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Drugs acting in the central nervous system (CNS) were among the first to be discovered by humans and are still the most widely used group of pharmacologic agents. In addition to their use in therapy, many drugs acting on the CNS are used without prescription to increase one’s sense of well-being.

The mechanisms by which various drugs act in the CNS have not always been clearly understood. Since the causes of many of the conditions for which these drugs are used (eg, schizophrenia, anxiety) are themselves poorly understood, it is not surprising that in the past much of CNS pharmacology has been purely descriptive. However, dramatic advances in the methodology of CNS pharmacology have made it possible to study the action of a drug on individual cells and even on single ion channels within synapses. This information has provided the basis for several major developments in studies of the CNS.

Nearly all drugs with CNS effects act on specific receptors that modulate synaptic transmission, either directly by affecting the receptors themselves or indirectly through various second-messenger coupling systems, ion channels, or other mechanisms. Drugs are also among the most important tools for studying all aspects of CNS physiology, from the mechanism of convulsions to the laying down of long-term memory. Synthetic agonists that mimic natural transmitters (and in many cases are more selective than the endogenous substances) and antagonists are extremely useful in such studies. Unraveling the actions of drugs with known clinical efficacy has led to some of the most fruitful hypotheses regarding the mechanisms of disease. For example, information about the action of antipsychotic drugs on dopamine receptors has provided the basis for important hypotheses regarding the pathophysiology of schizophrenia. Studies of the effects of a variety of agonists and antagonists on gamma-aminobutyric acid (GABA) receptors have resulted in new concepts pertaining to the pathophysiology of several diseases, including anxiety and epilepsy.

This chapter provides an introduction to the functional organization of the CNS and synaptic transmitters as a basis for understanding the actions of the drugs described in the following chapters.


Most drugs that act on the CNS appear to do so by changing ion flow through transmembrane channels of nerve cells. Neuronal membranes contain two types of ion channels: voltage gated and ligand gated. These channels are defined on the basis of the mechanisms that control their gating (opening and closing). Voltage-gated (or, voltage-sensitive) channels open and close in response to changes in membrane potential (Figure 12-1A). In neurons, voltage-gated sodium channels are concentrated at the axon initial segment. Activation of voltage-gated sodium channels is responsible for the fast action potential that transmits the electrical signal from the cell body to the axon terminal. There are also many types of voltage-sensitive calcium and potassium channels on the cell body, dendrites, and initial ...

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