166
Chapter 6
Recall from Chapter 5 that drugs that bind to a recep-
tor and produce a response similar to the normal activation
of that receptor are called
agonists,
and drugs that bind to
the receptor but are unable to activate it are
antagonists.
By
occupying the receptors, antagonists prevent binding of the
normal neurotransmitter at the synapse. Specifi c agonists and
antagonists can affect receptors on both pre- and postsynaptic
membranes.
Diseases can also affect synaptic mechanisms. For exam-
ple, the toxin that causes the neurological disorder tetanus is
produced by the bacillus
Clostridium tetani
(tetanus toxin).
It is a protease that destroys SNARE proteins in the presynap-
tic terminal so that fusion of vesicles with the membrane is pre-
vented, inhibiting neurotransmitter release. Because tetanus
toxin specifi cally affects inhibitory neurons, tetanus is charac-
terized by an increase in muscle contraction. The toxin of the
Clostridium botulinum
bacilli, which causes
botulism,
also
affects neurotransmitter release from synaptic vesicles by inter-
fering with actions of SNARE proteins. However, because it
targets the excitatory synapses that activate muscles, botulism
is characterized by muscle paralysis.
Table 6–5
summarizes the factors that determine syn-
aptic strength.
Neurotransmitters and
Neuromodulators
We have emphasized the role of neurotransmitters in elicit-
ing EPSPs and IPSPs. However, certain chemical messengers
elicit complex responses that cannot be simply described as
EPSPs or IPSPs. The word
modulation
is used for these com-
plex responses, and the messengers that cause them are called
neuromodulators.
The distinctions between neuromodula-
tors and neurotransmitters are not always clear. In fact, cer-
tain neuromodulators are often synthesized by the presynaptic
cell and co-released with the neurotransmitter. To add to the
complexity, many hormones, paracrine agents, and messengers
that the immune system uses serve as neuromodulators.
Neuromodulators often modify the postsynaptic cell’s
response to specifi c neurotransmitters, amplifying or dampen-
ing the effectiveness of ongoing synaptic activity. Alternatively,
they may change the presynaptic cell’s synthesis, release, reup-
take, or metabolism of a transmitter. In other words, they alter
the effectiveness of the synapse.
In general, the receptors for neurotransmitters infl uence
ion channels that directly affect excitation or inhibition of
the postsynaptic cell. These mechanisms operate within mil-
liseconds. Receptors for neuromodulators, on the other hand,
more often bring about changes in metabolic processes in neu-
rons, often via G proteins coupled to second-messenger sys-
tems. Such changes, which can occur over minutes, hours, or
even days, include alterations in enzyme activity or, through
infl uences on DNA transcription, in protein synthesis. Thus,
neurotransmitters are involved in rapid communication,
whereas neuromodulators tend to be associated with slower
events such as learning, development, motivational states, or
even some sensory or motor activities.
The number of substances known to act as neurotrans-
mitters or neuromodulators is large and still growing.
Table
6–6
provides a framework for categorizing that list. A huge
amount of information has accumulated concerning the
synthesis, metabolism, and mechanisms of action of these
messengers—material well beyond the scope of this book.
The following sections will therefore present only some basic
generalizations about some of the neurotransmitters that are
deemed most important. For simplicity’s sake, we use the term
neurotransmitter
in a general sense, realizing that sometimes
the messenger may more appropriately be described as a neu-
romodulator. A note on terminology should also be included
here: Neurons are often referred to as
-ergic;
the missing pre-
fi x is the type of neurotransmitter the neuron releases. For
example,
dopaminergic
applies to neurons that release the
neurotransmitter dopamine.
Acetylcholine
Acetylcholine (ACh)
is a major neurotransmitter in the
peripheral nervous system at the neuromuscular junction
(Chapter 9) and in the brain. Neurons that release ACh are
called
cholinergic
neurons. The cell bodies of the brain’s cho-
linergic neurons are concentrated in relatively few areas, but
their axons are widely distributed.
Table 6–5
Factors that Determine Synaptic
Strength
I
.
PRESYNAPTIC
FACTORS
A. Availability of neurotransmitter
1. Availability of precursor molecules
2. Amount (or activity) of the rate-limiting enzyme
in the pathway for neurotransmitter synthesis
B. Axon terminal membrane potential
C. Axon terminal calcium
D. Activation of membrane receptors on presynaptic
terminal
1. Axo-axonic synapses
2. Autoreceptors
3. Other receptors
E. Certain drugs and diseases, which act via the above
mechanisms A–D
II
.
POSTSYNAPTIC
FACTORS
A. Immediate past history of electrical state of postsynaptic
membrane (e.g., excitation or inhibition from temporal
or spatial summation)
B. Effects of other neurotransmitters or neuromodulators
acting on postsynaptic neuron
C. Up- or down-regulation and desensitization of receptors
D. Certain drugs and diseases
III
.
GENERAL
FACTORS
A. Area of synaptic contact
B. Enzymatic destruction of neurotransmitter
C. Geometry of diffusion path
D. Neurotransmitter reuptake
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