Neuronal Signaling and the Structure of the Nervous System
171
pain. The opioids have been implicated in the runner’s “sec-
ond wind,” when the athlete feels a boost of energy and a
decrease in pain and effort, and in the general feeling of well-
being experienced after a bout of strenuous exercise, the so-
called “runner’s high.” There is also evidence that the opioids
play a role in eating and drinking behavior, in regulation of
the cardiovascular system, and in mood and emotion.
Substance P,
another of the neuropeptides, is a trans-
mitter released by afferent neurons that relay sensory infor-
mation into the central nervous system. It is known to be
involved in pain sensation.
Miscellaneous
Surprisingly, at least two gases—
nitric oxide
and
carbon
monoxide
—serve as neurotransmitters. Gases are not released
from presynaptic vesicles, nor do they bind to postsynaptic
plasma membrane receptors. They simply diffuse from their
sites of origin in one cell into the intracellular fl
uid of nearby
cells. These gases serve as messengers between some neurons
and between neurons and effector cells. Both are produced by
cytosolic enzymes and bind to and activate guanylyl cyclase
in the recipient cell. This increases the concentration of the
second-messenger cyclic GMP in that cell.
Nitric oxide plays a role in a bewildering array of neu-
rally mediated events—learning, development, drug tolerance,
penile erection, and sensory and motor modulation, to name
a few. Paradoxically, it is also implicated in neural damage that
results, for example, from the stoppage of blood fl ow to the
brain or from a head injury. In later chapters we will see that
nitric oxide is produced not only in the central and peripheral
nervous systems, but also by a variety of non-neural cells, and
it plays an important paracrine role in the cardiovascular and
immune systems, among others.
Other nontraditional neurotransmitters include the
purines,
ATP
and
adenosine,
which are considered excitatory
neuromodulators. ATP is present in all pre-synaptic vesicles and
is coreleased with one or more of the classical neurotransmit-
ters in response to calcium infl
ux into the terminal. Adenosine
is derived from ATP via extracellular enzymatic activity. Both
presynaptic and postsynaptic receptors have been described for
adenosine, though the exact roles these substances play in neu-
rotransmission is unknown.
Neuroeffector Communication
Thus far we have described the effects of neurotransmitters
released at synapses. Many neurons of the peripheral nervous
system end, however, not at synapses on other neurons but at
neuroeffector junctions on muscle and gland cells. The neu-
rotransmitters released by these efferent neurons’ terminals or
varicosities provide the link by which electrical activity of the
nervous system regulates effector cell activity.
The events that occur at neuroeffector junctions are simi-
lar to those at a synapse. The neurotransmitter is released from
the efferent neuron upon the arrival of an action potential at
the neuron’s axon terminals or varicosities. The neurotrans-
mitter then diffuses to the surface of the effector cell, where it
binds to receptors on that cell’s plasma membrane. The recep-
tors may be directly under the axon terminal or varicosity, or
they may be some distance away so that the diffusion path the
neurotransmitter follows is long. The receptors on the effector
cell may be either ionotropic or metabotropic. The response
(altered muscle contraction or glandular secretion) of the effec-
tor cell will be described in later chapters. As we will see in the
next section, the major neurotransmitters released at neuroef-
fector junctions are acetylcholine and norepinephrine.
Ethanol: A Pharmacological Hand Grenade
After caffeine, the ethanol found in alcoholic beverages is
the second most widely used drug in the world. Although
the psychological and behavioral effects of ethanol ingestion
have been known about (and sought after) for much of
recorded human history, only recently are the physiological
mechanisms of its complex effects and side effects being
investigated. Experiments done in the 1890s showed that the
lipid solubility of different alcohols varied with the number of
carbon molecules in their structure, which in turn correlated
with their anesthetizing/intoxicating strength. This led to
the hypothesis that ethanol simply dissolved and disrupted
the lipid bilayers of neurons, causing generalized malfunction
of the brain. It has more recently become clear that while
other alcohols do effectively dissolve the plasma membrane
(often with irreversible and lethal consequences), the two-
carbon ethanol molecule has specifi c pharmacological effects
on a wide variety of cellular proteins.
ADDITIONAL CLINICAL EXAMPLES
Among ethanol’s targets are proteins involved in
synaptic transmission throughout the brain. Effects on
dopaminergic and endogenous opioid signaling result in
short-term mood elevation or euphoria, and may also explain
the long-term addictive effects some people experience.
Ethanol has a global depressant effect on the activity of the
brain and brainstem, arising from the fact that it strongly
inhibits glutamate signaling (the brain’s main excitatory
neurotransmitter) while stimulating GABA signaling (the
brain’s main inhibitory neurotransmitter). Thus, as a person’s
blood alcohol content rises, there is a progressive reduction
in overall mental processing capability, and side-effects begin
to emerge such as reduced sensory perception (hearing
in particular), motor incoordination, impaired judgment,
memory loss, and unconsciousness. Very high doses of
ethanol are sometimes fatal, due to suppression of brainstem
centers responsible for regulating the cardiovascular and
respiratory systems.
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