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The brain is a complex assembly of interacting cells that regulate many of life’s activities in a dynamic fashion, generally through a communication process termed neurotransmission. Because the CNS drives so many physiological responses, it stands to reason that centrally acting drugs are invaluable for a plethora of conditions. CNS-acting drugs are used not only to treat anxiety, depression, mania, and schizophrenia, but also to target diverse pathophysiological conditions such as pain, fever, movement disorders, insomnia, eating disorders, nausea, vomiting, and migraine. However, as the CNS dictates such diverse physiology, the recreational use of some CNS-acting drugs can and does lead to physical dependence (see Chapter 28) with enormous societal impacts. The sheer breadth of physiological and pathological activities mediated by drug molecules acting in the CNS makes this class of therapeutics both wide-ranging and important.

The identification of CNS targets and the development of drug molecules for those targets present extraordinary scientific challenges. While years of investigation have begun to dissect the cellular and molecular bases for many aspects of neuronal signaling, complete understanding of the functions of the human brain remains in its infancy. Complicating the effort is the fact that a CNS-active drug may act at multiple sites with disparate and even opposing effects. Furthermore, many CNS disorders likely involve multiple brain regions and pathways, which can frustrate efforts that focus on a single therapeutic agent.

The pharmacology of CNS-acting drugs is primarily driven by two broad and overlapping goals:

  • To develop/use drugs as biochemical probes to both elucidate and manipulate the normal CNS; and

  • To develop drugs to correct pathophysiological changes in the abnormal CNS.

Modern advances in molecular biology, neurophysiology, structural biology, epigenetics, biomarkers, immunology, and an array of other fields have facilitated both our understanding of the brain and the development of an ever-expanding repertoire of drugs that can selectively treat diseases of the CNS. An important goal in drug discovery is to determine receptor structure at the atomic level and understand how neurotransmitters and drug molecules interact with receptors to stimulate or inhibit receptor-mediated signaling. This has spurred the use of complex techniques such as x-ray crystallography and cryo-electron microscopy to solve receptor structures to a high degree of accuracy, followed by computer-aided molecular dynamic simulations and modeling as essential components to understand how neurotransmitters and drug molecules affect signaling. As more atomic level structures of receptors, transporters, ion channels, and other relevant drug targets are elucidated, such structural biology techniques will likely become even more prevalent in drug discovery and development.

This chapter introduces fundamental principles and guidelines for the comprehensive study of drugs that affect the CNS. Specific therapeutic approaches to neurological and psychiatric disorders are discussed in subsequent chapters. For further detail, see specialized texts such as Sibley et al. (2007), Brady et al. (2012), Nestler et al. (2020), and Kandel et al. ...

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