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Drugs acting in the central nervous system (CNS) were among the
first to be discovered by primitive 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.
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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 (e.g., 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 now make
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.
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First, it is clear that 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. Second, drugs are 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. As will be described below,
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. Third, 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 on 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.
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This chapter provides an introduction to the functional organization
of the CNS and its synaptic transmitters as a basis for understanding
the actions of the drugs described in the following chapters.
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Most drugs that act on the CNS appear to do so by changing ion
flow through transmembrane channels of nerve cells. The membranes
of nerve cells contain two types of ion channels defined on the
basis of the mechanisms that control their gating (opening and closing)
as voltage-gated and ligand-gated channels (Figure 12–1a
and b). Voltage-gated channels respond to changes in the membrane
potential of the cell. In nerve cells, voltage-gated sodium channels
are concentrated near and on the axon and are responsible for the
action potential which transmits the signal from cell body to nerve
terminal. There are also many types of voltage-sensitive calcium
and potassium channels on the cell body, dendrites, and initial
segment, which act on a slower time scale and modulate ...