Handbook of Anxiety and Fear (eBook)

D. Caroline Blanchard, Guy Griebel, David J Nutt (Herausgeber)

eBook Download: EPUB

2011 | 1. Auflage
450 Seiten
Elsevier Science (Verlag)
978-0-08-055952-0 (ISBN)

Infos

This Handbook brings together and integrates comprehensively the core approaches to fear and anxiety. Its four sections: Animal models, neural systems, pharmacology, and clinical approaches, provide a range of perspectives that interact to produce new light on these important and sometimes dysfunctional emotions. Fear and anxiety are analyzed as patterns that have evolved on the basis of their adaptive functioning in response to threat. These patterns are stringently selected, providing a close fit with environmental situations and events, they are highly conservative across mammalian species, producing important similarities, along with some systematic differences, in their human expression in comparison to that of nonhuman mammals. These patterns are described, with attention to both adaptive and maladaptive components, and related to new understanding of neuroanatomic, neurotransmitter, and genetic mechanisms. Although chapters in the volume acknowledge important differences in views of fear and anxiety stemming from animal vs. human research, the emphasis of the volume is on a search for an integrated view that will facilitate the use of animal models of anxiety to predict drug response in people, on new technologies that will enable direct evaluation of biological mechanisms in anxiety disorders, and on strengthening the analysis of anxiety disorders as biological phenomena.

. Integrates animal and human research on fear and anxiety
. Presents emerging and developing fields of human anxiety research including imaging of anxiety disorders, the genetics of anxiety, the pharmacology of anxiolysis, recent developments in classification of anxiety disorders, linking these to animal work
. Covers basic research on innate and conditioned responses to threat
. Presents work from the major laboratories, on fear learning and extinction
. Reviews research on an array of neurotransmitter and neuromodulator systems related to fear and anxiety
. Compares models, and neural systems for learned versus unlearned responses to threat
. Relates the findings to the study, diagnostics, and treatment of anxiety disorders, the major source of mental illness in modern society (26 % of Americans are affected by anxiety disorders!)

Inhalt

Front cover 1
Handbook of Anxiety and Fear 4
Copyright page 5
List of Contributors 6
Preface 10
Acknowledgments 12
Contents 14
Section 1: Introduction 18
Chapter 1.1. Introduction to the handbook on fear and anxiety 20
References 23
Section 2: Animal Models of Anxiety, Fear and Defense 26
Chapter 2.1. Theoretical approaches to the modeling of anxiety in animals 28
I. Introduction 28
II. The nature of anxiety 28
III. The nature of an animal model 32
IV. The nature of a specific test: the elevated plus-maze 35
V. Other animal models of anxiety 38
VI. Models of anxiety and their control by the brain 40
VII. Conclusions 40
References 42
Chapter 2.2. The use of conditioning tasks to model fear and anxiety 46
I. A deceptively simple experiment 47
II. A brief history of Pavlovian fear conditioning 49
III. Behavioral measures of conditional fear 50
IV. Other unconditional stimuli 52
V. Key developments in the neuroanatomy of fear conditioning 53
VI. Pavlovian extinction 55
VII. Individual differences in anxiety disorders 57
VIII. Post-traumatic stress disorder 58
IX. Conclusion 60
Acknowledgment 60
References 60
Chapter 2.3. Extinction of fear: from animal studies to clinical interventions 66
I. Introduction 66
II. Behavioral features of extinction 67
III. Theoretical accounts of extinction 69
IV. Facilitation of extinction by d-cycloserine 69
V. Emerging evidence for multiple mechanisms of extinction 73
VI. Conclusion 76
Acknowledgments 76
References 77
Chapter 2.4. Defensive behaviors, fear, and anxiety 80
I. Fear and anxiety 80
II. Defensive behaviors: what, when, where, and why? 81
III. Relationships to learning 86
IV. Danger learning: conditioning to painful unconditioned stimuli (US) 87
V. Unconditioned and conditioned responses to non-painful stimuli (predators or predator odors) 88
VI. Learning of defense to partial predator stimuli 88
VII. Effects of stress and stress ameliorating conditions on defense 88
VIII. Defense and learning: relationship to anxiety 89
IX. Responses to anxiolytic and panicolytic drugs 89
X. Human defensive behaviors 90
XI. Defensive behavior, fear, and anxiety 93
References 94
Chapter 2.5. Unconditioned models of fear and anxiety 98
I. Introduction 98
II. Models 99
III. Ethological approaches: predator confrontation 103
IV. Conclusions 107
References 110
Section 3: Neural Systems for Anxiety, Fear, and Defense 118
Chapter 3.1. Brain mechanisms of Pavlovian and instrumental aversive conditioning 120
I. Introduction 120
II. Pavlovian fear conditioning 121
III. Aversive instrumental conditioning 126
IV. Using EFF to investigate an aversive ‘‘motive circuit’’ 131
V. Summary/conclusions 133
Abbreviations 134
References 134
Chapter 3.2. Neural systems activated in response to predators and partial predator stimuli 142
I. Introduction 142
II. The hypothalamus and its central role in the organization of anti-predator defensive responses 143
III. The medial hypothalamic defensive system 144
IV. Neural inputs to the medial hypothalamic defensive system 145
V. Neural outputs from the medial hypothalamic defensive system 150
VI. Overview of the circuits involved in processing anti-predator defensive responses 152
VII. Neural systems involved in anti-predator contextual conditioning responses 153
References 154
Chapter 3.3. A behavioral and neural systems comparison of unconditioned and conditioned defensive behavior 158
I. Neural system analysis: comparison among models using Pavlovian fear conditioning or predator-related unconditioned and conditioned responses 158
II. Comparisons of use of conditioned and unconditioned animal models of anxiety over time 162
III. Validity of animal models of fear and anxiety 165
Appendix: accessing articles using conditioned and unconditioned models of anxiety 168
References 169
Section 4: The Pharmacology of Anxiety, Fear, and Defense 172
Chapter 4.1. Peptide receptor ligands to treat anxiety disorders 174
I. Introduction 174
II. Neuropeptide systems in anxiety patients 177
III. Anxiety-related behavior and neuropeptides: preclinical evidence 183
IV. Neurochemical evidence linking neuropeptides and the mechanism of action of clinically used anxiolytic drugs 196
V. Many peptide candidates: convergence onto common pathways? 202
VI. Development of small molecule, non-peptide compounds for peptidergic targets 204
VII. Conclusion 212
References 212
Chapter 4.2. Subtype-selective GABAA/benzodiazepine receptor ligands for the treatment of anxiety disorders 240
I. Introduction 240
II. A brief history of anxiolytic development and use 241
III. Benzodiazepines and GABAA receptor heterogeneity 242
IV. Subtype-dependent effects of benzodiazepines: evidence from transgenic mice 244
V. Subtype-dependent effects of benzodiazepines: recent findings with subtype-selective ligands 244
VI. Reducing anxiety selectively: how might this work? 248
VII. Controversies and comments: points of contention between (and within) the ‘‘old’’ and the ‘‘new’’ benzodiazepine pharmacology 253
VIII. Where do we go from here? 254
Acknowledgments 255
References 255
Chapter 4.3. Modulation of anxiety behaviors by 5-HT-interacting drugs 258
I. Introduction 258
II. The serotonin system in the central nervous system 259
III. Human findings: serotonin and pathological anxiety 260
IV.Human findings: experimental studies with patients 261
V. Neuroendocrine studies 262
VI. Human findings: experimental studies with healthy volunteers 263
VII. Human studies: neuroimaging 264
VIII. Summary of clinical studies 265
IX. Serotonin and defensive behavior in animal models 265
X. Dual role of serotonin 268
XI. Serotonin and the hippocampus 271
XII. Genetic manipulations of the 5-HT system 271
XIII.Plasticity of the 5-HT systems and anxiety 274
XIV. Mechanisms of the anxiolytic effects of SSRIs and buspirone 274
XV. Conclusions 276
References 276
Chapter 4.4. The glutamatergic system as a potential therapeutic target for the treatment of anxiety disorders 286
I. Introduction 286
II. Glutamate receptor diversity 287
III. Glutamate receptor structure 288
IV. Advancing glutamate receptor research in anxiety: selective molecules and mutant animals 289
V. Animal models of anxiety 293
VI. Modelling cognitive dysfunction in anxiety 295
VII. Pharmacology of glutamate in animal models of anxiety 295
VIII. NMDA receptors 300
IX. AMPA receptors 302
X. mGluRs 302
XI. Conclusions and future directions 304
References 305
Chapter 4.5. The endocannabinoid system and anxiety responses 320
I. Introduction 320
II. The endocannabinoid system 321
III. Effects of cannabinoids on anxiety 325
IV. Role of the endocannabinoid system in anxiety 327
V. Methodological issues in the study of endocannabinoids in anxiety 329
VI. Mechanisms for the endocannabinoid role in anxiety 330
VII. Endocannabinoids as a pharmacological target for anxiety treatment 332
VIII. Conclusions 333
Acknowledgments 333
References 333
Chapter 4.6. Genetic factors underlying anxiety-behavior: a meta-analysis of rodent studies involving targeted mutations of neurotransmission genes 342
I. Introduction 342
II. Are some particular behavioral tests used in these studies? 343
III. Which genetic method has been used? 360
IV. Was there any particular choice of construction (knock-in, knock-out, and over-expressed models) made for each neurotransmission system? 360
V. Which phenotypes are observed? 361
VI. Can these results be explained by the species or the strain used? 361
VII. Did this strategy enable to precise the brain area involved in these processes? 362
VIII. Is the contribution of the genetic factor limited to the developmental period? 362
IX. Do the effects of the mutation correlate with the results of pharmacological challenge? 362
X. Does the mutation modify the response to anxiolytic or anxiogenic agents? 363
XI. What do these findings tell us about the link between neurotransmitter systems and anxiety? Do these studies provide useful information about the role played by the various GABAergic, serotoninergic, glutamatergic, and neuropeptidergic targets in the anxi 363
XII. Conclusion and perspectives 364
References 365
Chapter 4.7. The pharmacology of anxiolysis 372
I. Introduction 372
II. Recent developments and emerging targets 372
III. Concluding remarks and future directions 376
References 376
Section 5: Handbook of Fear and Anxiety: Clinical and Experimental Considerations 380
Chapter 5.1. Phenomenology of anxiety disorders 382
I. Anxiety disorders: clinical features 382
II. Social anxiety disorder (SAnD) 383
III. Obsessive-compulsive disorder 388
IV. Panic disorder 393
V. Generalized anxiety disorder 398
VI. Post-traumatic stress disorder 402
VII. Conclusions 405
Abbreviations 405
References 405
Chapter 5.2. How effective are current drug treatments for anxiety disorders, and how could they be improved? 412
I. Which pharmacological treatments are efficacious in anxiety disorders? 412
II. What is the mechanism of action in anxiety disorders? 413
III. Do randomised controlled trials reveal consistent differences in efficacy? 415
IV. Why don’t randomised controlled trials reveal more differences between treatments? 415
V. Could clinical outcomes be improved with better use of current treatments? 416
VI. Can psychological therapies enhance the efficacy of pharmacological treatments? 417
VII. Could clinical outcomes be improved, with new targets for anxiolytic drugs? 418
VIII. Could clinical outcomes be improved through using genetic approaches? 419
IX. The insights offered by studies of pharmacological modulation of emotion processing 420
X. Do neuroimaging studies explain the neuroanatomy of the treatment response? 421
References 422
Chapter 5.3. Experimental models: panic and fear 430
I. Introduction 430
II. Sodium lactate and other hyperosmotic infusion techniques 432
III. Carbon dioxide 435
IV. Cholecystokinin 437
V. Voluntary hyperventilation 440
VI. Doxapram 442
VII. Other experimental models of panic 442
VIII. General conclusions 444
Abbreviations 444
References 444
Chapter 5.4. Principles and findings from human imaging of anxiety disorders 454
I. Introduction 454
II. Choice of imaging modality 455
III. Molecular imaging 457
IV. Molecular imaging in anxiety disorders 460
References 467
Chapter 5.5. Stress hormones and anxiety disorders 472
I. Introduction: stress, fear and anxiety 472
II. Anxiety disorders and stressful events: is there a connection? – The role of life events 473
III. Stress response systems: stress and neuroendocrine regulation 474
IV. Links between HPA and noradrenergic function in animal studies 474
V. The SNS in anxiety disorders 482
VI. Summary and conclusions 484
References 485
Chapter 5.6. The genetics of human anxiety disorders 492
I. Introduction 492
II. Genetic epidemiology 492
III. Molecular genetics 501
IV. Functional genetics 512
V. Summary and further directions 513
Abbreviations 514
References 515
Subject Index 528

Textauszug

Chapter 1.1 Introduction to the handbook on fear and anxiety

Robert J. Blanchard1,*, D. Caroline Blanchard2,*, Guy Griebel3, David Nutt4

1 Department of Psychology, University of Hawaii at Manoa, Honolulu, HI, USA

2 Department of Genetics and Molecular Biology, John A. Burns School of Medicine; and Pacific Biosciences Research Center, University of Hawaii at Manoa, Honolulu, HI, USA

3 Sanofi-Aventis, Psychopharmacology Department, Bagneux, France

4 Psychopharmacology Unit, University of Bristol, Bristol, UK

* Corresponding author.

E-mail address: [e-mail]

E-mail address: [e-mail]

Any volume that seeks to analyze two concepts – here fear and anxiety – needs to start by differentiating them. This volume will bring up this distinction in a number of contexts, and it will become clear that different authors may have somewhat different conceptions of what the distinction may be (e.g., chapter by McNaughton and Zangrossi). For current purposes, and because the editors have a robust position on this topic, we will start with this distinction: fear is the motivation associated with a number of behaviors that normally occur on exposure to clearly threatening stimuli. Anxiety is the motivation associated with behaviors that occur to potential, signaled, or ambiguous threat. Both anxiety and fear are often measured through the intensity or persistence of the behaviors with which they are associated, and may further be assessed by their ability to be conditioned to stimuli associated with these threats. These characterizations make it clear that fear and anxiety may intergrade or overlap, just as the stimuli that elicit them represent extremes of continua of clarity and immediacy of threat, such that a particular threat might appear at various points along these continua.

From an ethological perspective, both fear and anxiety are highly adaptive responses. Both are persistent and intense under appropriate conditions, in all vertebrate species in which they have been examined. However, the behaviors associated with fear and anxiety are time- and labor intensive; they may have to be, in order to be successful in meeting the array of dangers that every living organism faces. Failures of intensity or persistence are some of, but certainly not all, the ways that fear and anxiety systems may be insufficient. The simple fact that each of us is alive to read these words indicates that every one of our direct ancestors, human or prehuman, displayed fear and anxiety patterns that were at least adequate to keep them alive through successful reproduction. It is not a negligible legacy.

The problem with all such intense and persistent reactions is that they take effort and time. The evolutionary history of all species has included a world of threatening events. Left unchecked, the motivations and behavioral expression of fear and anxiety might easily consume a disproportionate portion of the energy and time budgets of individual animals, to the detriment of other crucial behaviors like obtaining food, sex, reproduction, and self-care. The major mechanisms limiting fear and anxiety, such as habituation and extinction, and behaviors facilitating these limitation processes, for example, risk assessment, are described in several chapters in this volume (Fanselow and Ponnusamy; Myers and Davis; Blanchard et al.). The Myers and Davis chapter, in particular, highlights some of the potential therapeutic values of promoting factors that limit the duration of conditioned fear or anxiety reactions.

Fear and anxiety are both complex reactions. The range of ways in which they can be maladaptive reflects this complexity. In addition to being too intense or too persistent, they may be elicited by incorrect stimuli, that is, those that are not genuinely threatening. In turn, the perceived threat qualities of a given stimulus may depend on many factors, including innate or preprogrammed tendencies, specific learning by direct experience or by observation of the experiences of others, nonspecific stressors past or present, etc. This multiplicity of factors contributing to the threatening qualities of stimuli that elicit fear and anxiety has led to parallel variation in the stimuli used as models of anxiety (see chapters by Fanselow and Ponnusamy for conditioned, and by Litvin et al. for unconditioned models of anxiety).

The behavioral expression of these emotions is another area where fear, anxiety, and, in particular, anxiety disorders, show great variability. A foundation for this, in terms of normal mammalian response to threat, is outlined in the chapter by Blanchard and Blanchard, potentially providing a counterpart to the later chapter by Nutt, describing, in part, behavioral aspects of current classifications of anxiety disorders. Other focal behaviors commonly used in animal models relevant to fear or anxiety are described in Myers and Davis, as well as in Cain and LeDoux: both chapters additionally provide information on neural systems and neurotransmitters involved in these behaviors and their conditioning. Canteras outlines brain systems that are activated in response to a particularly high intensity, unconditioned, threat stimulus, a predator; and Canteras and Blanchard compare the brain systems engaged in particular unconditioned and conditioned paradigms, as well as trends in use of these paradigms.

The use of animal models is described in greater detail in the third section of the text, which deals with the pharmacology of fear and anxiety. It would perhaps be more precise to say the pharmacology of anxiety, as the goal of discovering new mechanisms in the pharmacological treatment of anxiety disorders is a major driving force behind research in this area. These chapters are organized in terms of major neurotransmitter systems, including peptide receptor ligands (Steckler); GABAA/benzodiazepine receptor ligands (Rowlett); 5-HT interacting drugs (Guimarăes et al.); glutamatergic compounds (J. Cryan and K. Dev); and the endocannabinoid system (D. Piomelli and M. Bortolato). Andrew Holmes provides an overview of the pharmacology of anxiolysis, and Catherine Belzung et al. provide a meta-analysis of rodent studies of targeted mutations of neurotransmission genes related to anxiety.

The clinical section of the book was designed to clarify and focus on the key issues that often complicate and confuse individuals researching translational approaches to fear and anxiety disorders. The chapter by Young et al. offers a powerful fusion of animal and human research approaches to the neuroendocrinology and related brain mechanisms of fear and anxiety. The chapter on diagnostics (Nutt et al.) provides an approach to the issues of diagnostic specificities and overlaps, to give a clear and succinct overview of this complex field that animal model researchers will find of benefit in understanding their current models and developing new ones. The drug treatment chapter (Baldwin and Garner) presents an overview of the current clinical treatments of anxiety disorders, based on recent high-level consensus meetings.

The chapter on imaging by Malizia and Nutt looks at the achievements of this approach in anxiety and fear, and the ways in which current and future developments may – or may not – help in drug discovery and possibly in future animal research. Similarly, the section on challenge tests (Esquivel et al.) offers a current state of the art in this complex arena that has only little been translated to the human drug discovery field despite its clear potential; it also presents a real challenge – or opportunity – to those working in the animal study field as a way of improving translational models. Finally the genetics section (Maron et al.) will provide a useful framework for those working on both human disorders and those exploring related issues in rodents, especially transgenics and trait loci approaches.

As these brief descriptions of the chapters indicate, the scope of the phenomena encompassed by the concepts of fear and anxiety is very wide, reaching from an analysis of animal behavior through neural systems and pharmacology to human psychopathologies. Many readers of this volume, perhaps the majority, are likely to be interested primarily because of the latter, which brings up the question of how firm is the relationship between these anxiety psychopathologies, and the procedures designed to model them, using animal subjects. It is a question that also speaks directly to the value of both neural system and pharmacological research that is based largely on such models, but aimed at intervention and treatment of the human disorders. Some trends in the use of these models are presented in the Canteras and Blanchard chapter.

Our basic goal for this handbook was simply to present this multiplicity of facets to fear and anxiety, describing particular aspects of relevant animal models and their physiological mechanisms, as well as research and analysis on anxiety psychopathologies. This material speaks to great progress on both “pure science” and “applied” fronts during the past couple of decades.

Nonetheless, it is tempting to try to go one step further, to attempt to integrate this material in such a way as to point out a systematic future direction to research on anxiety. A useful corrective for such dramatic effort is that the editors are by no means in total agreement about a core premise for much of this work, that there is a substantial relationship between at least some, or some components of, animal models of anxiety and clinical anxiety. On this topic, our...

Produkt-Details

• Erscheint lt. Verlag: 2.9.2011
• Sprache: englisch
• Themenwelt: Geisteswissenschaften ► Psychologie ► Allgemeine Psychologie
• Themenwelt: Geisteswissenschaften ► Psychologie ► Biopsychologie / Neurowissenschaften
• Themenwelt: Geisteswissenschaften ► Psychologie ► Entwicklungspsychologie
• Themenwelt: Geisteswissenschaften ► Psychologie ► Klinische Psychologie
• Themenwelt: Geisteswissenschaften ► Psychologie ► Verhaltenstherapie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Neurologie
• ISBN-10: 0-08-055952-2 / 0080559522
• ISBN-13: 978-0-08-055952-0 / 9780080559520