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

Ca 2+ channels, arachidonic acid levels (via PLA 2
), extracellular
signal-regulated kinase, and IP 3
-sensitive Ca 2+ stores and L-type
Ca 2+ channels. The D 2
receptor has the ability to activate G i/o
proteins
independent of agonist, a property known as constitutive activity
(Strange, 1999). As with the D 1
receptor, the D 2
DA receptor can
also form stable complexes with other proteins, including the AMPA
receptor, Na + ,K + -ATPase, calnexin, and the DA transporter
(Hazelwood et al., 2009).
D 3
Receptors. The D 3
receptor contains five introns. It
is less abundant than the D 2
receptor, and is only
expressed in the limbic regions of the brain. The highest
levels of the D 3
receptor are found in the islands
of Calleja, nucleus accumbens, substantia nigra pars
compacta, and ventral tegmental area. Splice variants
of the human D 3
receptor exist, but do not code functional
protein products. The D 3
receptor signals through
pertussis toxin-sensitive G i/o
proteins, though not as
effectively as the D 2
receptor.
D 4
Receptors. The D 4
receptor contains three introns. It
is abundantly expressed in the retina, and is also found
in the hypothalamus, prefrontal cortex, amygdala, hippocampus,
and pituitary. D 4
is the most polymorphic of
the DA receptors, containing a variable number of tandem
repeats (VNTR) within the third intracellular loop
(Van Tol et al., 1992). In humans, the four-repeat variant
is the most common. There are several single
nucleotide polymorphisms (SNPs) in the D 4
receptor,
one of which results in dramatic alterations in ligand
binding (Liu et al., 1996). There are associations
between a seven-repeat D 4
VNTR variant and attention
deficit hyperactivity disorder (see below).
D 5
Receptors. The D 5
gene, like the D 1
gene, is intronless.
Pseudogenes of the D 5
receptor yield protein products
with no known functional role. Like the D 4
receptor, the D 5
gene is polymorphic; several functional
SNPs within the transmembrane domains alter binding
properties of numerous ligands, including DA
(Cravchik and Gejman, 1999). The D 5
receptor couples
primarily to G s
and exhibits ligand-independent constitutive
activity. The D 5
receptor also activates G z
, but the
functional consequences of this interaction remain
unclear. The D 5
receptor is most highly expressed in the
substantia nigra, hypothalamus, striatum, cerebral cortex,
nucleus accumbens, and olfactory tubercle.
Actions of DA on Physiologic Systems
Heart and Vasculature. At low concentrations, circulating DA primarily
stimulates vascular D 1
receptors, causing vasodilation and
reducing cardiac afterload. The net result is a decrease in blood pressure
and an increase in cardiac contractility. As circulating DA concentrations
rise, DA is able to activate β adrenergic receptors to
further increase cardiac contractility. At very high concentrations,
circulating DA activates α adrenergic receptors in the vasculature,
thereby causing vasoconstriction; thus, high concentrations of DA
increase blood pressure. Clinically, DA administration is used to treat
severe congestive heart failure, sepsis, or cardiogenic shock. It is
only administered intravenously and is not considered a long-term
treatment.
Kidney. DA is a paracrine/autocrine transmitter in the kidney and
binds to both D1-like and D2-like receptors. Renal DA primarily
serves to increase natriuresis, though it can also increase renal blood
flow and glomerular filtration. Under basal sodium conditions, DA
regulates Na + excretion by inhibiting the activity of various Na + transporters,
including the apical Na + -H + exchanger and the basolateral
Na + ,K + -ATPase. DA can also influence the renin–angiotensin system:
activation of D 1
receptors increases renin secretion, whereas DA,
acting on D 3
receptors, reduces renin secretion. Abnormalities in the
DA system and its receptors have been implicated in human hypertension
(Jose et al., 1998). In some cases, poor regulation of natriuresis
occurs due to constitutive desensitization of the D 1
receptor
and uncoupling of the receptor from the signal transduction machinery.
Although multiple polymorphisms exist in the DA receptors,
none has been consistently associated with human hypertension.
Pituitary Gland. DA is the primary regulator of prolactin secretion
from the pituitary gland. DA is released from the hypothalamus into
the hypophyseal portal blood supply, directly infusing lactotrophs
in the pituitary with high concentrations of DA. DA acts on lactotroph
D 2S
and D 2L
receptors to decrease prolactin secretion
(Chapter 38).
Catecholamine Release. Both D 1
and D 2
receptors modulate the
release of NE and epinephrine. The D 2
receptor provides tonic inhibition
of epinephrine release from chromaffin cells of the adrenal
medulla, and of norepinephrine release from sympathetic nerve terminals.
In contrast, the D 1
receptor responds to high-frequency DA
stimulation to promote the release of catecholamines from the adrenal
medulla. This D 1
receptor stimulation is thought to contribute to
the “fight or flight” response.
CNS. DA in the brain projects via four main pathways (Figure 13–9)—
mesolimbic, mesocortical, nigrostriatal and tuberoinfundibular—
to regulate a variety of functions. The physiological processes
under dopaminergic control include reward, emotion, cognition,
memory, and motor activity. Dysregulation of the dopaminergic
system is critical in a number of disease states, including Parkinson
disease, Tourette’s syndrome, bipolar depression, schizophrenia,
attention-deficit hyperactivity disorder, and addiction/substance
abuse.
The mesolimbic pathway is associated with reward and, less
so, with learned behaviors. Dysfunction in this pathway is associated
with addiction, schizophrenia, and psychoses (including bipolar
depression), and learning deficits. The mesocortical pathway is
important for “higher-order” cognitive functions including motivation,
reward, emotion, and impulse control. It is also implicated in
psychoses, including schizophrenia, and in attention-deficit hyperactivity
disorder. The mesolimbic and mesocortical pathways are sometimes
grouped together as mesolimbocortical. The nigrostriatal
pathway is a key regulator of movement (Chapter 22). Impairments
in this pathway are evident in Parkinson disease and underlie
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CHAPTER 13
5-HYDROXYTRYPTAMINE (SEROTONIN) AND DOPAMINE