168
Chapter 6
released. Autoreceptors on the presynaptic terminals strongly
modulate synthesis and release of the catecholamines.
After activation of the receptors on the postsynaptic cell,
the catecholamine concentration in the synaptic cleft declines,
mainly because a membrane transporter protein actively trans-
ports the catecholamine back into the axon terminal. The cat-
echolamine neurotransmitters are also broken down in both
the extracellular fl uid and the axon terminal by enzymes such
as
monoamine oxidase (MAO).
Drugs known as MAO
inhibitors increase the amount of norepinephrine and dopa-
mine in a synapse by slowing their metabolic degradation.
They are used in the treatment of mood disorders such as
some types of depression.
Within the central nervous system, the cell bodies of
the catecholamine-releasing neurons lie in parts of the brain
called the brainstem and hypothalamus. Although these neu-
rons are relatively few in number, their axons branch greatly
and may go to virtually all parts of the brain and spinal cord.
These neurotransmitters play essential roles in states of con-
sciousness, mood, motivation, directed attention, movement,
blood-pressure regulation, and hormone release, all functions
that later chapters will cover in more detail.
The British word for epinephrine is “adrenaline.” However,
nerve fi
bers that release either epinephrine or norepinephrine
are referred to as
adrenergic
fi bers. Norepinephrine-releasing
fi bers are also sometimes called
noradrenergic.
There are two major classes of receptors for norepineph-
rine and epinephrine:
alpha-adrenergic receptors
and
beta-
adrenergic receptors
(also called alpha-adrenoceptors and
beta-adrenoceptors). All catecholamine receptors are metabo-
tropic, and thus use second messengers to transfer a signal from
the surface of the cell to the cytoplasm. Beta-adrenoceptors act
via stimulatory G proteins to increase cAMP in the postsynaptic
cell. There are three subclasses of beta-receptors,
β
1
,
β
2
, and
β
3
,
which function in different ways in different tissues (see Table
6–11). Alpha-adrenoceptors exist in two subclasses,
α
1
and
α
2
.
They act presynaptically to inhibit norepinephrine release (
α
2
)
or postsynaptically to either stimulate or inhibit activity at dif-
ferent types of potassium channels (
α
1
). The subclasses of alpha-
and beta-receptors are distinguished by the drugs that infl uence
them and their second-messenger systems.
Serotonin
While not a catecholamine,
serotonin
(5-hydroxy-tryptamine,
or 5-HT) is an important biogenic amine. It is produced from
tryptophan, an essential amino acid. Its effects generally have
a slow onset, indicating that it works as a neuromodulator.
Serotonin-releasing neurons innervate virtually every struc-
ture in the brain and spinal cord and operate via at least 16
different receptor types.
In general, serotonin has an excitatory effect on path-
ways that are involved in the control of muscles, and an inhibi-
tory effect on pathways that mediate sensations. The activity
of serotonergic neurons is lowest or absent during sleep and
highest during states of alert wakefulness. In addition to their
contributions to motor activity and sleep, serotonergic path-
ways also function in the regulation of food intake, reproduc-
tive behavior, and emotional states such as mood and anxiety.
Serotonin reuptake blockers such as
paroxetine
(Paxil
®
)
are thought to aid in the treatment of depression by inacti-
vating the 5-HT transporter and increasing the synaptic con-
centration of the neurotransmitter. Interestingly, such drugs
are often associated with decreased appetite but paradoxically
cause weight gain due to disruption of enzymatic pathways
that regulate fuel metabolism. This is one example of how the
use of reuptake inhibitors for a specifi c neurotransmitter—one
Figure 6–35
Catecholamine biosynthetic pathway. Tyrosine hydroxylase is the rate-limiting enzyme, but which neurotransmitter is ultimately released
from a neuron depends on which of the other three enzymes are present in that cell. The colored screen indicates the more common CNS
catecholamine neurotransmitters.
Tyrosine
Tyrosine
hydroxylase
Dopa
decarboxylase
Dopamine
β
-hydroxylase
Phenylethanolamine
N-methyltransferase
L-Dopa
Dopamine
Norepinephrine
Epinephrine
OH
OH
C
C
COOH
H
NH
2
H
H
OH
OH
OH
OH
OH
OH
OH
C
C
COOH
H
NH
2
H
H
C
C
H
H
NH
2
H
H
C
C
H
H
NH
2
OH
H
C
C
H
H
N
CH
3
H
OH
H
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