Targets and Emerging Therapies for Schizophrenia E-Book

Jeffrey S. Albert

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 886

Veröffentlichungsjahr: 2012

Beschreibung

New and emerging directions in pharmaceutical research to better treat schizophrenia Although the dopamine hypothesis has been the cornerstone of schizophrenia therapeutics, it is clear that dopamine-based approaches do not treat all aspects of the disease. Moreover, many schizophrenia patients fail to respond to current antipsychotics. Integrating chemistry, biology, and pharmacology, this book explores emerging directions in pharmaceutical research for drug targeting and discovery in order to find more effective treatments for schizophrenia, one of the most serious and widespread psychiatric diseases. Targets and Emerging Therapies for Schizophrenia presents the basics of schizophrenia, drug targets for the disease, and potential new drugs and therapeutics. It begins with a discussion of prevalence and etiology. Then, it describes therapies such as dopamine agonists and phosphodiesterase (PDE) inhibitors as well as growing research aimed at addressing untreated symptoms. Next, the authors discuss receptor modulators, inhibitors, and targeting strategies for drug discovery. Both the neurobiological and chemical aspects of all major pharmacological targets are examined. With contributions from an international team of pioneering pharmaceutical researchers, this book compiles the current knowledge in the field, setting the stage for new breakthroughs in the treatment of schizophrenia. Targets and Emerging Therapies for Schizophrenia: * Provides a comprehensive resource for neuro-drug discovery and the development of molecular targets for schizophrenia treatment * Draws from chemistry, biology, and pharmacology for more effective drug targeting and discovery * Explores a wide range of receptors and molecular targets, including dopamine, PDEs, and neuropeptides With Targets and Emerging Therapies for Schizophrenia as their guide, drug discovery and development scientists have the information they need to advance their own research so that new, more effective treatments for schizophrenia will soon be a reality.

Leseprobe

Table of Contents

Cover

Title page

Copyright page

PREFACE

CONTRIBUTORS

INTRODUCTION

1 DOPAMINERGIC HYPOTHESIS OF SCHIZOPHRENIA: A HISTORICAL PERSPECTIVE

1.1 DOPAMINE SYSTEM: NEUROANATOMY AND MODE OF ACTIVITY

1.2 DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

1.3 SUMMARY AND CONCLUSIONS

ACKNOWLEDGEMENT

2 DOPAMINE D2/D3 PARTIAL AGONISTS AS ANTIPSYCHOTICS

2.1 INTRODUCTION

2.2 DOPAMINE D2/D3 PARTIAL AGONISTS

2.3 MECHANISMS OF ACTION OF THE DOPAMINE PARTIAL AGONIST DRUGS

2.4 CONCLUSION

3 D1/D5 DOPAMINE AGONISTS AS PHARMACOTHERAPY FOR SCHIZOPHRENIA

3.1 HISTORY OF D1-LIKE RECEPTOR LIGANDS FOR THE TREATMENT OF SCHIZOPHRENIA

3.2 POTENTIAL VALUE OF D1-LIKE ACTIVATION IN THE TREATMENT OF SCHIZOPHRENIA

3.3 MECHANISMS OF DOPAMINE AGONIST ACTION

3.4 CURRENT STATUS OF D1 AGONIST DEVELOPMENT

3.5 FUTURE RESEARCH DIRECTIONS

ACKNOWLEDGMENTS

CONFLICT OF INTEREST

4 PHOSPHODIESTERASE INHIBITORS AS A NOVEL THERAPEUTIC APPROACH FOR SCHIZOPHRENIA

4.1 INTRODUCTION: THE PHOSPHODIESTERASE (PDE) FAMILY

4.2 PDE4 FAMILY

4.3 PDE10A

4.4 OTHER PDE FAMILIES

4.5 CONCLUSION

5 GLUTAMATERGIC SYNAPTIC DYSREGULATION IN SCHIZOPHRENIA

5.1 INTRODUCTION

5.2 ORIGINS OF THE GLUTAMATE HYPOTHESIS: DISSOCIATIVE ANESTHETICS AND SCHIZOPHRENIA

5.3 NEUROCHEMISTRY OF THE GLUTAMATERGIC SYNAPSE IN SCHIZOPHRENIA

5.4 ARE THERE SENSITIVE DEVELOPMENTAL PERIODS FOR NMDAR HYPOFUNCTION IN SCHIZOPHRENIA RISK?

5.5 SCHIZOPHRENIA RISK GENES AND GLUTAMATERGIC NEUROTRANSMISSION

5.6 CORTICOLIMBIC GABAERGIC DEFICTS IN SCHIZOPHRENIA

5.7 WHICH NMDA RECEPTORS ARE HYPOFUNCTIONAL?

5.8 PSYCHOSIS AS A DOWNSTREAM EVENT

5.9 CONCLUSION

6 METABOTROPIC GLUTAMATE 2/3 RECEPTOR AGONISTS AND POSITIVE ALLOSTERIC MODULATORS OF METABOTROPIC GLUTAMATE RECEPTOR 2 AS NOVEL AGENTS FOR THE TREATMENT OF SCHIZOPHRENIA

6.1 INTRODUCTION

6.2 METABOTROPIC GLUTAMATE RECEPTORS 2 AND 3: STRUCTURE, FUNCTION, AND LOCALIZATION

6.3 STRUCTURE–ACTIVITY RELATIONSHIPS FOR ORTHOSTERIC MGLU2 AND MGLU3 RECEPTOR AGONISTS

6.4 STRUCTURE–ACTIVITY RELATIONSHIPS FOR POSITIVE ALLOSTERIC MODULATORS (PAMS) OF MGLU2 RECEPTORS

6.5 ELECTROPHYSIOLOGICAL PROPERTIES OF ORTHOSTERIC MGLU2 AND MGLU3 RECEPTOR AGONISTS

6.6 ELECTROPHYSIOLOGICAL PROPERTIES OF MGLU2 RECEPTOR POSITIVE ALLOSTERIC MODULATORS

6.7 NEUROCHEMICAL EFFECTS OF ORTHOSTERIC MGLU2 AND MGLU3 AGONISTS

6.8 BEHAVIORAL PHARMACOLOGY OF ORTHOSTERIC MGLU2 AND MGLU3 AGONISTS

6.9 BEHAVIORAL PHARMACOLOGY OF MGLU2 RECEPTOR POSITIVE ALLOSTERIC MODULATORS

6.10 CLINICAL ASPECTS OF ORTHOSTERIC MGLU2 AND MGLU3 RECEPTOR AGONISTS

6.11 SUMMARY AND CONCLUSIONS

7 AMPA RECEPTOR POSITIVE MODULATORS

7.1 INTRODUCTION

7.2 AMPA RECEPTOR STRUCTURE AND FUNCTION

7.3 AMPA RECEPTOR MODULATION AND THE GLUTAMATE HYPOTHESIS OF SCHIZOPHRENIA

7.4 AMPA RECEPTOR POSITIVE MODULATORS: CHEMISTRY AND PHARMACOLOGY

7.5 PRECLINICAL EVIDENCE FOR THE USE OF AMPA RECEPTOR MODULATORS IN SCHIZOPHRENIA: TESTS PREDICTIVE OF ANTIPSYCHOTIC-LIKE ACTIVITY

7.6 TARGETING COGNITION IN SCHIZOPHRENIA

7.7 CLINICAL STUDIES WITH AMPA RECEPTOR MODULATORS

7.8 CONCLUSION

8 PROGRESS IN THE EXPLORATION AND DEVELOPMENT OF GlyT1 INHIBITORS FOR SCHIZOPHRENIA

8.1 BACKGROUND

8.2 THE NMDAR HYPOFUNCTION MODEL

8.3 EXPRESSION AND GENETICS

8.4 SUPPORT FOR GlyT1 AS A THERAPEUTIC TARGET FOR SCHIZOPHRENIA

8.5 SAFETY CONSIDERATIONS

8.6 MECHANISTIC DIFFERENCES AMONG GlyT1 INHIBITORS

8.7 CLINICAL DEVELOPMENT

8.8 SUMMARY

9 COMBINED DOPAMINE D2 AND 5-HYDROXYTRYPTAMINE (5-HT)1A RECEPTOR STRATEGIES FOR THE TREATMENT OF SCHIZOPHRENIA: A PHARMACOLOGICAL AND CHEMICAL PERSPECTIVE

9.1 INTRODUCTION

9.2 THERAPEUTIC STRATEGIES FOR THE TREATMENT OF SCHIZOPHRENIA

9.3 COMBINED 5-HT1A AND D2 RECEPTOR LIGANDS: CHEMICAL CONSIDERATIONS

9.4 EVIDENCE FOR THE UTILITY OF 5-HT1A RECEPTOR AGONISTS IN THE TREATMENT OF SCHIZOPHRENIA

9.5 THE THERAPEUTIC EFFICACY OF COMBINED 5-HT1A RECEPTOR (PARTIAL) AGONISTS AND D2 RECEPTOR (PARTIAL) ANTAGONISTS AGAINST SCHIZOPHRENIA

9.6 EFFECTS ON COMORBID AFFECTIVE DISORDERS

9.7 CONCLUSIONS

10 5-HT2C AND 5-HT6 RECEPTOR TARGETED EMERGING APPROACHES IN SCHIZOPHRENIA

10.1 5-HT2C

10.2 5-HT2C ANTAGONISM VERSUS AGONISM

10.3 5-HT6

10.4 NEUROCHEMISTRY

10.5 COGNITION

10.6 SYNAPTIC PLASTICITY

10.7 SENSORY GATING

10.8 SUMMARY

11 THE CHOLINERGIC HYPOTHESIS: AN INTRODUCTION TO THE HYPOTHESIS AND A SHORT HISTORY

11.1 INTRODUCTION

11.2 ORGANIZATION OF THE CENTRAL CHOLINERGIC SYSTEM

11.3 THE RELATIONSHIP BETWEEN CENTRAL CHOLINERGIC NEUROTRANSMISSION AND COGNITION

11.4 ALTERATIONS OF CENTRAL CHOLINERGIC FUNCTIONS IN SCHIZOPHRENIA

11.5 CHOLINERGICALLY BASED PHARMACOLOGICAL STRATEGIES FOR COGNITIVE ENHANCEMENT IN SCHIZOPHRENIA

11.6 CONCLUSIONS AND THERAPEUTIC IMPLICATIONS

12 α7 NICOTINIC ACETYLCHOLINE RECEPTORS IN THE TREATMENT OF SCHIZOPHRENIA

12.1 STRUCTURE AND FUNCTIONAL PROPERTIES OF α7 NACHRS

12.2 LINKAGE OF α7 NACHRS TO SCHIZOPHRENIA

12.3 ACTIVATION OF α7 NACHRS BY AGONISTS

12.4 ACTIVATION OF α7 NACHRS BY POSITIVE ALLOSTERIC MODULATORS

12.5 PHARMACOLOGICAL EFFECTS OF α7 NACH RECEPTOR AGONISTS AND PAMS: RELEVANCE FOR TREATMENT OF SCHIZOPHRENIA

12.6 THERAPEUTIC PROMISES AND UNCERTAINTIES ABOUT α7 NACHR LIGANDS IN TREATMENT OF SCHIZOPHRENIA: FUTURE DIRECTIONS

12.7 CONCLUSIONS

13 MUSCARINIC ACETYLCHOLINE RECEPTORS AS NOVEL TARGETS FOR THE DEVELOPMENT OF THERAPEUTICS FOR SCHIZOPHRENIA

13.1 INTRODUCTION

13.2 OVERVIEW OF MUSCARINIC RECEPTOR STRUCTURE, FUNCTION, AND LOCALIZATION

13.3 ROLE OF EACH MUSCARINIC RECEPTOR SUBTYPE AND SCHIZOPHRENIA

13.4 CLINICAL STUDIES

13.5 MEDICINAL CHEMISTRY

13.6 M1 AGONISTS

13.7 M1 POSITIVE ALLOSTERIC MODULATORS

13.8 M4 POSITIVE ALLOSTERIC MODULATORS

13.9 M5 POSITIVE ALLOSTERIC MODULATOR

13.10 FUTURE DIRECTIONS

14 WILL MODULATION OF NEUROPEPTIDE RECEPTORS PRODUCE THE NEXT GENERATION OF ANTIPSYCHOTIC DRUGS? A FOCUS ON THE NEUROKININ AND NEUROTENSIN SYSTEMS

14.1 INTRODUCTION

14.2 BACKGROUND

14.3 THE TACHYKININ/NEUROKININ FAMILY

14.4 THE NEUROTENSIN SYSTEM

14.5 CLINICAL PERSPECTIVE

15 GABA AND SCHIZOPHRENIA

15.1 GABA PATHWAYS AND DRUGS, AND UNMET NEEDS IN SCHIZOPHRENIA

15.2 GABA: ROLE IN SCHIZOPHRENIA

15.3 TARGETING GABAERGIC PATHWAYS FOR SCHIZOPHRENIA

15.4 SUMMARY AND FUTURE DIRECTIONS

ACKNOWLEDGMENT

Index

Copyright © 2012 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Targets and emerging therapies for schizophrenia / edited by Jeffrey S. Albert, Michael W. Wood.

p. ; cm.

 Includes bibliographical references and index.

 ISBN 978-0-470-32282-6 (cloth)

 I. Albert, Jeffrey S. II. Wood, Michael W. (Michael William), 1961-

 [DNLM: 1. Schizophrenia–drug therapy. WM 203]

 616.89'8061–dc23

2011051091

PREFACE

When we began this project several years ago, we envisioned a collection of chapters that represented a summary view of a highly dynamic field and a body of work that would serve as a transient snapshot of the current state of research into new therapies for schizophrenia. The search for new treatments for schizophrenia was being robustly pursued by many pharmaceutical and biotechnology companies. New hypotheses in disease biology were being generated from the insights of gifted academic researchers. Substantial investments were being made toward the identification and validation of emerging drug targets arising from those insights. The field of schizophrenia research was teeming with opportunity and the clinical validation of promising treatment hypotheses seemed imminent. Since that time, the aura surrounding the research of emerging therapies for schizophrenia has changed considerably.

Expenditures in schizophrenia-focused drug discovery from larger pharmaceutical and biotechnology companies have been scaled back substantially. The combination of rising research and development costs, more challenging payer environments, and increasingly stringent regulatory hurdles has pushed schizophrenia-focused drug discovery toward the bottom of the risk/reward prioritization analysis advanced by industry consultants. In fact, investments in psychiatric drug discovery overall have suffered major cutbacks within industry. Moreover, the liquidity crisis in the global financial markets negatively impacted the funding of the smaller biotechnology firms, the sector that has traditionally driven the higher risk research investments exploring new therapies.

The liquidity crisis and the austere reaction to that crisis decreased the pool of money available to government granting agencies as well. Academic research in the area of schizophrenia continues, but funding is under constant threat. In addition, the funding of basic science research in many countries is confronted by public attitudes that do not appreciate the impact that these expenditures have on advancing the human condition, increasing the quality of life, and stimulating economic expansion. Moreover, in the particular case of spending on mental health research, there still exists an unwillingness to accept mental illness as a bona fide condition and a discipline worthy of research support.

The wholesale reduction in support for schizophrenia research does not stem from a lack of need for improved treatments for schizophrenia. Although the current treatment options are a major advancement over the primitive approaches to mental illness before pharmacotherapies, there remains ample opportunity for improvement. Many current therapies engender profound side effects and none treat all facets of the disease. The scientific understanding of schizophrenia will continue to evolve, and new hypotheses and novel targets will undoubtedly emerge from those findings. The need to translate these basic science findings into potential therapies in future looks to be addressed through creative, public–private partnerships, and philanthropic foundations. It remains to be seen whether these enterprises will be able to span the translation gap and fill the current void to effectively bring new therapies to patients. As new scientific frontiers are pushed back, there is some cause for hope that the basic understanding of the underlying biological mechanisms and the advance of new translational methodologies will reinvigorate investment into new, more effective therapies

Against a backdrop of diminishing investment in research and development for new therapies for schizophrenia, there is cause to consider what has been captured inside this collection of chapters. The organizing principle for the book was straightforward. We reasoned that since most drug discovery programs are traditionally focused on selectively modulating individual neurotransmitter systems, the book chapters could be arranged according to neurotransmitter systems. The collection begins by establishing the historical framework for neurotransmitter-based drug discovery in schizophrenia by examining the dopamine system. From there, individual dopamine rece­ptors and an intracellular signaling method to modulate dopaminergic pathways are examined. The chapters that follow explore the predominant modern hypothesis of neurotransmitter-based deficits, the role of glutamatergic dysfunction. The progress on individual glutamate-based approaches is then reviewed. Finally, the chapters progress through several other important neurotransmitter systems being investigated as potential therapeutic targets; current serotoninergic, cholinergic, peptidergic, and γ-aminobutyric (GABA)ergic approaches are all discussed.

The authors that agreed to contribute their time and expertise to carefully construct and contribute their reviews were both diligent in their efforts and patient in their demeanor. In the end, they have effectively captured the state of affairs during a major paradigm shift in the field of schizophrenia research treatment. We hope that this book will be used as a starting point for future investigators. To that end, it is our sincere desire that readers will find this book both useful and inspiring. Most importantly, we hope that this snapshot will serve as a foundation for a field reinvigorated in the coming years and that future research built on this foundation will deliver new, more effective treatments for the serious and devastating illness schizophrenia.

JEFFREY S. ALBERTMICHAEL W. WOOD

CONTRIBUTORS

Jeffrey S. Albert, PhD, Department of Chemistry, CNS & Pain Innovative Medicines, AstraZeneca, Wilmington, DE, USA

Alo Basu, PhD, Department of Psychology, College of the Holy Cross, Worcester, MA, USA

Michael Benneyworth, PhD, Department of Pharmacology, University of Minnesota School of Medicine, Minneapolis, MN, USA

Kevin N. Boyd, PhD, Department of Pharmacology, Penn State Univerity College of Medicine, Hershey, PA, USA

Thomas A. Comery, PhD, Pfizer Worldwide Research & Development, Pfizer Inc., Groton, CT, USA

Joseph T. Coyle, MD, Department of Psychiatry, Harvard Medical School, The Laboratory of Molecular Psychiatry and Neuroscience, McLean Hospital, Belmont, MA, USA

Alan J. Cross, PhD, CNS & Pain Innovative Medicines Unit, AstraZeneca, Wilmington, DE, USA

Lee A. Dawson, PhD, Neurosciences PCU, Eisai Ltd, European Knowldege Centre, Hatfield, Herts, UK

John Dunlop, PhD, Pfizer Worldwide Research & Development, Pfizer Inc., Groton, CT, USA

Roelof W. Feenstra, Solvay Pharmaceuticals Research Laboratories, The Netherlands

Christian C. Felder, PhD,  Neuroscience Discovery, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA

Joseph I. Friedman, MD,   Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

Jonathan Gross, PhD, Cranbury, NJ, USA

Mihály Hajós, Yale University School of Medicine, New Haven, CT, USA

Craig Jamieson, PhD, Department of Medicinal Chemistry, Schering-Plough Corporation, Newhouse, Motherwell, UK

Caitlin A. Jones, PhD, Solvay Pharmaceuticals Research Laboratories, The Netherlands

Aurelija Jucaite, MD, PhD, CNS & Pain Innovative Medicines Unit, AstraZeneca, Södertälje, Sweden

Isabella Kanellopoulou, MD, Pilgrim Psychiatric Center, Clinical Neuroscience Center, W. Brentwood, NY and Manhattan Psychiatric Center, New York, NY, USA

John H. Kehne, Translational Neuropharmacology Consulting, LLC, Potomac, MD, USA

Bruce J. Kinon, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA

Bin Liu, PhD, Division of Chemistry and Research Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA

Andrew C. McCreary, PhD, Solvay Pharmaceuticals Research Laboratories, the Netherlands. Present Address: Brains On-Line, Groningen, the Netherlands

David L. McKinzie, PhD, Neuroscience Discovery, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA

John K.F. Maclean, PhD, Department of Medicinal Chemistry, Schering-Plough Corporation, Newhouse, Motherwell, UK

Richard B. Mailman, PhD, Departments of Pharmacology, Penn State University College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, USA

Gerard J. Marek, MD, PhD, Abbott Laboratories, Abbott Park, IL, USA

Karen L. Marquis, Yardley, PA, USA

George D. Maynard, Axerion Therapeutics, New Haven, CT, USA

James A. Monn, PhD, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA

John A. Morrow, PhD, Department of Molecular Pharmacology, Schering-Plough Corporation, Newhouse, Motherwell, UK

Vladan Novakovic, MD, Pilgrim Psychiatric Center, Clinical Neuroscience Center, W. Brentwood, NY, and Manhattan Psychiatric Center, New York, NY, USA

Svante Nyberg, MD, PhD, CNS & Pain Innovative Medicines Unit, AstraZeneca, Södertälje, Sweden

William J. Pitts, PhD, Inflammation Chemistry, Bristol-Myers Squibb Co., Princeton, NJ, USA

Bruce N. Rogers, Pfizer Global Research & Development, Pfizer Inc., Groton, CT, USA

Sharon Rosenzweig-Lipson, PhD, IVS Pharma Consulting, LLC, East Brunswick, NJ, USA

Lee E. Schechter, Pfizer Worldwide Research & Development, Pfizer Inc., Groton, CT, USA

Jeffrey M. Schkeryantz, PhD, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA

Judith A. Siuciak, PhD, The Biomarkers Consortium, Foundation for the National Institutes of Health, Bethesda, MD, USA

Richard C. Thompson, PhD, Department of Chemistry, Tusculum College, Greeneville, TN, USA

Paul W. Smith, PhD, Novartis Institute for Tropical Diseases, Singapore

Philip G. Strange, PhD, Emeritus Professor of Pharmacology, University of Reading School of Pharmacy, Reading, UK

Jeannette M. Watson, PhD, Immune Targeting Systems Ltd, London, UK

Michael W. Wood, PhD, CNS & Pain Innovative Medicines Unit, AstraZeneca, Wilmington, DE, USA

INTRODUCTION

Alan J. Cross

Schizophrenia is a severe and debilitating illness that is generally recognized as starting with a first diagnosis in young adulthood and lasts throughout the patient’s lifetime, often with chronic progression. The incidence of schizophrenia in the general population is around 1%, and according to the World Health Organization [1], schizophrenia accounts for a significant proportion of the global burden of illness in terms of disability and mortality. The nature of schizophrenia, including fragmentation of personality, cognitive impairment, and inability to function, makes it a particularly damaging illness for patients, families, and the community.

For more than 50 years, pharmacotherapy of schizophrenia has relied on a single concept, the dopamine hypothesis [2, 3], based on the pioneering work of Carlsson and Linquist [4]. The so-called first- and second-generation antipsychotic drugs all incorporate an interaction with the dopamine D2 receptor in their pharmacological properties, with differences in the degree of selectivity and the more recent introduction of partial agonism as variations on the theme. These drugs have well-defined antipsychotic properties and as such have had a tremendous impact on the treatment of schizophrenia. Despite this, it is equally well understood that antipsychotic drugs do not treat the entire spectrum of the illness, nor do all patients respond to these drugs. There thus remains a considerable unmet patient need, and novel approaches for the treatment of schizophrenia must address key areas such as cognitive deficits, negative symptoms, and poor response to current antipsychotics. Our understanding of the underlying neurobiology of schizophrenia is improving considerably, driven by the impact of genetics and neuroimaging studies. Genetic studies have identified a growing list of rare, highly penetrant structural variants many of which implicate genes involved in the development of the central nervous system (CNS) and in maintaining synaptic integrity and function [5]. Neuroimaging studies have provided the substrate for understanding abnormalities in neural circuitry and how these might underlie certain neuropsychological features of illness. These advances in our understanding of the disease biology offer hope that in the longer term, treatments may be devised which address the underlying neuropathological processes leading to the development and chronicity of illness, as well as addressing the heterogeneity of disease.

It is always tempting to speculate that disease-modifying treatments are on the horizon, but it is worth remembering that even in such well-defined neuropsychiatric illnesses as Huntington’s disease, such breakthroughs have proven to be enigmatic. In the case of schizophrenia, it is clear that a great deal has to be done to fill the gap between understanding of genetic risk and identification of viable drug targets. Thus, emerging approaches to pharmacotherapy of schizophrenia rely less on an understanding of disease etiology and more on understanding changes in neurophysiology and neuropharmacology associated with the illness.

Although the dopamine hypothesis has been the cornerstone of therapeutics, our understanding of the neurobiology of dopaminergic systems and the relation to schizophrenia continues to advance, and there is scope remaining to produce improved treatments based on novel pharmacology relating to dopamine. It is clear, however, that dopamine-based approaches do not treat all features of the illness and many patients fail to respond to current antipsychotics, suggesting that alternative approaches are required. Some of the most promising approaches relate to the glutamate hypothesis, which, despite being formulated over 25 years ago, arguably has not been adequately tested in the clinic. It is to be hoped that novel glutamatergic pharmacological agents will provide the tools for adequately testing this very attractive hypothesis. Beyond this, a number of neurotransmitters systems clearly modulate the effects of dopamine. On listing these approaches one may comment that little has changed over the last few decades and indeed many of these neurotransmitters systems have been extensively reviewed in the context of involvement in schizophrenia. There are, however, several key changes worth noting, most importantly that the field has moved from formulating hypotheses to testing hypotheses using drug candidates with the appropriate pharmacology and drug-like properties to enable definitive clinical studies. Moreover, clinical and preclinical studies can be designed from a background of improved disease understanding, leading to the use of more relevant intermediate phenotypes, translational tools, and endpoints. It is encouraging that several of these emerging treatments are delivering positive signals in the clinic. Although much work still has to be done to understand how these therapies should be used optimally, it is clear that meaningful and novel pharmacological treatments for schizophrenia are moving closer to reality.

REFERENCES

1. World Health Organization (2001) The World Health Report 2011: Mental Health: New Understanding, New Hope. World Health Organization: Geneva.

2. Crow, T.J. (1980). Positive and negative schizophrenic symptoms and the role of dopamine. British Journal of Psychiatry, 137, 383–386.

3. Carlsson, A. (2002). The dopamine hypothesis of schizophrenia: new aspects. Advances in Behavioral Biology, 53, 417–422.

4. Carlsson, A., Lindqvist, M. (1963). Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacologica et Toxicologica, 20, 140–144.

5. Tam, G.W.C., Redon, R., Carter, N.P., Grant, S.G.N. (2009). The Role of DNA Copy Number Variation in Schizophrenia. Biological Psychiatry, 66, 1005–1012.

1

DOPAMINERGIC HYPOTHESIS OF SCHIZOPHRENIA: A HISTORICAL PERSPECTIVE

Aurelija Jucaite and Svante Nyberg

In search of evidence for the dopamine hypothesis of schizophrenia, this review focuses on studies of patients with schizophrenia. The review is composed of two parts: the first serves as a short reminder of the anatomy and function of the dopamine system, and the second guides the reader through the history of scientific discoveries and paradigms used to investigate the role of dopamine in the pathophysiology of schizophrenia.

1.1 DOPAMINE SYSTEM: NEUROANATOMY AND MODE OF ACTIVITY

Dopamine is a phylogenetically old neurotransmitter intrinsic to brain function and behavior. It is of central importance in movement, reward-associated behavior, and emotions. Abnormal patterns of dopamine neurotransmission have been suggested to underlie several neurological and psychiatric disorders, for example, Parkinson’s and Huntington’s diseases, schizophrenia, drug abuse, and attention-deficit/hyperactivity disorder (ADHD).

1.1.1 Macroanatomy

Dopamine is synthesized in dopaminergic neurons from the amino acid tyrosine by the enzymes tyrosine hydroxylase (forming L-3,4-dihydroxylphenylalanine [L-DOPA]) and L-amino acid decarboxylase (AACD). Tyrosine hydroxylase is a rate-limiting enzyme in the synthesis of dopamine, and its mRNA expression is abundant in human mesencephalon.

Dopaminergic neurons showing the highest expression of tyrosine hydroxylase mRNA are aggregated in distinct clusters: the ventral midbrain (A8-9-10), diencephalon (A11-15), and telencephalon (A16-olfactory bulb, A17, and the retina). Dopaminergic neurons cluster into the three major nuclei in the brain that contain cell bodies: (1) the substantia nigra pars compacta (SN, A9), located in the ventral midbrain; (2) the ventral tegmental area (VTA) or A10, lying medial to SN; and (3) the arcuate nucleus of the hypothalamus, throughout the posterior and dorsomedial nuclei of hypothalamus (A11–15, in the diencephalon) [1, 2]. Smaller groups of dopaminergic neurons are located in the retina and the olfactory bulb, in the human cerebral cortex [3, 4], in the subcortical white matter, and in the striatum [5, 6].

The dopaminergic projections from these neurons are distributed throughout the anatomically segregated neuronal systems that control motor, limbic, and cognitive aspects of behavior (Fig. 1.1). The dopaminergic projections form three major long pathways:

1. The nigrostriatal pathway contains over 80% of all dopaminergic innervation, primarily targeting the striatal medium spiny projection neurons. Dopamine modulates cortical innervation to the striatum and is involved in the control of movement.

2. The mesolimbic pathway, with neurons from VTA synapsing in the nucleus accumbens and amygdala, is engaged in emotions, motivation, goal-directed behavior, pleasurable sensations, the euphoria of drug abuse, and the delusions and hallucinations of psychosis [7].

3. The mesocortical pathway originates in the VTA and terminates in the forebrain with its most abundant innervation in the prefrontal cortex, anterior cingulate, insula, entorhinal cortices. The majority of target neurons are excitatory pyramidal cells and minor target group are dendrites of local inhibitory neurons [8, 9] largely involved in cognitive functions.

FIGURE 1.1 Dopamine projections in the human brain. A schema of the major dopamine projection systems is superimposed on an MR image of a human brain.

There is a topographic organization of the SN/VTA innervation to the cortical regions (e.g., dorsal prefrontal and anterior cingulate cortices receive innervation from the dorsal group of cells of the SN and the retrobulbar area), while ventromedial limbic cortices receive input from the VTA [10]. In addition, several shorter pathways distinct from the major projections have been identified: the tubero-infundibular pathway, which projects from the hypothalamic nucleus to the anterior pituitary and contributes to the neurohumoral regulation of lactation; the mesohippocampal tract, which originates in the SN/VTA and terminates at the hippocampus and is involved in memory formation; and the mesofrontal tract, which traverses from the SN to the prefrontal cortex and is active in reward mechanisms. Ultrashort dopaminergic pathways connecting inner and outer layers of the retina (interplexiform amacrine-like neurons) and cells in the olfactory bulb (periglomerular dopamine cells) have also been reported [11], although their function is less well understood.

1.1.2 Microanatomy

Neurotransmission, including the synthesis–storage–release–receptor binding of the monoamine neurotransmitter as well as its uptake or degradation, is a highly controlled process. The complex balance of this cascade determines the intensity of dopaminergic signaling.