Characteristics 467
4 Pharmacokinetics Characteristics 468
5 Clinical Efficacy: Indiplon Immediate-Release 469
6 Clinical Efficacy: Indiplon Modified-Release 470
7 Safety and Tolerability 471
8 Comments 473
References 474
Polysomnographic and Clinical Assessment of Zaleplon for the Treatment of Primary Insomnia 476
1 Introduction 477
2 Pharmacologic Profile 478
3 Clinical Efficacy 478
3.1 Evening Dosing 479
3.2 Middle-of-the-Night Dosing 480
3.3 Daytime Naps/Acute Sedation 481
3.4 Elderly Patients 481
3.5 Special Populations 482
4 Adverse Effects 482
4.1 Sedation, Psychomotor/Memory Impairment 483
4.2 Driving Impairment 483
4.3 Tolerance, Rebound, and Withdrawal 484
4.4 Abuse Potential 484
4.5 Drug Interactions 485
4.6 Respiratory Depression 485
4.7 Other Adverse Effects 486
5 Effects on Sleep Architecture 486
6 Conclusion 487
References 488
Index 492