Serotonin and Sleep: Molecular, Functional and Clinical Aspects (eBook)

Contents 5
List of contributors 8
Glossary 13
Dedication 18
Credits and acknowledgements 19
Foreword 21
References 22
Preface 23
Evolution of concepts 25
Changing concepts on the role of serotonin in the regulation of sleep and waking 26
Abstract 26
Introduction 26
The early history 27
The concept of serotonin as a sleep transmitter 27
The concept changes – Is serotonin a waking neurotransmitter? 30
Current concept: Complex role of serotonin in modulation of sleep and waking 33
A different concept: Modulation of motor activity 38
Conclusion 38
References 39
The dorsal raphe nucleus and median raphe nucleus: organization and projections 45
Topographic organization and chemoarchitecture of the dorsal raphe nucleus and the median raphe nucleus 46
Abstract 46
Introduction 46
Topography of serotonergic neurons within the midbrain and pontine raphe complex 49
Topographically organized subpopulations of serotonergic neurons within the midbrain raphe complex 51
The dorsal raphe nucleus 52
The median raphe nucleus 66
Ascending fiber tracts arising from the midbrain and pontine raphe complex 68
Intra-raphe interactions 72
Afferent regulation of dorsal and median raphe nuclei by arousal systems 73
Summary and conclusions 74
Acknowledgements 74
References 74
Efferent and afferent connections of the dorsal and median raphe nuclei in the rat 89
Abstract 89
Introduction 90
Serotonergic neurons of the DR and MR 90
Ascending projections of the dorsal raphe nucleus 92
DR projections to the brainstem 96
Projections of the MR 97
Differential DR and MR projections 102
Differential serotonergic DR and MR projections to the forebrain 103
Afferent projections to the DR 108
Afferents to the MR 113
Acknowledgements 115
References 115
Reciprocal connections between the suprachiasmatic nucleus and the midbrain raphe nuclei: A putative role in the circadian control of behavioral states 123
Abstract 123
Introduction 124
Circadian rhythms in midbrain raphe serotonergic activity 126
Indirect neuronal projections from the SCN to the DRN and MRN 129
Feedback projections from the DRN and MRN to the SCN 138
Conclusions and future directions 141
Acknowledgement 143
References 143
Serotonin receptors 152
Localization of 5-HT receptors in the mammalian cortex 153
Abstract 153
Introduction 153
The prefrontal cortex: 5-HT localization 155
5-HT1A and 5-HT2A receptor localization in mammalian cortex 155
5-HT1B and 5-HT1D receptors 161
Other cortical 5-HT receptors 163
Acknowledgements 165
References 165
Molecular biology of 5-HT receptors 172
Electrophysiology of serotonergic neurons and the regulation of serotonin release 200
Brain serotonergic neuronal activity in behaving cats 201
Abstract 201
Introduction 201
Basic neuronal characteristics 203
Neuronal activity across the sleep–wake arousal cycle 203
Neuronal response to stressors 205
Neuronal activity in relation to autonomic function 206
Neuronal activity and muscle tone/tonic motor activity 210
Neuronal activity and phasic motor activity 212
Neuronal activity and fatigue 215
Discussion 217
Acknowledgement 218
References 218
Electrophysiological studies on serotonergic neurons and sleep 221
Abstract 221
Introduction 222
General characteristics of presumed 5-HT neurons in conscious animals 223
Classification of brainstem 5-HT neurons 228
Neuromodulation of serotonergic DRN neurons during sleep-waking states 235
Functional role of serotonergic neurons in behavioral state control 243
Role of 5-HT in the regulation of sleep and wakefulness 246
References 247
Role and origin of the GABAergic innervation of dorsal raphe serotonergic neurons 253
Abstract 253
Introduction 253
Effect of the application of GABA antagonists on the activity of the rat DRN neurons during sleep 255
Spontaneous activity of DRN neurons during the sleep-waking cycle 255
Iontophoretic applications of bicuculline 256
Pharmacological and physiological significances 256
Origin of the GABAergic projections to the DRN 257
Origin of the GABAergic input to the DRN 258
GABAergic neurons projecting to the DRN 258
GABAergic input inhibiting DRN serotonergic neurons during SWS 259
GABAergic input inhibiting DRN serotonergic neurons during PS 260
Acknowledgements 262
References 262
Regulation of serotonin release by inhibitory and excitatory amino acids 267
Abstract 267
Introduction 268
Methodological issues 270
GABA in the raphe 274
Physiological and behavioral significance of GABA in the raphe 280
Excitatory amino acids in the raphe 284
Physiological and behavioral significance of EAAs in the raphe 290
References 292
Neurophysiological aspects of the regulation of serotonin neurons by the orexinergic system 302
Abstract 302
Introduction 302
The orexin neuropeptide system 304
Serotonin and the ascending arousal system 306
Anatomical considerations 307
Orexin directly influences serotoninergic cell activity 309
Orexin indirectly influences serotoninergic cell activity 311
Serotonin influences orexinergic cell activity 313
Orexin and serotonin: a summary of the interactions 313
Functional implications 314
References 315
Serotonin receptors and the regulation of behavioural state 320
Serotonin and dreaming 321
Abstract 321
Introduction 322
Effects of serotonergic drugs on dreaming 322
Alterations of human sleep electrophysiology by serotonergic drugs 326
Pharmacology of serotonergic effects on REM sleep and dreaming 327
Evidence from animal studies: Cellular neurophysiology of serotonergic hallucinogens 328
Effects of serotonergic drugs on waking consciousness relevant to dreaming 329
Possible mechanisms for SSRI dream augmentation and implications for normal dreaming 330
References 333
Involvement of the 5-HT1A and the 5-HT1B receptor in the regulation of sleep and waking 339
Abstract 339
Introduction 339
5-HT1 receptors family 340
Characteristics of the 5-HT1A receptors 340
Characteristics of the 5-HT1B 356
Conclusions 368
References 369
Mechanisms involved in the inhibition of REM sleep by serotonin 384
Abstract 384
Introduction 385
Brainstem structures involved in the promotion and generation of REMS 385
The structure of the DRN and of the PPT 386
Operational characteristics of the 5-HT1A and the 5-HT2 receptors 387
Mechanisms involved in the regulation of the activity of DRN serotonergic neurons during sleep and waking 388
Serotonergic influences on the LDT cholinergic and the mPRF glutamatergic neurons 391
Effects of microdialysis perfusion or direct infusion of a 5-HT1A receptor agonist into the DRN, LDT, or mPRF on REMS occurrence 392
Effects of direct infusion of a 5-HT2A/2C receptor agonist into the DRN or LDT on REMS occurrence 393
Conclusions 394
References 394
Effect of 5-HT2A/2B/2C receptor agonists and antagonists on sleep and waking in laboratory animals and humans 399
Abstract 399
Localization and cellular function of 5-HT2A, 5-HT2B and 5-HT2C receptors related to sleep regulation 400
Distribution of 5-HT2A, 5-HT2B and 5-HT2C receptors in the brain 400
Sleep patterns of mice lacking 5-HT2 receptors 402
Sleep effects of drugs acting on the 5-HT2 receptors 403
Effect of antipsychotic drugs with high affinity to 5-HT2 receptors on vigilance 422
References 422
Effect of the selective activation of serotonin 5-HT3 receptors on sleep and waking 427
Abstract 427
Introduction 427
General description of the 5-HT3 receptor 428
Role of 5-HT3 receptors in sleep-wake physiology 433
Implication of the 5-HT3 receptor in sleep disorder 436
Conclusion 440
References 441
5-HT7 receptor modulation of sleep patterns 450
Abstract 450
Introduction to 5-HT7 receptors 451
5-HT7 receptor brain tissue localization 453
5-HT7 receptor modulation of neuronal activity in brain regions implicated in sleep 454
Evidence for a role for the 5-HT7 receptor in sleep modulation 458
Therapeutic potential of 5-HT7 receptor ligands in sleep and sleep-related disorders 462
Summary and future studies 463
Acknowledgements 463
References 463
Sleep and waking in mutant mice that do not express various proteins involved in serotonergic neurotransmission such as the serotonergic transporter, monoamine oxidase A, and 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C and 5-HT7 receptors 468
Introduction 469
Sleep-wakefulness regulations in knockout mice – comparison with pharmacological inactivation of the protein 470
Homeostasis and sleep 477
Stress and sleep 478
Compensatory mechanisms in constitutive knockouts: pharmacological challenges 479
Critical periods of development for the setting up of the sleep phenotype 481
Conclusion 482
References 483
Circadian control by serotonin and melatonin receptors: Clinical relevance 487
Abstract 487
Introduction 488
SCN as the central oscillator 488
Serotonin and midbrain raphe contribution to circadian rhythm regulation 489
Melatonin receptors in SCN 492
Agomelatine, a melatonergic agonist with 5-HT2C and 5-HT2B antagonist properties 494
Circadian rhythm sleep disorders 495
Conclusion 502
References 502
Serotonergic mechanisms contributing to arousal and alerting 510
Abstract 510
Introduction 510
Relationship of DRN neuronal activity to arousal and alerting 512
PGO waves as indicators of alerting 514
Serotonin and pontine regulation of arousal and alerting 516
Role of serotonin in the amygdala in regulating arousal and alerting 520
Conclusion 525
References 526
Relevance of serotonin to clinical disorders and drug actions 535
Contribution of chemosensitive serotonergic neurons to interactions between the sleep-wake cycle and respiratory control 536
Abstract 536
Introduction 536
The role of serotonin in breathing 538
State-dependent respiratory modulation 540
Role of serotonin in arousal 542
Serotonergic neurons are central respiratory chemoreceptors 544
Clinical implications 549
Summary 551
References 552
Obstructive sleep apnea: The potential for serotonergic pharmacotherapies 562
Abstract 562
Obstructive sleep apnea syndrome: clinical presentation and pathogenesis 562
OSAS: epidemiology and co-morbidities 564
Effectiveness of non-pharmacological therapies for sleep apnea 564
Neurochemical mechanisms underlying sleep apnea events 565
The pharmacology of serotonergic control of respiration 567
Clinical trials of serotonergic drugs for OSAS 569
Future directions 572
References 572
The effects of antidepressant drugs and 5-HT agonists on human sleep 576
Abstract 576
Introduction 576
The study of human sleep 577
Sleep architecture in depression and anxiety 578
Effects of SSRIs on REM sleep 579
Effects of SSRIs on sleep initiation and continuity 580
Slow wave sleep and delta sleep ratio with SSRIs 581
Sleep effects of the SNRIs 582
5-HT1A agonists (azapirones) and sleep 582
Subjective sleep effects of the SSRIs and SNRIs 585
SSRIs and dreaming 587
Subjective sleep effects of the azapirones 588
Practical implications of the effects of antidepressants on sleep 588
Reference 588
The effect of typical and atypical antipsychotic drugs on sleep of schizophrenic patients 593
Abstract 593
Introduction 594
Sleep alterations in schizophrenic patients 594
Objective assessments of sleep physiology in patients with schizophrenia 595
Neurobiological mechanisms of sleep regulation 598
Effects of typical antipsychotic drugs on sleep 600
Effects of atypical antipsychotic drugs on sleep 602
Summary 611
References 613
Subject Index 617

Brain serotonergic neuronal activity in behaving cats (p. 185-186)

Barry L. Jacobs and Casimir A. Fornal

Program in Neuroscience, Green Hall, Princeton University, Princeton, NJ 08540, USA

Abstract

A series of studies was conducted on the electrophysiological activity of brain serotonergic neurons in behaving cats. The studies explored a wide variety of behavioral and physiological conditions. In general, neuronal activity of both rostral (mesencephalic and pontine) and caudal (medullary) groups of serotonergic neurons was strongly related to spontaneous changes in behavioral state (highest in active waking and lowest during REM sleep).

Across a wide variety of behavioral and physiological conditions (including stressors), the activity of these neurons was relatively unperturbed. However, one condition, motor activity, strongly affected neuronal activity. A general relationship exists between level of tonic motor activity and serotonergic neuronal activity across all groups of serotonergic neurons. Superimposed upon this in some neurons is an additional relationship in which a further, often dramatic, activation is seen in association with repetitive, central motor program-mediated behaviors (e.g., feeding, licking, respiration, and locomotion). The exact nature of this relationship varies both with the serotonergic neuronal group (e.g., locomotor-related medullary neuronal activity versus grooming-related mesencephalic neuronal activity) and within a particular group (e.g., respiratory-related and feeding-related medullary neuronal activity). We hypothesize that the primary function of this increased serotonergic neuronal activity in association with tonic and repetitive motor activity is to facilitate behavioral output by coordinating autonomic and neuroendocrine function in association with the existing motor demand, and by concomitantly suppressing activity in most sensory information processing channels.

Introduction

For the past 30 years, the major goal of our laboratory’s research has been the elucidation of the behavioral/physiological role of the mammalian CNS serotonin (5-hydroxytryptamine, 5-HT) system. Does it have a specific role or roles, or is it a ubiquitous neurotransmitter, like GABA or glutamate, exerting effects on virtually all brain processes, and thus serving no specifiable behavioral or physiological function? Our feeling was that much of the research on brain serotonin was like the fable of the blind men and the elephant. Many people who studied the action of serotonin in a particular region of the CNS or in relation to a specific behavior or physiological process concluded, correctly, that this is what serotonin’s role was. For us, this was insufficient, it did not take the next step. Could all of these individual bits of data be integrated to form a whole, animated "elephant"? In other words, was there an overarching theory of CNS serotonin function that could account, at least in part, for the vast body of data on this topic?

The primary tool that we employed in our work was measuring the electrical activity of individual serotonergic neurons ("single-unit recordings") in unanesthetized, freely behaving domestic cats (F. catus). Our philosophy was to allow ourselves to be guided by the leads provided by observing the variations in neuronal activity that emerged under a diversity of behavioral and physiological conditions.

We are deeply indebted to a number of pioneering scientists whose research inspired, guided, and made our own work feasible. First, the value of the single- unit approach was dramatically and elegantly shown by the work of two laboratories. In the late 1950s and early 1960s, Hubel and Wiesel delineated the operating characteristics and function of visual system neurons in cats and monkeys. At the same time, Evarts showed the value of adapting this approach to behaving animals to study the function of various structures within the motor system of monkeys. Second, invertebrate neurophysiologists, led by Eric Kandel, showed the value of studying identifiable individual neurons in relation to various functional outputs. In our version of this, we studied "members" of identifiable groups of neurons (in vertebrates one cannot identify a "specific" serotonergic neuron). Third, in an extraordinary series of studies, in the late 1960s and early 1970s, George Aghajanian demonstrated that one could identify and reliably record the single-unit activity of brain serotonergic neurons in rats. Finally, the elegant research and brilliant theorizing of our friend and mentor, Michel Jouvet, regarding the role of serotonin in state control, was a direct inspiration and motivating force for our work.