DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

the cytological characteristics of highly active secretory cells with
large nuclei: large amounts of smooth and rough endoplasmic reticulum;
and frequent clusters of specialized smooth endoplasmic reticulum
(Golgi complex), in which secretory products of the cell are
packaged into membrane- bound organelles for transport from
the perikaryon to the axon or dendrites. Neurons and their cellular
Apical
dendrite
Basal dendrite
Presynaptic
cell
Synaptic
cleft
Postsynaptic
cells
Perikaryon
Nucleus
Excitatory
terminal
Axon
Inhibitory
terminal
Postsynaptic
dendrite
Myelin sheath
Node of Ranvier
Presynaptic
terminal
Excitatory
terminal
Inhibitory
terminal
Figure 14–1. Principal features of a typical vertebrate neuron.
Dendrites, including apical dendrites, receive synapses from
presynaptic terminals. The cell body contains the nucleus and is
the site of transcription and translation. The axon carries information
from the perikaryon to the presynaptic terminals, which
form synapses with the dendrites of other neurons. Axo- somatic
synapses also occur. Many CNS-active pharmacological agents
act at the presynaptic and postsynaptic membranes of the synaptic
clefts, and at areas of transmitter storage near the synapses.
(Adapted with permission from Kandel ER, Schwartz JH, Jessell
TM (eds). Principles of Neuroscience, 4th ed. New York:
McGraw-Hill, 2000, p 22. Copyright © 2000 by The McGraw-
Hill Companies, Inc. All rights reserved.)
extensions are rich in microtubules, which support the complex cellular
structure and assist in the reciprocal transport of essential macromolecules
and organelles between the cell body and distant axon or
dendrites. The sites of interneuronal communication in the CNS are
termed synapses Although synapses are functionally analogous to
“junctions” in the somatic motor and autonomic nervous systems,
central junctions contain an array of specific proteins presumed to be
the active zone for transmitter release and response (Husi et al., 2000).
Like peripheral “junctions,” central synapses are denoted by accumulations
of tiny (50-150 nm) synaptic vesicles. The proteins of these
vesicles have specific roles in transmitter storage, vesicle docking
onto presynaptic membranes, voltage- and Ca 2+ -dependent secretion,
and recycling and restorage of released transmitter (Jahn, 2004,
Murthy and Camilli, 2003; Nestler et al., 2009).
Support Cells. Neurons are not the only cells in the CNS. According
to most estimates, neurons are outnumbered, perhaps by an order of
magnitude, by various types of support cells. These include
macroglia, microglia, the cells of the vascular elements comprising
the intracerebral vasculature, the cerebrospinal fluid-forming cells
of the choroid plexus found within the intracerebral ventricular system,
and the meninges, which cover the surface of the brain and
comprise the cerebrospinal fluid-containing envelope. Macroglia
are the most abundant support cells; some are categorized as astrocytes
(cells interposed between the vasculature and the neurons,
often surrounding individual compartments of synaptic complexes).
Astrocytes play a variety of metabolic support roles including furnishing
energy intermediates and supplementary removal of neurotransmitters
following release (Pellerin and Magistretti, 2003). The
oligodendroglia, a second prominent category of macroglia, are
myelin- producing cells. Myelin, made up of multiple layers of compacted
membranes, insulate segments of axons bioelectrically and
permit non- decremental propagation of action potentials. Microglia
are relatively uncharacterized support cells believed to be of mesodermal
origin and related to the macrophage/monocyte lineage
(Carson, 2002). Some microglia reside within the brain, while additional
cells of this class may be recruited to the brain during periods
of inflammation following either microbial infection or brain
injury. The response of the brain to inflammation differs strikingly
from that of other tissues (Glass et al., 2010).
Blood-Brain Barrier. Apart from exceptional instances in which drugs
are introduced directly into the CNS, the concentration of an agent
in the blood after oral or parenteral administration may differ substantially
from its concentration in the brain. The blood- brain barrier
(BBB) is an important boundary between the periphery and the
CNS that forms a permeability barrier to the passive diffusion of
substances from the bloodstream into the CNS. Evidence for the
existence of the BBB is provided by the greatly diminished rate of
access of many chemicals from plasma to the brain and the localization
of several drug export systems in the cells that constitute the
BBB (Chapter 5). An exception exists for lipophilic molecules,
which diffuse fairly freely across the BBB and accumulate in the
brain. This barrier is nonexistent in the peripheral nervous system,
and is much less prominent in the hypothalamus and in several small,
specialized organs (the circumventricular organs) lining the third and
fourth ventricles of the brain: the median eminence, area postrema,
pineal gland, subfornical organ, and subcommissural organ. While
the BBB may impose limitations on the diffusion of macromolecules
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CHAPTER 14
NEUROTRANSMISSION AND THE CENTRAL NERVOUS SYSTEM