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

Table 14–7
5-HT Receptors in the CNS
RECEPTOR AGONISTS ANTAGONISTS TRANSDUCER LOCALIZATION
5HT 1A
8-OH-DPAT, buspirone, WAY 100135, G i
hippocampus, septum,
lisuride NAD 299 amygdala, dorsal raphe, cortex
5HT 1B
sumatriptan, dihydroergota- GR-127935, G i
substantia nigra, basal ganglia
mine, oxymetazoline ketanserin
5HT 1D
sumatriptan, GR127935, methysergide, G i
substantia nigra, striatum,
dihydroergotamine, L-772405 nucleus accumbens,
oxymetazoline
hippocampus
5HT 1E
eletriptan, ORG-5222 G i
5HT 1F
LY334370, naratriptan methysergide G i
dorsal raphe, hippocampus,
cortex
5HT 2A
DMT, DOB, DOI, amoxapine, chlorpro- G q
cortex, olfactory tubercle,
ergotamine, LSD mazine, ketanserin claustrum
5HT 2B
cabergoline, 5-MeOT clozapine, lisuride, G q
not located in the brain
LY53857
5HT 2C
ergotamine, DOI, lisuride amoxepine, fluoxetine, G q
basal ganglia, choroid plexus,
mesulergine
substantia nigra
5HT 3
ondansetron, granisetron Ligand-gated spinal cord, cortex,
channel hippocampus, brainstem nuclei
5HT 4
cisapride, metoclopramide GR113808, G s
hippocampus, nucleus
SB204070
accumbens
striatum, substantia nigra
5HT 5A
methiothepin G s
cortex, hippocampus,
cerebellum
5HT 5B
ergotamine, methiothepin ?G i
habenula, hippocampal CA1
5HT 6
bromocriptine methiothepin, clozapine, G s
striatum, olfactory tubercle,
amiltriptyline
cortex, hippocampus
5HT 7
pergolide, 5-MeOT methiothepin, clozapine, G s
hypothalamus, thalamus, cortex,
metergoline
suprachiasmatic nucleus
8-OH-DPAT, 8-hydroxy-N,N-dipropyl-2-aminotetralin; DOB, 2,5-Dimethoxy-4-bromoamphetamine; DOI, (±)-2,5-dimethoxy-4-iodoamphetamine;
DMT, N,N-dimethyltryptamine; 5-MeOT, 2-(5-methoxy-1H-indol-3-yl) ethanamine; LSD, Lysergic acid diethylamide.
H 2
receptors couple via G S
to the activation of adenylyl
cyclase. H 3
receptors, which have the greatest sensitivity to histamine,
are localized primarily in basal ganglia and olfactory regions
in rat brain and act through G i
to inhibit adenylyl cyclase.
Consequences of H 3
receptor activation remain unresolved but may
include reduced Ca 2+ influx and feedback inhibition of transmitter
synthesis and release (Chapter 32). H 4
receptors are expressed on
cells of hematopoietic origin: eosinophils, T cells, mast cells,
basophils, and dendritic cells. H 4
receptors appear to couple to G i
and G q
and are postulated to play a role in inflammation and chemotaxis
(Thurmond et al., 2004). Unlike the monoamines and amino
acid transmitters, there does not appear to be an active process for
reuptake of histamine after its release. Inhibition of H 1
receptors
causes drowsiness, an effect that limits the use of H 1
antagonists to
treat allergic reactions. The development of H 1
antagonists with low
CNS penetration has reduced the incidence of these side effects.
Peptides. The discovery during the 1980s of numerous novel
peptides in the CNS, each capable of regulating neuronal function,
produced considerable excitement and an imposing catalog
of substances as well as potential medications based upon interaction
with peptide receptors (Darlison and Richter, 1999;
Hökfelt et al., 2003). In addition, certain peptides previously
thought to be restricted to the GI tract or to endocrine glands
have been found in the CNS. Most of these peptides bind to
GPCRs. Many of the effects are modulatory rather than causing
direct excitation or inhibition. Myriad peptide neurotransmitters
or neuromodulators have been described (Table 14–8). Relatively
detailed neuronal maps are available that identify immunoreactivity
to peptide- specific antisera. While some CNS peptides
may function on their own, most are now thought to act primarily
in concert with co-existing transmitters, both amines and
amino acids.