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

Table 14–4
Subtypes of Muscarinic Receptors in the CNS
SUBTYPE SELECTIVE ANTAGONISTS G-PROTEIN FAMILY LOCALIZATION IN THE CNS
M 1
pirenzepine, telenzepine, 4-DAMP G q
cortex, hippocampus, striatum
M 2
AF-Dx-384, methoctramine G i
basal forebrain, thalamus
M 3
darifenacin, 4-DAMP G q
cortex, hippocampus, thalamus
M 4
AF-Dx384, 4-DAMP G i
cortex, hippocampus, striatum
M 5
4-DAMP G q
substantia nigra
Non-selective agonists include carbachol, pilocarpine, and oxotremorine. Non-selective antagonists include atropine and scopolamine. McN-A-3436
is a selective agonist at the M 1
receptor. 4-DAMP, 4-diphenylacetoxy-N-methylpiperidine.
In most regions of the CNS, the effects of ACh result from
interaction with a mixture of nicotinic and muscarinic receptors.
Nicotinic ACh receptors are found in autonomic ganglia, the adrenal
gland, and in the CNS. Activation by ACh results in a rapid increase
in the influx of Na + and Ca 2+ and subsequent depolarization.
Nicotinic cholinergic receptors appear to desensitize rapidly. The
receptors are composed by five heterologous subunits arranged
around a central pore (see Figure 14–4). A total of 17 subunits,
including 10 α, 4 β, as well as δ, ε, and γ subunits, have been identified.
The nicotinic receptor at the neuromuscular junction has the
composition α 2
βεδ. However, some α subunits, including α7, α8,
and α9, can form functional homo- oligomers. For additional information
on neuronal nicotinic ACh receptors, see Chapter 11.
There are five subtypes of muscarinic receptors, all of which
are expressed in the brain. M 1
,M 3
, and M 5
couple to G q
while the
M 2
and M 4
receptors couple to G i
(Table 14–4). Several presumptive
cholinergic pathways have been proposed in addition to that of
the motoneuron-Renshaw cell.
Catecholamines. The brain contains separate neuronal systems that
utilize three different catecholamines—dopamine, norepinephrine, and
epinephrine. Each system is anatomically distinct and serves separate,
functional roles within its field of innervation (Nestler et al., 2009)
Dopamine. Although DA was originally regarded only as a precursor
of NE, assays of distinct regions of the CNS revealed that the distributions
of DA and NE are markedly different. In fact, more than half
the CNS content of catecholamine is DA and extremely large
amounts of DA are found in the basal ganglia. There are three major
DA-containing pathways in the CNS (Figure 14–14):
• the nigrostriatal pathway
• the mesocortical pathway, where neurons in the ventral tegmental
nucleus project to a variety of midbrain structures and to the
frontal cortex
• the tuberoinfundibular pathway, which delivers DA to cells in
the anterior pituitary
Initial pharmacological studies discriminated between two
subtypes of DA receptors: D 1
(which couples to G S
to stimulate
adenylyl cyclase) and D 2
(which couples to G i
to inhibit adenylyl
cyclase). Subsequent studies identified three additional genes encoding
subtypes of DA receptors: the D 5
receptor, which is related to
the D 1
receptor; and the D 3
and D 4
receptors, which are part of what
is called the D2 receptor family. There are also two isoforms of the
D 2
receptor that differ in the predicted length of their third intracellular
loops (Nestler et al., 2009). The D 1
and D 5
receptors activate the
G s
- adenylyl cyclase- cyclic AMP- PKA system. The D 2
receptors
couple to multiple effector systems, including inhibition of adenylyl
cyclase activity, suppression of Ca 2+ currents, and activation of K +
currents. The effector systems to which the D 3
and D 4
receptors couple
have not been unequivocally defined (Greengard, 2001) (Table
14–5). DA- containing pathways and receptors have been implicated
in the pathophysiology of schizophrenia and Parkinson disease and
in the side effects seen following pharmacotherapy of these disorders
(Chapters 16 and 22).
Norepinephrine. There are relatively large amounts of NE within
the hypothalamus and in certain parts of the limbic system, such as
the central nucleus of the amygdala and the dentate gyrus of the
Frontal
cortex
Nucleus
accumbens
Cingulate gyrus
Striatum
Substantia
nigra
Ventral
tegmental
area
Pituitary Arcuate Hippocampus
nucleus
Figure 14–14. The three major dopaminergic projections in the
CNS. 1. The mesostriatal (or nigrostriatal) pathway. Neurons in
the substantia nigra pars compacta (SNc) project to the dorsal
striatum (upward dashed blue arrows); this is the pathway that
degenerates in Parkinson disease. 2. Neurons in the ventral
tegmental area project to the ventral striatum (nucleus accumbens),
olfactory bulb, amygdala, hippocampus, orbital and
medial prefrontal cortex, and cinguate gyrus (solid blue arrows).
3. Neurons in the arcuate nucleus of the hypothalamus project
by the tuberoinfundibular pathway in the hypothalamus, from
which DA is delivered to the anterior pituitary (red arrows).