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CHAPTER 21 Introduction to the Pharmacology of CNS Drugs 369

using an amino acid transporter, whereas dopamine cannot cross to changes in the membrane potential of the cell. The voltage-gated
the BBB. Thus, the orally administered drug l-DOPA, but not sodium channel described in Chapter 14 for the heart is an example
dopamine, can be used to boost CNS dopamine levels in the treat- of this type of channel. In nerve cells, these channels are highly con-
ment of Parkinson’s disease. Some parts of the brain, the so-called centrated on the initial segment of the axon (Figure 21–1), which
circumventricular organs, lack a normal BBB. These include regions initiates the all-or-nothing fast action potential, and along the
that sample the blood, such as the area postrema vomiting center, length of the axon where they propagate the action potential to the
and regions that secrete neurohormones into the circulation. nerve terminal. There are also many types of voltage-sensitive cal-
cium and potassium channels on the cell body, dendrites, and initial
segment, which act on a much slower time scale and modulate the
ION CHANNELS & NEUROTRANSMITTER rate at which the neuron discharges. For example, some types of
RECEPTORS potassium channels opened by depolarization of the cell result in
slowing of further depolarization and act as a brake to limit further
The membranes of neurons contain two types of channels action potential discharge. Plant and animal toxins that target vari-
defined on the basis of the mechanisms controlling their gat- ous voltage-gated ion channels have been invaluable for studying
ing (opening and closing): voltage-gated and ligand-gated the functions of these channels (see Box: Natural Toxins: Tools for
channels (Figure 21–2A and B). Voltage-gated channels respond Characterizing Ion Channels; Table 21–1).

A B C
Voltage-gated Ligand-gated Metabotropic
ion channel ion channel receptor

++
– –
α
β γ

D Membrane-delimited regulation of ion channels
by metabotropic receptors

++
– –
α
β γ
Receptor
G protein

E Diffusible second messenger-mediated regulation
of ion channels by metabotropic receptors

++
– –
α
β γ
Receptor G protein Enzyme PO 4

Diffusible messenger
Kinase
FIGURE 21–2 Types of ion channels and neurotransmitter receptors in the CNS. A shows a voltage-gated channel in which a voltage sen-
sor component of the protein controls the gating (broken arrow) of the channel. B shows a ligand-gated channel in which the binding of the
neurotransmitter to the ionotropic channel receptor controls the gating (broken arrow) of the channel. C shows a G protein-coupled (metabo-
tropic) receptor, which, when bound, activates a heterotrimeric G protein. D and E show two ways metabotropic receptors can regulate ion
channels. The activated G protein can interact directly to modulate an ion channel (D) or the G protein can activate an enzyme that generates a
diffusible second messenger (E), eg, cAMP, which can interact with the ion channel or can activate a kinase that phosphorylates and modulates
a channel.