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Neuropharmacology, the study of drug actions on the nervous system, comprises several areas of critical importance to science and medicine. Neurophar-macology 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 that we know about the nervous system has come from such studies. Indeed, 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.

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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 in the nervous system. 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, the subsequent changes in the output of the neuron, and their consequences for the functioning of circuits within which the targeted neuron exists are all important for gaining a real understanding of drug action. Likewise, it is crucial to delineate the actions of a drug on the many types of non-neuronal cells in the brain and spinal cord. 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.

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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.

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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 functions. This permits the reader to relate fundamental neuropharmacology to neural systems and ultimately to clinical neuroscience.

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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 24), 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.

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In Part 2 information about the major neurotransmitter systems in the brain and spinal cord is presented (Chapters 58). 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 in recent years have been shown to profoundly influence the adult nervous system and to be potentially important in therapeutics.

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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—new to this third edition—on neuroinflammation, 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, 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 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 neural circuits involved in both normal function and specific disease states.

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The organization of Molecular Neuropharmacology: A Foundation for Clinical Neuroscienceallows individual drugs to be discussed in several contexts. A drug is first 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 neural 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).

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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 with neuropharmacology. New insights on the molecular mechanisms 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 molecular underpinnings of normal brain function and disease, particularly in cases that have been successfully investigated by genetics, may be in advance of developments 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.

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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, and anesthesiology, 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.

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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, and third editions, and we welcome David Holtzman as a new coauthor. We also would like to thank Anne Sydor and her colleagues at McGraw-Hill, and Ritu Joon and her team at Thomson Digital, for their crucial role in production of this third edition.

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Eric J. Hall

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Steven E. Hyman

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David M. Holtzman

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Robert C. Malenka

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June, 2014

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