CHAPTER 7Neurotransmitters & Neuromodulators 145identified (SSTR1 through SSTR5). All are G protein-coupled
receptors. They inhibit adenylyl cyclase and exert various oth-
er effects on intracellular messenger systems. It appears that
SSTR2 mediates cognitive effects and inhibition of growth
hormone secretion, whereas SSTR5 mediates the inhibition of
insulin secretion.
Vasopressin and oxytocin are not only secreted as hormones
but also are present in neurons that project to the brain stem
and spinal cord. The brain contains bradykinin, angiotensin II,
and endothelin. The gastrointestinal hormones VIP, CCK-4,
and CCK-8 are also found in the brain. There are two kinds of
CCK receptors in the brain, CCK-A and CCK-B. CCK-8 acts at
both binding sites, whereas CCK-4 acts at the CCK-B sites.
Gastrin, neurotensin, galanin, and gastrin-releasing peptide are
also found in the gastrointestinal tract and brain. Neurotensin
and VIP receptors have been cloned and shown to be G pro-
tein-coupled receptors. The hypothalamus contains both gas-
trin 17 and gastrin 34. VIP produces vasodilation and is found
in vasomotor nerve fibers. The functions of these peptides in
the nervous system are unknown.
Calcitonin gene-related peptide (CGRP) is a polypeptide
that exists in two forms in rats and humans: CGRPα and
CGRPβ. In humans, these two forms differ by only three
amino acid residues, yet they are encoded by different genes.
In rats, and presumably in humans, CGRPβ is present in the
gastrointestinal tract, whereas CGRPβ is found in primary
afferent neurons, neurons that project which taste impulses to
the thalamus, and neurons in the medial forebrain bundle. It is
also present along with substance P in the branches of primary
afferent neurons that end near blood vessels. CGRP-like
immunoreactivity is present in the circulation, and injection of
CGRP causes vasodilation. CGRPα and the calcium-lowering
hormone calcitonin are both products of the calcitonin gene.
In the thyroid gland, splicing produces the mRNA that codes
for calcitonin, whereas in the brain, alternative splicing pro-
duces the mRNA that codes for CGRPα. CGRP has little effect
on Ca2+ metabolism, and calcitonin is only a weak vasodilator.
Neuropeptide Y is a polypeptide containing 36 amino acid
residues that acts on at least two of the four known G protein-
coupled receptors: Y 1 , Y 2 , Y 4 , and Y 5. Neuropeptide Y is found
throughout the brain and the autonomic nervous system.
When injected into the hypothalamus, this polypeptide
increases food intake, and inhibitors of neuropeptide Y syn-
thesis decrease food intake. Neuropeptide Y-containing neu-
rons have their cell bodies in the arcuate nuclei and project to
the paraventricular nuclei.
OTHER CHEMICAL TRANSMITTERS
Purine & Pyrimidine Transmitters
After extended debate, it now seems clear that ATP, uridine,
adenosine, and adenosine metabolites are neurotransmitters
or neuromodulators. Adenosine is a neuromodulator that acts
as a general CNS depressant and has additional widespread ef-
fects throughout the body. It acts on four receptors: A 1 , A2A,
A2B, and A 3. All are G protein-coupled receptors and increase
(A2A and A2B) or decrease (A 1 and A 3 ) cAMP concentrations.
The stimulatory effects of coffee and tea are due to blockade of
adenosine receptors by caffeine and theophylline. Currently,
there is considerable interest in the potential use of A 1 antag-
onists to decrease excessive glutamate release and thus to min-
imize the effects of strokes.
ATP is also becoming established as a transmitter, and it has
widespread receptor-mediated effects in the body. It appears
that soluble nucleotidases are released with ATP, and these
accelerate its removal after it has produced its effects. ATP has
now been shown to mediate rapid synaptic responses in the
autonomic nervous system and a fast response in the habenula.
ATP binds to P2X receptors which are ligand-gated ion chan-
nel receptors; seven subtypes (P2X 1 –P2X 7 ) have been identi-
fied. P2X receptors have widespread distributions throughout
the body; for example, P2X 1 and P2X 2 receptors are present in
the dorsal horn, indicating a role for ATP in sensory transmis-
sion. ATP also binds to P2Y receptors which are G protein-
coupled receptors. There are eight subtypes of P2Y receptors:
P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2Y 13 , and P2Y 14.Cannabinoids
Two receptors with a high affinity for Δ^9 -tetrahydrocannab-
inol (THC), the psychoactive ingredient in marijuana, have
been cloned. The CB 1 receptor triggers a G protein-mediated
decrease in intracellular cAMP levels and is common in cen-
tral pain pathways as well as in parts of the cerebellum, hippo-
campus, and cerebral cortex. The endogenous ligand for the
receptor is anandamide, a derivative of arachidonic acid. This
compound mimics the euphoria, calmness, dream states,
drowsiness, and analgesia produced by marijuana. There are
also CB 1 receptors in peripheral tissues, and blockade of these
receptors reduces the vasodilator effect of anandamide. How-
ever, it appears that the vasodilator effect is indirect. A CB 2 re-
ceptor has also been cloned, and its endogenous ligand may be
palmitoylethanolamide (PEA). However, the physiologic
role of this compound is unsettled.Gases
Nitric oxide (NO), a compound released by the endothelium
of blood vessels as endothelium-derived relaxing factor
(EDRF), is also produced in the brain. It is synthesized from
arginine, a reaction catalyzed in the brain by one of the three
forms of NO synthase. It activates guanylyl cyclase and, unlike
other transmitters, it is a gas, which crosses cell membranes
with ease and binds directly to guanylyl cyclase. It may be the
signal by which postsynaptic neurons communicate with pre-
synaptic endings in long-term potentiation and long-term de-
pression. NO synthase requires NADPH, and it is now known
that NADPH-diaphorase (NDP), for which a histochemical
stain has been available for many years, is NO synthase.