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

somatic motor and autonomic nervous systems. In the 1960s, serotonin
(5-hydroxy tryptamine, 5-HT), epinephrine, and dopamine
(DA) were investigated as potential CNS transmitters; although histochemical,
biochemical, and pharmacological data yielded results
consistent with their roles as neurotransmitters, not all criteria were
fully satisfied. In the early 1970s, the availability of selective and
potent antagonists of gamma- aminobutyric acid (GABA), glycine,
and glutamate, all known to be enriched in brain, led to their general
acceptance as transmitters. At about the same time, a search for
hypothalamic- hypophyseal factors led to an improvement in the
technology to isolate, purify, sequence, and synthetically prepare a
growing family of neuropeptides (Hökfelt et al., 2003). These
advances, coupled with the widespread application of immunohistochemistry,
strongly supported the view that neuropeptides act as
transmitters. Adaptation of bioassay technology developed in studies
of pituitary secretions, and later, competitive binding assays with
radioactive ligands, gave rise to the discovery of endogenous peptide
ligands for drugs acting at opiate receptors (Chapter 18). The
search for endogenous factors whose receptors constituted drug
binding sites later was extended to the benzodiazepine receptors and
to a series of endogenous lipid amides as the natural ligands for
cannabinoid receptors, termed the endocannabinoids (Piomelli,
2003).
Identification of Central Transmitters. An essential step in understanding
the functional properties of neurotransmitters within the
context of the circuitry of the brain is to identify substances that are
transmitters at specific interneuronal connections. The criteria for
the rigorous identification of central transmitters require the same
data set used to establish the transmitters of the autonomic nervous
system (Chapter 8).
1. The transmitter must be shown to be present in the presynaptic
terminals of the synapse and in the neurons from which those
presynaptic terminals arise.
2. The transmitter must be released from the presynaptic nerve concomitantly
with presynaptic nerve activity.
3. When applied experimentally to target cells, the effects of the
putative transmitter must be identical to the effects of stimulating
the presynaptic pathway.
4. Specific pharmacological agonists and antagonists should mimic
and antagonize, respectively, the measured functions of the putative
transmitter with appropriate affinities and order of potency.
Other studies, especially those implicating peptides
as neurotransmitters, suggest that many brain and
spinal- cord terminals contain more than one transmitter
substance (Hökfelt et al., 2003). Substances that coexist
in a given synapse are presumed to be released
together. In some systems release has been shown to be
frequency- dependent, with higher- frequency bursts
mediating peptide release. Co-existing substances may
either act jointly on the postsynaptic membrane, or may
act presynaptically to affect release of transmitter from
the presynaptic terminal. Clearly, if more than one substance
transmits information, no single agonist or
antagonist would be expected to faithfully mimic or
fully antagonize activation of a given presynaptic element.
Co- storage and co- release of ATP and NE are an
example (Burnstock, 1995). In addition to being
released as a co- transmitter with other biogenic amines,
purines including ATP and adenosine have been shown
to mediate diverse effects through interactions with distinct
families of cell- surface purinergic receptors
(Ralevic and Burnstock, 1998).
Ion Channels. The electrical excitability of neurons is
achieved through modification of ion channels in neuronal
plasma membranes. We now understand in considerable
detail how three major cations, Na + , K + and
Ca 2+ , as well as Cl − anions, are regulated in their flow
through highly discriminative ion channels (Figures
14–2 and 14–3). The relatively high extracellular concentration
of Na + (~140 mM) compared to its concentration
intracellularly (~14 mM) means that increases
in permeability to Na + causes depolarization, ultimately
leading to the generation of action potentials. In contrast,
the intracellular concentration of K + is relatively
high (~120 mM, vs. 4 mM outside the cell) and
increased permeability to K + results in hyperpolarization.
Changes in the concentration of intracellular Ca 2+
(100 nM l 1 μM) affects multiple processes in the cell
and are critical in the release of neurotransmitters.
Cellular homeostatic mechanisms (Na + ,K + -ATPase,
Na + ,Ca 2+ exchanger, Ca 2+ -ATPases, etc.) maintain the
basal concentrations of these ions, as does intracellular
sequestration of releasable Ca 2+ in storage vesicles.
The Cl − gradient across the plasma membrane
(~116 mM outside vs 20 mM inside the cell) explains
the fact that activation of Cl − channels causes an
inhibitory postsynaptic potential (IPSP) that dampens
neuronal excitability and inactivation of these channels
can lead to hyperexcitability. There are three distinct
types of Cl − channel (Figure 14-3). Ligand- gated channels
are linked to inhibitory transmitters including
GABA and glycine. ClC channels, of which nine subtypes
have been cloned, affect Cl − flux, membrane
potential, and the pH of intracellular vesicles. Cystic
fibrosis transmembrane conductance regulated (CFTR)
channels bind ATP and are regulated by phosphorylation
of serine residues.
Voltage- dependent ion channels provide for rapid
changes in ion permeability along axons and within
dendrites and for excitation- secretion coupling that
releases neurotransmitters from presynaptic sites
(Catterall, 1993; Catterall and Epstein, 1992). The intrinsic
membrane- embedded domains of the α-subunit of
Na + and Ca 2+ channels are envisioned as four tandem
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CHAPTER 14
NEUROTRANSMISSION AND THE CENTRAL NERVOUS SYSTEM