Neuropharmacology, the study of drug actions on the nervous system, comprises several areas of critical importance to science and medicine. Neuropharmacology includes the translation of basic neuroscience into the discovery of new therapeutic agents, studies aimed at elucidating the mechanism by which drugs act in disease, and also the use of chemical compounds as tools to investigate the function of cells, synapses, and circuits in the nervous system. Much of what we know about the nervous system has come from such studies. Numerous foundational discoveries in neuroscience, including the identification of many neurotransmitters and their receptors, transporters, and signaling molecules, came from investigation into mechanisms of drug action.
To comprehend the actions of a drug on the nervous system, a great deal more is needed than simply identifying the drug’s initial target. Rather, one must understand the entire sequence of events that commences with the binding of a drug to an initial molecular target. The resulting alteration in the functioning of that target, the influence of that occurrence on the complex biochemical networks that exist within neurons and nonneuronal cells, the subsequent changes in the output of the cells, and their consequences for the functioning of neural circuits within which the targeted cells exist are all important for gaining a true understanding of drug action. Only with an awareness of the many steps in the process can we grasp how a drug changes complex nervous system functions such as movement, cognition, pain, or mood.
Neuropharmacology is entering an exciting new era as genetic analysis of many diseases of the nervous system is beginning to identify molecular mechanisms of pathogenesis that suggest new therapeutic targets. Even highly heterogeneous and genetically complex disorders, for instance, many forms of intellectual disability, autism, schizophrenia, epilepsy, and neurodegenerative diseases, among others, are beginning to yield to modern technologies. If these discoveries are ultimately going to yield effective therapeutics, new experimental approaches to neuropharmacology will be much in need.
The organization of this textbook represents an attempt to build an understanding of drug action by adding the different levels of explanation, layer by layer. As a result this book differs significantly from many other pharmacology texts, which are usually organized by drug class or by neurotransmitter. In this book, information on fundamental molecular and cellular building blocks is provided first so that it can serve as the basis for the material associated with neural and glial functions. This permits the reader to relate fundamental neuropharmacology to neural systems and ultimately to clinical neuroscience.
The book is divided into three parts. Part 1 includes a brief discussion of general principles of neuropharmacology (Chapter 1), followed by a detailed presentation of nervous system function (Chapters 2, 3, 4), from electrical excitability to signal transduction to gene expression. Drugs that act on these basic components of neuronal function are mentioned in these early chapters.
In Part 2 information about the major neurotransmitter systems in the brain and spinal cord is presented (Chapters 5, 6, 7, 8). Highlighted in these chapters are the molecular details of neurotransmitter synthetic and degradative enzymes, receptors, and transporter proteins. These proteins represent the initial targets for the large majority of known psychotropic drugs. Also included in Part 2 is a discussion of several types of atypical neurotransmitters, eg, neurotrophic factors, adenosine, endocannabinoids, and nitric oxide, among others (Chapter 8), which have been shown to profoundly influence the adult nervous system and to be potentially important in therapeutics.
Part 3 uses the basic information contained in Parts 1 and 2 to build a systems–level description of the major domains of complex nervous system function. Chapter 9 focuses on the autonomic nervous system; Chapter 10 on neuroendocrine function, Chapter 11 on pain and analgesia, Chapter 12 on neuroinflammation and autoimmune disorders, Chapter 13 on sleep and arousal, Chapter 14 on cognition and behavioral control, Chapter 15 on emotion and mood, Chapter 16 on reinforcement and addiction, Chapter 17 on schizophrenia and other psychotic disorders (eg, bipolar disorder), Chapter 18 on neurodegenerative diseases, in particular, Alzheimer disease and Parkinson disease, Chapter 19 on seizure disorders, and Chapter 20 on cerebrovascular illnesses such as stroke and migraine. Each chapter begins with a description of the normal neural and glial mechanisms underlying a particular domain of nervous system functioning, followed by a discussion of the diseases that affect that domain. Drugs are discussed within the context of their influence on the molecules, cells, and circuits involved in both normal function and specific disease states.
The organization of Molecular Neuropharmacology: A Foundation for Clinical Neuroscience allows individual drugs to be discussed in several contexts. A drug is mentioned when its initial target is described in Part 1 or 2. The drug is mentioned again in Part 3 in the context of its effect on complex brain and spinal cord functions. Many drugs are discussed in several chapters of Part 3 because they affect more than one domain; for example, first generation antipsychotic drugs not only reduce psychosis (Chapter 17), but also affect motor function (Chapter 18), sleep (Chapter 13), and neuroendocrine function (Chapter 10).
The book’s structure also permits the incorporation of a great deal of clinical information, much of it representing the integration of modern molecular genetics and brain imaging with neuropharmacology. New insights on the molecular, cellular, and circuit mechanisms—including mechanisms involving nonneuronal cells—underlying such disorders as Parkinson disease, Huntington disease, depression, schizophrenia, Alzheimer disease, stroke, and epilepsy, to name a few, are provided. Our knowledge of the biologic underpinnings of normal brain function and disease have generally preceded advances in pharmacology. Consequently, the book includes many molecular insights, even though drugs may not yet exist that exploit such molecular knowledge. In this regard the book can be seen as presenting a template for the future, in identifying molecular mechanisms for novel therapeutic approaches. We anticipate that subsequent editions of this book will describe the development of such novel medications and thereby gradually fill in these gaps in pharmacology.
Indeed, there is good reason to be optimistic. After several decades of few advances in the treatment of most nervous system disorders, there is, at long last, significant progress. Since the publication of this book’s previous edition in 2015, we have seen the marketing of numerous drugs with fundamentally new mechanisms of action. Suvorexant is a dual OX1 and OX2 orexin receptor antagonist approved for the treatment of insomnia (Chapter 13), pitolisant is an H3 histamine receptor antagonist/inverse agonist approved for the treatment of narcolepsy (Chapter 13), ketamine is a noncompetitive NMDA glutamate receptor antagonist among several other actions approved for the treatment of depression (Chapter 15), brexanolone is a neuroactive steroid approved for the treatment of postpartum depression (Chapter 15), pimavanserin is a 5HT2A serotonin antagonist/inverse agonist approved for the treatment of psychosis associated with Parkinson disease (Chapter 18), and several monoclonal antibodies directed against either calcitonin gene–related peptide (CGRP) or its receptor have been approved for the treatment of migraine (Chapter 20). Numerous anti-inflammatory agents—for both parenteral and oral administration—have significantly improved the treatment of multiple sclerosis. Additionally, we are beginning to see highly novel modalities of treatment, such as approved antisense oligonucleotides—delivered intrathecally—for the treatment of spinal muscular atrophy and increased interest in circuit–based treatments (eg, deep brain stimulation) for a range of neurologic and psychiatric disorders. This is an unprecedented degree of progress in neuropharmacology which far exceeds the advances achieved since the book’s first edition in 2000.
Despite this progress, there have also been major disappointments. Several amyloid–based treatments for Alzheimer disease failed large clinical trials and we are no closer to nonopioid treatments of opioid or other addictions despite the fact that the health and economic well–being of the world depends in part on devising definitive treatments for these disorders. Nevertheless, the rich science of neuropharmacology—coupled with breakthrough advances in molecular, cellular, and circuit analyses of the brain across species—promises additional clinical achievements in the coming years. The US BRAIN initiative and related programs in several other countries recognize the potential of these groundbreaking new technologies. There is particular excitement for the power of computational approaches for studying neural networks, genomics and several other “omics,” brain and cell imaging, and electronic health records, among other applications. We hope and expect that future editions of this book will present clinical progress driven by these and other innovations.
The scientific and clinical explanations in Molecular Neuropharmacology: A Foundation for Clinical Neuroscience are written in a style that makes them accessible to a wide audience: undergraduate and graduate students as well as students in the medical and allied health professions. This book is also an excellent resource for residents in psychiatry, neurology, neurosurgery, rehabilitation medicine, anesthesiology, and ophthalmology, and practicing clinicians and scientists in these areas. As a concise treatise of clinical information that provides descriptions of basic mechanisms and their clinical relevance, this book is suitable for both scientists and clinicians.
We would like to acknowledge the contributing authors who were instrumental in the initial phases of the preparation of this book for the first, second, third, and now fourth editions. We thank Steven Hyman, Robert Malenka, and David Holtzman as past authors of this book, and welcome a new team of coauthors—representing a new generation of neuropharmacologists—to take the reins of the newly named Nestler, Hyman & Malenka’s Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. Finally, we would like to thank Andrew Moyer and Kim Davis, and their colleagues at McGraw-Hill, for their crucial role in production of this fourth edition, and You Jeong Park for the beautiful artwork that begins each section of the book.
Eric J. Nestler
Paul J. Kenny
Scott J. Russo