Chapter 11
Fundamentals of the Nervous System and Nervous Tissue
417
11
drugs (LSD and mescaline) can bind to biogenic amine recep-
tors and induce hallucinations.
Amino Acids
It is difficult to prove a neurotransmitter role when the suspect
is an amino acid, because amino acids occur in all cells of the
body and are important in many biochemical reactions. Te
amino acids for which a neurotransmitter role is certain include
glutamate
,
aspartate
,
glycine
, and
gamma (γ)-aminobutyric
acid (GABA)
, but there may be others.
Peptides
Te
neuropeptides
, essentially strings of amino acids, include a
broad spectrum of molecules with diverse effects. For example,
a neuropeptide called
substance P
is an important mediator of
pain signals. By contrast,
endorphins
, which include
beta en-
dorphin
,
dynorphin
, and
enkephalins
(en-kef
9
ah-linz), act as
natural opiates, reducing our perception of pain under stressful
conditions. Enkephalin activity increases dramatically in preg-
nant women in labor. Endorphin release is enhanced when an
athlete gets a so-called second wind and is probably respon-
sible for the “runner’s high.” Additionally, some researchers
claim that the placebo effect is due to endorphin release. Tese
painkilling neurotransmitters remained undiscovered until in-
vestigators began to ask why morphine and other opiates re-
duce anxiety and pain, and found that these drugs attach to the
same receptors that bind natural opiates, producing similar but
stronger effects.
Some neuropeptides, known as
gut-brain peptides
, are also
produced by nonneural body tissues and are widespread in
the gastrointestinal tract. Examples include somatostatin and
cholecystokinin (CCK).
Purines
Purines are nitrogen-containing chemicals (such as guanine and
adenine) that are breakdown products of nucleic acids.
Adeno-
sine triphosphate (ATP)
, the cell’s universal form of energy, is
now recognized as a major neurotransmitter (perhaps the most
primitive one) in both the CNS and PNS. Like the receptors
for glutamate and acetylcholine, certain receptors produce fast
excitatory responses when A±P binds, while other A±P recep-
tors trigger slow, second-messenger responses. Upon binding to
receptors on astrocytes, A±P mediates Ca
2
1
influx.
In addition to the neurotransmitter action of extracellular
A±P,
adenosine
, a part of A±P, also acts outside of cells on aden-
osine receptors. Adenosine is a potent inhibitor in the brain.
Caffeine’s well-known stimulatory effects result from blocking
these adenosine receptors.
Gases and Lipids
Not so long ago, it would have been scientific suicide to sug-
gest that small, short-lived, toxic gas molecules might be
neurotransmitters. Nonetheless, the discovery of these un-
likely messengers has opened up a new chapter in the story
of neurotransmission.
Gasotransmitters
Tese gases—the so-called “gasotransmit-
ters” nitric oxide, carbon monoxide, and hydrogen sulfide—
defy all the classical descriptions of neurotransmitters. Rather
than being stored in vesicles and released by exocytosis, they are
synthesized on demand and diffuse out of the cells that make
them. Instead of attaching to surface receptors, they zoom
through the plasma membrane of nearby cells to bind with par-
ticular intracellular receptors.
Both
nitric oxide (NO)
and
carbon monoxide (CO)
acti-
vate
guanylyl cyclase
, the enzyme that makes the second mes-
senger
cyclic GMP
. NO and CO are found in different brain
regions and appear to act in different pathways, but their mode
of action is similar. NO participates in a variety of processes in
the brain, including the formation of new memories by increas-
ing the strength of certain synapses. In this process, neurotrans-
mitter binding to the postsynaptic receptors indirectly activates
nitric oxide synthase
(
NOS
), the enzyme that makes NO. Te
newly synthesized NO diffuses out of the postsynaptic cell back
to the presynaptic terminal, where it activates guanylyl cyclase.
In this way NO is thought to act as a retrograde messenger that
sends a signal to increase synaptic strength.
Excessive release of NO contributes to much of the brain
damage seen in stroke patients (see p. 463). In the myenteric
plexus of the intestine, NO causes intestinal smooth muscle
to relax.
Less is known about
hydrogen sulfide (H
2
S)
, the most re-
cently discovered gasotransmitter. Unlike NO and CO, it ap-
pears to act directly on ion channels and other proteins to alter
their function.
Endocannabinoids
Just as there are natural opiate neurotrans-
mitters in the brain, our brains make natural neurotransmit-
ters, the
endocannabinoids
(en
0
do-kă-nă
9
bĭ-noids), that act at
the same receptors as tetrahydrocannabinol (±HC), the active
ingredient in marijuana. Teir receptors, the
cannabinoid recep-
tors
, are the most common G protein–linked receptors in the
brain.
Like the gasotransmitters, the endocannabinoids are lipid
soluble and are synthesized on demand, rather than stored and
released from vesicles. Endocannabinoids are formed by clipping
the cell’s own plasma membrane lipids. Te newly synthesized
endocannabinoids diffuse freely from the postsynaptic neuron
to their receptors on presynaptic terminals where they act as a
retrograde messenger to decrease neurotransmitter release. Like
NO, they are thought to be involved in learning and memory. We
are only beginning to understand the many other processes these
neurotransmitters may be involved in, which include neuronal
development, controlling appetite, and suppressing nausea.
Classification of Neurotransmitters
by Function
In this text we can only sample the incredible diversity of func-
tions that neurotransmitters mediate. We limit our discussion
here to two broad ways of classifying neurotransmitters accord-
ing to function, adding more details in subsequent chapters.
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