that the medicinal chemist understands synaptic transmission when designing neuroactive
drugs. Synaptic transmission is not electrical but chemical, and is triggered by the
arrival of the action potential at the nerve ending. This causes a Ca^2 +ion influx across
the membrane and into the neuron, resulting in the release of an interneuronal chemi-
cal messenger (neurotransmitter) characteristic for that particular neuron. There seem
to be several different neurotransmitter release mechanisms, although none is well
understood. When released, the neurotransmitter crosses the synaptic gap by passive
diffusion and binds transiently to a receptor on the membrane of the postsynaptic neu-
ron. This receptor occupation initiates the electrical axonal wave of depolarization of
the next (postsynaptic) neuron; alternatively, it can trigger the activation of an enzyme
such as adenylate cyclase and the formation of cAMP as a second messenger. The
released neurotransmitter is then either destroyed enzymatically or taken back into the
synapse and recycled. Inhibitory neurotransmitters, on the other hand, activate Cl−ion
uptake through the postsynaptic neuronal membrane. This effect makes the intracellu-
lar potential more negative than the original resting potential and thus hyperpolarizes
the neuronal membrane. Naturally, a greater than normal impulse will be necessary to
fire such a hyperpolarized neuron, since the threshold value of the action potential
remains the same. Both excitatory and inhibitory impulses summate and trigger an
all-or-none response of a particular neuron, on which hundreds of other neurons may
synapse.
Besides binding to postsynaptic receptors, a released neurotransmitter also “back-
diffuses” to presynaptic receptors or autoreceptors on the neuron from which it was just
released, fulfilling an important feedback regulatory function by facilitating or inhibit-
ing transmitter release. It has been suggested that these presynaptic receptors are also
heteroreceptors—that is, they respond to cotransmitters as well as neurotransmitters
produced by the same neuron. For instance, it is known that neurotensin regulates the
release of norepinephrine, its cotransmitter. Now that the fallacy of the “one neuron—
one transmitter” dogma has been revealed, it is logical to assume that multiple trans-
mitters (neurotransmitter plus a cotransmitter) may regulate each other’s release and
metabolism in a given synapse and that there may be considerable overlap among
presynaptic auto- and heteroreceptor functions.
4.1.4 Neurotransmitters and NeuromodulatorsAneurotransmitter is a chemical messenger that mediates the passage of electrical
information from one neuron to an adjacent neuron. To be defined as a classical neuro-
transmitter, a molecule must be synthesized and stored in a neuron, released from that
neuron in a Ca^2 +dependent process, diffuse to an adjacent neuron, specifically dock
with a receptor on that adjacent neuron, and have its binding to this receptor blocked by
a competitive antagonist. A neuromodulator, on the other hand, is a molecule which is
present in the synaptic cleft and which modifies either the frequency or the efficiency
of the neurotransmitter molecule, thereby either amplifying or attenuating the neuro-
transmitter action.
The traditional neurotransmitters have been recognized for a number of decades and
include acetylcholine, norepinephrine, and glutamate. The number of neurotransmitters
has increased rapidly in the past 10–20 years as the methodology for their detection has
NEUROTRANSMITTERS AND THEIR RECEPTORS 197