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

384 thence to adenylyl cyclase. α 1
Adrenergic receptors are coupled to
G q
, resulting in stimulation of phospholipase C, and are associated
predominantly with neurons. α 2
Adrenergic receptors are found on
glial and vascular elements, as well as on neurons; they couple to G i
and thence to inhibition of adenylyl cyclase activity. α 1
Receptors on
noradrenergic target neurons of the neocortex and thalamus respond to
NE with prazosin-sensitive, depolarizing responses due to decreases
in K + conductance. However, stimulation of α 1
receptors also can augment
cyclic AMP accumulation in neocortical slices in response to
concurrent stimulation of the G s
pathway, possibly an example of G q
-
G S
cross-talk involving Ca 2+ /calmodulin and/or PKC (Ostrom et al.,
2003). α 2
Adrenergic receptors are prominent on noradrenergic neurons,
where they presumably couple to G i
, inhibit adenylyl cyclase,
and mediate a hyperpolarizing response due to enhancement of an
inwardly rectifying K + channel. As in the periphery, α 2
receptors are
located presynaptically, where they function as inhibitory autoreceptors.
There is also evidence for post synaptic α 2
receptors that modulate
sympathetic tone. Effects mediated through α 2
receptors on blood
pressure have been reported. It is believed, e.g., that the antihypertensive
effects of the α 2
selective agonist clonidine are due to stimulation
of α 2
receptors in the lower brainstem.
SECTION II
NEUROPHARMACOLOGY
Epinephrine. Neurons in the CNS that contain epinephrine were recognized
only after the development of sensitive enzymatic assays and
immunocytochemical staining techniques for phenylethanolamine- N-
methyltransferase, the enzyme that converts NE into epinephrine.
Epinephrine- containing neurons are found in the medullary reticular
formation and make restricted connections to pontine and diencephalic
nuclei, eventually coursing as far rostrally as the paraventricular
nucleus of the thalamus. Their physiological properties have not been
unambiguously identified.
5-Hydroxytryptamine (Serotonin). In mammals, 5-HT containing
neurons are found in nine nuclei lying in or adjacent to the midline
(raphe) regions of the pons and upper brainstem. Cells receiving
cytochemically demonstrable 5-HT input, such as the suprachiasmatic
nucleus, ventrolateral geniculate body, amygdala, and hippocampus,
exhibit a uniform and dense investment of serotinergic
terminals.
Molecular biological approaches have led to identification of
14 distinct mammalian 5-HT receptor subtypes (Table 14–7). These
subtypes exhibit characteristic ligand- binding profiles, couple to different
intracellular signaling systems, exhibit subtype- specific distributions
within the CNS, and mediate distinct behavioral effects of
5-HT. Most 5-HT receptors are GPCRs coupling to a variety of
G- protein α subunits. The 5-HT 3
receptor, however, is a ligand- gated
ion channel with structural similarity to the α-subunit of the nicotinic
acetylcholine receptor. As seen with subtypes of glutamate receptors,
mRNA editing has also been observed for the 5-HT 2C
receptor
(Niswender et al., 2001); the resulting isoforms differ in agonist
affinity and distribution in the brain.
The family of 5-HT 1
receptors is composed of at least five
receptor subtypes (Table 14–7) that are linked to inhibition of adenylyl
cyclase activity or to regulation of K + or Ca 2+ channels. 5-HT 1A
Receptors are abundantly expressed on 5-HT neurons in the dorsal
raphe nucleus, where they are thought to be involved in temperature
regulation. They also are found in regions of the CNS associated
with mood and anxiety such as the hippocampus and amygdala.
Activation of 5-HT 1A
receptors opens an inwardly rectifying K +
conductance, which leads to hyperpolarization and neuronal inhibition.
These receptors can be activated by drugs including buspirone,
which is used for the treatment of anxiety and also used off- label for
panic disorders. In contrast, 5-HT 1D
receptors are activated by low
concentrations ofsumatriptan, which is currently prescribed for acute
management of migraine headaches (Chapters 13 and 34). The 5-
HT 2
receptor class has three subtypes: 5-HT 2A
, 5-HT 2B
, and 5-HT 2C
;
these receptors couple to pertussis toxin-insensitive G proteins (e.g.,
G q
and G 11
) and link to activation of PLC. Based on ligand binding
and mRNA in situ hybridization patterns, 5-HT 2A
receptors are
enriched in forebrain regions such as the neocortex and olfactory
tubercle, as well as in several nuclei arising from the brainstem. The
5-HT 2C
receptor, which is very similar in sequence and pharmacology
to the 5-HT 2A
receptor, is expressed abundantly in the choroid
plexus, where it may modulate cerebrospinal fluid production. Many
of the effects of antidepressants are thought to be a consequence of
increased stimulation of 5-HT receptors following inhibition of 5-HT
reuptake by SERT. On the other hand, inhibition of 5-HT 2c
receptors
may account for the increased weight gain associated with neuroleptics
used to treat schizophrenia.
5-HT 3
receptors function as ligand- gated ion channels; these
receptors were first recognized in the peripheral autonomic nervous
system. Within the CNS, they are expressed in the area postrema and
solitary tract nucleus, where they couple to potent depolarizing
responses that show rapid desensitization to continued 5-HT exposure.
Actions of 5-HT at central 5-HT 3
receptors can lead to emesis
and anti- nociceptive actions, and 5-HT 3
antagonists are beneficial
in the management of chemotherapy- induced emesis (Chapter 46).
Within the CNS, 5-HT 4
receptors occur on neurons within
the inferior and superior colliculi and in the hippocampus. Activation
of 5-HT 4
receptors stimulates the G s
-adenylyl cyclase-cyclic AMP
pathway. Other 5-HT receptors are less well studied in the CNS. The
5-HT 6
and 5-HT 7
receptors also couple to G s
; their affinity for
clozapine may contribute to its antipsychotic efficacy (Chapter 16).
The hallucinogen lysergic acid diethylamide (LSD) is a
potent partial agonist at 5-HT 2
receptors. When applied iontophoretically,
LSD inhibits the firing of raphe (5-HT) neurons. The
inhibitory effect of LSD on raphe neurons offers a plausible explanation
for its hallucinogenic effects, namely that these effects result
from depression of activity in a system that tonically inhibits visual
and other sensory inputs. However, typical LSD- induced behaviors
are seen in animals with destroyed raphe nuclei or after blockade of
the synthesis of 5-HT by p- chlorophenylalanine (Aghajanian and
Marek, 1999); Nichols, 2004).
Histamine. Histamine and antihistamines have long been known to
produce significant effects on animal behavior. Biochemical detection
of histamine synthesis by neurons and direct cytochemical localization
of these neurons have defined a histaminergic system in the
CNS. Most of these neurons are located in the ventral posterior hypothalamus;
they give rise to long ascending and descending tracts that
are typical of the patterns characteristic of other aminergic systems.
Based on the presumptive central effects of histamine antagonists,
the histaminergic system is thought to affect arousal, body temperature,
and vascular dynamics. Four subtypes of histamine receptors have
been described; all are GPCRs (Figure 14–15). H 1
receptors, the most
prominent, are located on glia and vessels as well as on neurons and
act to mobilize Ca 2+ in receptive cells through the G q
-PLC pathway.