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Serotonin

I. Classification
Indoleamine: Serotonin (5-hydroxytryptamine)

II. Distribution
A. Central Distribution
1. Cell bodies in midline pontine raph cells. Ascending and descending projections to rest
of brain and spinal cord.
2. Only few hundred thousand 5-HT-producing cells in raph nuclei, but each cell may
exert an influence over as many as 500,000 neurons. 5-HT innervation of cerebral
cortex is much denser than NE innervation. There are non-5-HT as well as 5-HT-
containing cells in raph nuclei. Even in dorsal raph, only 40-50% of cells are
serotonergic.
3. Dorsal raph projects heavily to frontal cortex, striatum and amygdala while median
raph projects heavily to hippocampus, septum and hypothalamus. Fibers from DR are
small and have fine varicosities along the axon while fibers from MR are coarse and
have large varicosities at the terminals.
4. Axons of 5-HT neurons are highly bifurcated, suggesting that they can influence several
areas of the brain simultaneously.
5. 5-HT projections have been suggested as acting as a global synthesizer and
harmonizer of local brain activities: Because of diffuse terminal fields, these neurons
can simultaneously affect information processing throughout the brain. 5-HT action is
generally inhibitory, and this may ensure that only stimuli of sufficient intensity can
interfere with information processing.
6. 5-HT may influence many systems and functions, but these systems continue
functioning without 5-HT neurons. It is unlikely that 5-HT neurons are the sole
regulator of many behaviors affected by manipulating serotonergic systems.
7. The different raph groups receive innervation from other raph nuclei, from DA nigral
and VTA cells, from the locus ceruleus and other inputs.
B. Peripheral localization (Only 2% of body 5-HT in brain)
1. In enteric nervous system
a. 95% of body 5-HT is in this system.
b. ENS is a network of ~100 million neurons; similar to number in spinal cord
c. 5-HT is a major regulator of GI function
2. In mast cells, blood platelets (not produced there)

III. Firing Activity of 5-HT neurons
A. 5-HT neurons are generally described as having very regular firing rats, attributed to a
pacemaker cycle that involves a Ca
++
-dependent potassium current.
B. Discharge rate of neurons also regulated by somatodendritic autoreceptors (5-HT1A
receptors) and by heterosynaptic inputs onto cell bodies.
C. Firing activity of 5-HT neurons is quite stable during wake period, not affected by
environmental input or stressors.
D. Firing rate slows down during slow-wave sleep and ceases during REM sleep. Neurons
also cease firing during an orienting response.
E. Neuronal discharge rate in cats is impervious to many environmentally perturbing stimuli
(noise, fear, restraint, temperature, etc.). However, in rats, 5-HT release can be altered by a
variety of external stimuli. Regulation of 5-HT firing rates many be species specific, or,
and perhaps more likely, 5-HT release is controlled at the terminals by heterosynaptic
input, rather than at the cell bodies by altering firing rate.
F. Cells in DR vs. MR have quite different electrophysiologic characteristics. In DR, non-5-
HT and 5-HT cells behave similarly in terms of time constants and afterhyperpolarization
(AHP) amplitude.

IV. Synthesis
A. Steps in Synthetic Pathway
1. Tryptophan is precursor amino acid and must be taken up from the circulation via the
neutral amino acid transporter.
2. Initial step is hydroxylation of tryptophan to 5-HTP via action of tryptophan
hydroxylase. Enzyme is specific to 5-HT-releasing neurons
3. 5-HTP is decarboxylated to 5-HT via AADC.
4. Like DA, 5-HT is synthesized in the cytoplasm and must be pumped into vesicles for
storage and protection from MAO.
5. Try-OH is marker of 5-HT neurons.
6. Synthesis of releasable transmitter takes place at nerve terminal
B. Rate-limiting step
1. Try-OH limiting in 5-HT synthesis
a. Limiting factor may be availability of tryptophan
Km of try for enzyme is 30-60 M
Concentration of Try in 5-HT cells is thought to be similar; thus enzyme
probably not saturated. Increases in cerebral Try levels repeatedly results in
increased synthesis of 5-HT. Brain use of Try represents only ~1% of total body
utilization of tryptophan.
b. Try must compete with other dietary amino acids for uptake at level of capillary
endothelial cells. Will increasing dietary tryptophan relative to other competing
amino acids enhance 5-HT synthesis in the brain?
c. Availability of PtH4 may be secondary limiting factor
2. High carbohydrate diets enhance the delivery of tryptophan to the brain by changing the
relative relationship of tryptophan to other competing amino acids; whether this alters the
amount of 5-HT released upon terminal discharge is not clear.
C. Regulation of 5-HT synthesis
1. No apparent end product inhibition of 5-HT onto TRY-OH; 5-HT levels increase 3-fold
after MAO inhibition
2. Enzyme activation linked to neural activity
a. Stimulation of specific cell groups in the raph leads to enhanced TRY-OH activity in
select 5-HT terminal regions. Stimulate dorsal raph increases enzyme activity in
cortex and striatum but not hippocampus. HC innervation comes from a different
raph cell group.
b. Stimulation-induced increase is Ca
++
dependent and probably linked to
phosphorylation. Whether this changes Km or Vmax is a matter of contention.
3. Long-term enzyme induction
Partial destruction of 5-HT neurons results in an increase in TRY-OH mRNA in
residual cells and increase in enzyme activity.
4. Does dietary intake of tryptophan substantially change 5-HT synthesis in the brain?

V. Enzymatic degradation
A. Does not terminate synaptic action of released transmitters
B. Intracellular degradation by monoamine oxidase (mainly MAO
A
) metabolizes
considerable amounts of intracellular 5-HT.
C. MAO
B
has been observed in 5-HT cell bodies, but MAO
A
may be more active at the
terminals. MAO
B
, which does not metabolize 5-HT, may be present in serotonergic
neurons to help prevent accumulation of other amines in these terminals. DA is a substrate
for MAO
B
.

VI. Vesicular Storage
A. Serves Two Functions
1. Protects 5-HT from enzymatic degradation
2. Storage makes transmitter available for release
C. Serotonin uptake into vesicles is not ATP dependent, but is coupled to a
+
H-ATP
transporter. 5-HT vesicles contain serotonin-binding protein (SBP).
F. Different populations of vesicles have been identified
1. Large dense core vesicles (70-120 nm) are believed to store 5-HT
2. small, translucent vesicles (40-60 nm) also seen, function unclear. Recent studies have
shown that some monoamine neurons utilize glutamic acid s a co-transmitter. Small,
clear vesicles may contain vesicle glutamate transporter.

VII. Synaptic inactivation
A. 5-HT is cleared from synaptic cleft mainly by reuptake of transmitter back into the
presynaptic terminal via a Na
+
-Cl
-
linked and energy dependent process, the serotonin
transporter (SERT). Energy requirement probably maintains sodium gradient across cells
rather than drives carrier mechanism. Reaccumulated transmitter can be repackaged for
release.
B. Carrier molecule may not be unique to 5-HT neurons. In periphery carrier is located on
blood platelets, which do not synthesize 5-HT. Astrocytes have also been shown to
accumulate 5-HT.
C. Neither extracellular enzymatic degradation nor diffusion play a role in regulating synaptic
levels of transmitter, however, reuptake may not always be synaptic (see paracrine role
below).
D. SERT is a member of a gene family of transporters that includes NET, DAT and GABA
and glycine transporters. Many studies have evaluated regulation of these transporters.
1. Transport in general is reduced during depolarization: during depolarization, Na+
diffuses into cell via voltage-gated sodium channel, hence decreasing local extracellular
concentration of sodium. This would allow a build-up of extracellular transmitter and
increased time for transmitter to diffuse away from release sites and to interact with
distant as well as synaptic receptors. Conversely, hyperpolarization enhances rates of
transport.
2. In general, decreases in monoamine levels and release and autoreceptor agonists (which
decrease release) result in decreased expression of transporters and decreased activity of
transport, and the converse has also been observed: increase transmitter level or release
leads to increased transporter number and activity. This is only a tentative
generalization since there have been many negative studies.
3. Chronic inhibition of monoamine transporters has been associated with transporter
down-regulation.
4. Chronic drug exposure studies must be cautiously interpreted. Some drugs have been
shown to affect Na+-K+ ATPase, which would have an effect on monoamine transport.

VIII. Release of 5-HT
A. Physiologic release is calcium-dependent
B. Related to firing rate of neuron, although physiologically, firing rate seems to be fairly
constant
C. Increasing substrate availability may enhance amount of 5-HT released via influence on
terminal monoamine pool. Moderate increase in tryptophan supply to terminals (by
exercise, diet, or acute starvation) appear to elicit a moderate increase in 5-HT release in
projection fields.
D. Release is influenced by presence of autoreceptors and heteroreceptors on presynaptic
terminal and on cell body.
1. Autoreceptors and heteroreceptors on cell body will alter firing rate: activity
modulating receptors.
2. Terminal autoreceptors and heteroreceptors regulate synthesis and release:
release-modulating receptors. At a steady firing rate, 5-HT release can be altered by
these inputs.
3. Administration of large amounts of tryptophan, or 5-HT reuptake inhibitors or MAO-
inhibitors may completely inhibit raph-firing through activation of somatodentritic
autoreceptors via excess presence of 5-HT acting on raph neurons.
E. Drugs such as amphetamine, fenfluramine and MDMA (Ecstasy) release cytoplasmic
transmitter by reversing uptake carrier and interfering with vesicle storage.
1. Certain 5-HT terminals seem to be selectively destroyed by excess use of substituted
amphetamines. Terminals and fibers of DR are selectively destroyed by such neurotoxic
agents without affecting fibers from the MR.
2. Drugs severely tax energy metabolism in 5-HT terminals through their ability to
exchange with 5-HT and dissipate transmembrane ion gradients.
3. Release by these drugs is not calcium-dependent.
F. Transmitter can be released from dendrites of many monoamine and ACh cell groups.

IX. Serotonin, DA and NE as pacracrine messengers (volume transmission)
A. Defined as communication by transmitter that is released from neuron with no synaptic
contact or that diffuses into brain extracellular space away from synapse (spillover); Also
called volume transmission.
1. Junctional contacts are identified by zone of membrane plasma thickening on either side
of a slightly enlarged extracellular space.
2. Many mnoamine axon terminals and varicosities have synaptic vesicles for storage and
release of transmitter but no junctional complex.
B. Extrasynaptic receptors and transporters for 5-HT (and other monoamines) exist and 5-HT
escapes from synaptic cleft, but there are regional differences.
C. Ultrastructual studies indicate that 5-HT paracrine transmission may exist in regions where
5-HT release sites are either predominately junctional or nonjunctional.
1. Substantia nigra (SN): all release sites appear junctional, but perisynaptic volume
transmission can be detected. Presence of glial sheaths around synapses limits
perisynaptic volume transmission; if there are no such sheaths, then perisynaptic
volume transmission can occur..
2. Dorsal raph (DR): Non-junctional release sites predominate.
3. In both SN and DR, 5-HT transporters and receptors are located remotely from release
sites. If transmitter diffuses from synaptic cleft, it could act on distant receptors, before it
is taken back up into presynaptic terminal by distant transporters. Location of uptake
transporters to release sites is critical determinant of whether perisynaptic volume
transmission occurs.
D. Non-junctional volume transmission may account for many previously poorly understood
observations.
1. Frequent mismatch between regional distribution of many receptors and corresponding
innervation.
2. Extrasynaptic location of many transmitter receptors.
3. Effects of monoamines on non-neuronal targets, such as astrocytes and microvessels.
E. Not clear how monoamine asynaptic vs. synaptic axon varicosities differ in function. In
some monoamine neurons, axon varicosities that are synaptic release glutamate as co-
transmitter.
F. Since almost all monoamine receptors are of the metabotropic type, non-junctional
transmission could influence cell function in many ways in different types of cells.