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

Table 13–3
Some Actions of 5-HT in the Gastrointestinal Tract
SITE RESPONSE RECEPTOR
Enterochromaffin cells Release of 5-HT 5-HT 3
Inhibition of 5-HT release 5-HT 4
Enteric ganglion cells Release of ACh 5-HT 4
(presynaptic) Inhibition of ACh release 5-HT 1P
, 5-HT 1A
Enteric ganglion cells Fast depolarization 5-HT 3
(postsynaptic) Slow depolarization 5-HT 1P
Smooth muscle, intestinal Contraction 5-HT 2A
Smooth muscle, stomach fundus Contraction 5-HT 2B
Smooth muscle, esophagus Contraction 5-HT 4
ACh, acetylcholine.
contacts. 5-HT released at nonsynaptic varicosities is thought to diffuse
to outlying targets, rather than acting on discrete synaptic targets.
Such non-synaptic release with ensuing widespread effects is
consistent with the idea that 5-HT acts as a neuromodulator as well
as a neurotransmitter (Chapter 14).
Serotonergic nerve terminals contain the proteins needed to
synthesize 5-HT from L-tryptophan (Figure 13–2). Newly formed
5-HT is rapidly accumulated in synaptic vesicles (through VMAT2),
where it is protected from MAO. 5-HT released by nerve-impulse
flow is reaccumulated into the pre-synaptic terminal by the 5-HT
transporter, SERT (SLC6A4; Chapter 5). Pre-synaptic reuptake is a
highly efficient mechanism for terminating the action of 5-HT
released by nerve-impulse flow. MAO localized in postsynaptic elements
and surrounding cells rapidly inactivates 5-HT that escapes
neuronal reuptake and storage.
Electrophysiology. The physiological consequences of 5-HT release
vary with the brain area and the neuronal element involved, as well
as with the population of 5-HT receptor subtype(s) expressed
(Bockaert et al., 2006). 5-HT has direct excitatory and inhibitory
actions (Table 13–4), which may occur in the same preparation, but
with distinct temporal patterns. For example, in hippocampal neurons,
Table 13–4
Electrophysiological Effects of 5-HT Receptors
SUBTYPE
RESPONSE
5-HT 1A,B
Increase K + conductance
Hyperpolarization
5-HT 2A
/5-HT 2C
Decrease K + conductance
Slow depolarization
5-HT 3
Gating of Na + , K +
Fast depolarization
5-HT 4
Decrease K + conductance
Slow depolarization
5-HT elicits hyperpolarization mediated by 5-HT 1A
receptors followed
by a slow depolarization mediated by 5-HT 4
receptors.
5-HT 1A
receptor–induced membrane hyperpolarization and
reduction in input resistance results from an increase in K + conductance.
These ionic effects, which are blocked by pertussis toxin, are
independent of cAMP, suggesting that 5-HT 1A
receptors couple, by
means of G βγ
subunits, to receptor-operated K + channels (Andrade et
al., 1986). Somatodendritic 5-HT 1A
receptors on raphe cells also
elicit a K + -dependent hyperpolarization. The G protein involved is
pertussis toxin–sensitive, but the K + current apparently is different
from the current elicited at postsynaptic 5-HT 1A
receptors in the hippocampus.
The precise signaling mechanism involved in inhibition
of neurotransmitter release by the 5-HT 1B/1D
autoreceptor at synaptic
terminals is not known, although inhibition of voltage-gated Ca ++
channels likely contributes.
Slow depolarization induced by 5-HT 2A
receptor activation
in areas such as the prefrontal cortex and nucleus accumbens
involves a decrease in K + conductance. A second, distinct mechanism
involving Ca 2+ -activated membrane currents enhances neuronal
excitability and potentiates the response to excitatory signals such as
glutamate. The role of intracellular signaling cascades in these physiological
actions of 5-HT 2A
receptors has not been clearly defined.
In areas where 5-HT 1
and 5-HT 2A
receptors co-exist, the effect of
5-HT may reflect a combination of the two opposing responses: a
prominent 5-HT 1
receptor–mediated hyperpolarization and an
opposing 5-HT 2A
receptor–mediated depolarization. When 5-HT 2A
receptors are blocked, hyperpolarization is enhanced. In many cortical
areas, 5-HT 2A
receptors are localized on both GABAergic
interneurons and pyramidal cells. Activation of interneurons
enhances GABA (γ-aminobutyric acid) release, which secondarily
slows the firing rate of pyramidal cells. Thus, there is the potential
for the 5-HT 2A
receptor to differentially regulate cortical pyramidal
cells, depending on the specific target cells (interneurons versus
pyramidal cells). Activation of 5-HT 2C
receptors has been shown to
depress a K + current, an effect that may contribute to the excitatory
response. The 5-HT 4
receptor, which is coupled to activation of
adenylyl cyclase, also elicits a slow neuronal depolarization mediated
by a decrease in K + conductance. It is not clear why two distinct