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Neuropsychopharmacology continues to be organized pri-marily according to the neurotransmitters that are utilizedby various populations of neurons for synaptic transmission.This is because the vast majority of psychotropic drugs pres-ently used clinically to treat neuropsychiatric disorders stillhave as their initial targets proteins that regulate the avail-ability of a particular neurotransmitter (e.g., presynapticreuptake transporters, synthetic or degradative enzymes) orthat serve as ligands for particular neurotransmitter recep-tors. It is entirely appropriate then that this edition of  Neu-ropsychopharmacology: A Generation of Progress  begins with

a section devoted to the major neurotransmitter systems inthe brain. Rather than provide a comprehensive review of the now vast literature on neurotransmitter systems, the goalof this section is to highlight recent advances in the field.

Glutamate, as described in the chapter by Joseph Coyle,Michael Leski, and John Morrison, is the major excitatory neurotransmitter in the brain. During the past decade, nu-merous subtypes of glutamate transporters and glutamatereceptors have been identified and characterized. Each of these represents a potentially exciting target for new phar-macotherapeutic agents. Richard Olsen focuses on -ami-nobutyric acid (GABA), which serves as the major inhibi-tory neurotransmitter in the brain. GABA receptors and

GABA transporters are important targets for commonly used antianxiety, anticonvulsant, and antimanic medica-tions. Agents with improved specificity toward subtypes of these proteins may offer substantial benefit as future treat-ments.

The next several chapters focus on other small-moleculeneurotransmitters, which are used by relatively small frac-tions of neurons and generally serve to modulate the efficacy of glutamatergic and GABAergic synapses through diffuseprojections throughout the neuraxis. Such neurotransmit-

ters include the catecholamines, norepinephrine, and dopa-mine. Norepinephrine, covered in a chapter by Gary Aston-Jones, regulates mood, attention, and alertness and is a sub-strate for many commonly used antidepressants. Dopamine,discussed in a chapter by Anthony Grace, plays a criticalrole in movement and reward. Accordingly, it is involvedin movement disorders such as Parkinson’s disease and is acommon target for most drugs of abuse. The catechola-mines, along with serotonin and histamine, are often re-ferred to as monoamine neurotransmitters because they con-tain a single amine group. Serotonin is critically involved

in many brain functions and is the target for many com-monly used antidepressants. George Aghajanian and ElaineSanders-Bush focus on new findings about serotonin, in-cluding the discovery and characterization of 14 distinctserotonin receptors and their physiologic functions. Hista-mine is discussed by Jean-Charles Schwartz and Jean-MichelArrang. Although it has been known for some time thathistamine regulates alertness and sleep, new advances in his-tamine pharmacology have been made possible by the clon-ing of three distinct histamine receptors. Finally, acetylcho-line is often categorized along with the monoamines becauseit too is concentrated in discrete regions of the brain, many of which project diffusely to other parts of the brain. A 

major goal of neuropsychopharmacology research, as dis-cussed by Marina Picciotto, Meenakashi Alreja, andJ. David Jentsch, continues to be the development of drugsthat are selective for the many subtypes of cholinergic recep-tors expressed in the central nervous system.

Many other types of molecules serve neurotransmitterfunctions. Michael Williams covers the so-called purinergicneurotransmitters, which include adenosine and adenosinetriphosphate. The last few years have seen the cloning andcharacterization of a vast number of purinergic receptors,

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Neuropsychopharmacology: The Fifth Generation of Progress 2

with very different transmitter selectivities and functionalproperties. It is believed that selective ligands at these var-ious receptors may serve as novel drugs in the treatment of Parkinson’s disease, insomnia, anxiety, and pain, to name afew. Many types of polypeptides serve as neurotransmitters;these molecules are often termed neuropeptides. Significantrecent progress has been made in understanding the physio-

logic role and pharmacology of certain neuropeptides,which are discussed in several chapters in this section. GavanMcNally and Huda Akil cover the opioid peptides, includ-ing a newly discovered opioid-like peptide, termed or-phanin-FQ  or nociceptin, that promotes nociception. ErrolDe Souza and Dimitri Grigoriadis review recent advancesin the understanding of corticotropin-releasing factor, in-cluding the identification of two main types of receptorsfor corticotropin-releasing factor and other peptides (e.g.,urocortin) that serve as endogenous ligands for the recep-tors. Nadia Rupniak and Mark Kramer focus on substanceP and related neurokinins. Long known to be involved inthe regulation of pain perception, recent evidence suggeststhat antagonists at certain neurokinin receptors may be ef-fective antidepressants.

Despite the importance of neurotransmitter systems inneuropsychopharmacology, it must be emphasized that allthe proteins that account for neurotransmitter synthesis anddegradation, reuptake, and receptors, and for neuropeptidetransmitters themselves, represent a small fraction of theperhaps hundreds of thousands of proteins expressed in theadult brain. A central promise of neuropsychopharmacology as we enter a new century is to evaluate these vast arrays of other proteins as targets for entirely new families of pharma-cotherapeutic agents. Robert Malenka reviews what we

know about synaptic plasticity, the processes by which theefficacy of transmission at particular synapses is altered asa consequence of synaptic activity. Mark von Zastrow coversthe molecular and cellular mechanisms underlying receptorinternalization, a process in which the numbers of many and perhaps most types of neurotransmitter receptors onthe plasma membrane are regulated by synaptic activity.

David Russell and Ronald Duman offer an overview of neu-rotrophic factors and their signaling pathways. Neuro-trophic factors have long been recognized for their role inneural growth and differentiation during development, andwe now know they are also important for regulating thesurvival and plasticity of adult neurons. Eric Nestler andSteven Hyman review the intracellular signaling pathwaysby which neurotransmitters, acting on plasma membranereceptors, regulate gene expression. Such regulation repre-sents a prominent mechanism of long-term plasticity in thenervous system, including the actions of repeated exposureto psychotropic drugs (e.g., antidepressant action and drugaddiction). Pierre Magistretti and Bruce Ransom discuss therole of glial cells in the central nervous system—in particu-lar, their control of the energy metabolism in the brain.Finally, Fred Gage and Henriette van Praag summarize new knowledge of neurogenesis in the adult brain. The recentdiscovery that new neurons are born in certain regions of thebrain each day, and may be incorporated into the existingcircuitry within those regions, raises new hope for the treat-ment of neurodegenerative and other neuropsychiatric dis-orders. The subject matter of these last several chapters hasnot yet been exploited pharmacologically, but it is believedthat the next generation of progress will see new pharmaco-logic agents directed at these nontraditional mechanisms.