192 Chapter 7
Serotonin as a Neurotransmitter
Serotonin, or 5-hydroxytryptamine (5-HT), is used as a neuro-
transmitter by neurons with cell bodies in what are called the
raphe nuclei that are located along the midline of the brain
stem (chapter 8). Serotonin is derived from the amino acid
l-tryptophan, and variations in the amount of this amino acid
in the diet (tryptophan-rich foods include milk and turkey)
can affect the amount of serotonin produced by the neurons.
Physiological functions attributed to serotonin include a role
in the regulation of mood and behavior, appetite, and cerebral
circulation.
The classical hallucinogens—LSD, mescaline, and
psilocybin—exert their effects primarily by binding to and acti-
vating serotonin receptors in the cerebral cortex. Prior to 1970,
when these drugs were classified as Schedule 1 drugs (and were
thus highly regulated), scientists sometimes used these halluci-
nogens medically in attempts to treat psychiatric disorders. The
role of serotonin in the regulation of mood and emotion is cur-
rently exploited by the action of the antidepressant drugs Pro-
zac, Paxil, Zoloft, and Luvox, which act as serotonin-specific
reuptake inhibitors (SSRIs). The SSRIs reduce the produc-
tion of serotonin transporter (SERT) proteins, thereby reducing
the ability of SERT proteins in the presynaptic neuron plasma
membrane to clear serotonin from the synaptic cleft. This
increases the ability of serotonin to stimulate its receptors in the
postsynaptic membrane, an ability that aids in the treatment of
depression.
Serotonin’s diverse functions are related to the fact that
there are many different subtypes of serotonin receptors—
over a dozen are currently known. Thus, while Prozac may be
given to relieve depression, another drug that promotes sero-
tonin action is sometimes given to reduce the appetite of obese
patients. A different drug that may activate a different serotonin
receptor is used to treat anxiety, and yet another drug that pro-
motes serotonin action is given to relieve migraine headaches.
It should be noted that the other monoamine neurotransmitters,
dopamine and norepinephrine, also influence mood and behav-
ior in a way that complements the actions of serotonin.Dopamine as a Neurotransmitter
Neurons that use dopamine as a neurotransmitter are called
dopaminergic neurons. Neurons that have dopamine recep-
tor proteins on the postsynaptic membrane, and that there-
fore respond to dopamine, have been identified in the living
brain using the technique of positron emission tomography
(PET) (chapter 8, section 8.2). These investigations have been
spurred by the great clinical interest in the effects of dopami-
nergic neurons.
The cell bodies of dopaminergic neurons are highly con-
centrated in the midbrain. Their axons project to different parts
of the brain and can be divided into two systems: the nigros-
triatal dopamine system, involved in motor control, and the
mesolimbic dopamine system, involved in emotional reward
(see chapter 8, fig. 8.21).The monoamine neurotransmitters do not directly cause
opening of ion channels in the postsynaptic membrane. Instead,
these neurotransmitters act by means of an intermediate regula-
tor, known as a second messenger. In the case of some syn-
apses that use catecholamines for synaptic transmission, this
second messenger is a compound known as cyclic adenosine
monophosphate (cAMP). Although other synapses can use
other second messengers, only the function of cAMP as a sec-
ond messenger will be considered here. Other second-messenger
systems are discussed in conjunction with hormone action in
chapter 11, section 11.2.
Binding of norepinephrine, for example, with its recep-
tor in the postsynaptic membrane stimulates the dissociation
of the G-protein alpha subunit from the others in its complex
( fig. 7.31 ). This subunit diffuses in the membrane until it binds
to an enzyme known as adenylate cyclase (also called adenylyl
cyclase ). This enzyme converts ATP to cyclic AMP (cAMP)
and pyrophosphate (two inorganic phosphates) within the post-
synaptic cell cytoplasm. Cyclic AMP in turn activates another
enzyme, protein kinase, which phosphorylates (adds a phos-
phate group to) other proteins ( fig. 7.31 ). Through this action,
ion channels are opened in the postsynaptic membrane.
CLINICAL APPLICATION
Monoamine oxidase (MAO) inhibitors are drugs that block
the degradation of monoamine neurotransmitters, thereby
increasing the action of dopamine, serotonin, norepineph-
rine, and melatonin at synapses. MAO inhibitors have
proven useful in the treatment of depression, as well as of
panic disorder, anxiety, and others. MAO inhibitors are also
used to treat Parkinson’s disease by enhancing the synaptic
effects of dopamine. However, MAO inhibitors have poten-
tially dangerous interactions with over-the-counter trypto-
phan and St. John’s Wort, as well as with foods such as
cheeses, certain beans, pickled and fermented foods, and
others that contain the molecule tyramine (a monoamine
also degraded by MAO). Such interactions could provoke a
hypertensive crisis, because the increased norepinephrine
released by sympathetic axons (chapter 9) stimulates vaso-
constriction and increased cardiac pumping, dangerously
raising blood pressure.Clinical Investigation CLUES
Denise had a prescription for an MAO inhibitor to treat her
depression. She carefully avoided dishes with cheese.- What is the action of MAO inhibitors and how do
they affect depression? - What does cheese contain that could be dangerous
to Denise, and how would it be dangerous?