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Serotonin
Serotonin Synthesis, Release, and Inactivation
Serotonin synthesis is regulated by enzymatic activity and precursor availability
- Serotonin was discovered and isolated initially from the bloodstream, not the brain.
- Its name, serotonin, comes from "sero" (serum) and "tonin" (vascular tone).
- Serotonin is synthesized from the amino acid tryptophan.
- Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by the enzyme tryptophan
hydroxylase (TPH).
- 5-HTP is further converted to serotonin (5-HT) by aromatic amino acid decarboxylase (AADC).
- There are two forms of the TPH gene: TPH1 and TPH2.
- TPH2 is expressed by serotonergic neurons, while TPH1 is expressed by non-neuronal cells
like enterochroma n cells in the gut.
- The conversion of tryptophan to 5-HTP is the rate-limiting step in serotonin synthesis, similar
to the conversion of tyrosine to DOPA in dopamine synthesis.
- TPH is speci c to serotonergic neurons, similar to tyrosine hydroxylase in catecholamine
synthesis.
- AADC is the same for both catecholamines and serotonin.
- Telotristat inhibits both TPH1 and TPH2 and is used to treat carcinoid syndrome by reducing
peripheral serotonin levels without crossing the blood-brain barrier.
Tryptophan Metabolic Pathways and Their Functional Consequences
- Tryptophan is essential and must be obtained from the diet since humans cannot synthesize
it.
- Over 95% of ingested tryptophan is metabolized into kynurenine rather than serotonin.
- Manipulating tryptophan availability a ects serotonin synthesis.
- Large doses of tryptophan or 5-HTP stimulate serotonin synthesis more e ectively than
tryptophan alone.
- The ratio of tryptophan to other amino acids in the bloodstream a ects its entry into the brain
and subsequent serotonin synthesis.
- Meals high in carbohydrates but low in protein increase brain tryptophan and serotonin levels
due to insulin's e ect on amino acid uptake.
- Pharmacological depletion methods like acute tryptophan depletion (ATD) reduce brain
serotonin levels and are used in research.
- Elevating tryptophan availability through supplementation or dietary changes may enhance
cognitive functions, mood, and sleep.
- Reducing brain serotonin levels using ATD impairs memory consolidation and can induce a
negative cognitive bias.
- ATD e ects on patients with major depression suggest serotonin's role in mood regulation.
- The kynurenine pathway metabolizes tryptophan into kynurenine, in uenced by stress and
in ammation, and is implicated in psychiatric disorders and neurodegenerative diseases.
Similar processes regulate storage, release, and inactivation of serotonin and the
catecholamines
- Serotonergic neurons use vesicular monoamine transporter 2 (VMAT2) to transport serotonin
(5-HT) into synaptic vesicles, protecting it from enzymatic breakdown.
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- Serotonergic autoreceptors, particularly the 5-HT1A subtype, regulate 5-HT release by
inhibiting ring of serotonergic neurons.
- Some serotonergic neurons lack autoreceptors and re more rapidly.
- Release of 5-HT can be stimulated by drugs like para-chloroamphetamine, fen uramine, and
MDMA, a ecting the serotonergic system.
- Inactivation of 5-HT involves reuptake via the 5-HT transporter (SERT), targeted by drugs like
SSRIs (selective serotonin reuptake inhibitors).
- Mutant mice lacking functional SERT exhibit behavioral and physiological abnormalities due
to chronic enhancement of serotonergic activity.
- 5-HT is metabolized by monoamine oxidase-A (MAO-A) to yield 5-hydroxyindoleacetic acid
(5-HIAA), used as a measure of serotonergic neuron activity.
Basic Features of the Serotonergic System: Anatomical
Organization, Cell Firing, and Receptor Families
The serotonergic system originates in the brainstem and projects to all forebrain
areas
- Swedish researchers mapped the distribution of serotonin (5-HT) neurons in the CNS using
experimental techniques similar to those used for catecholamine systems.
- Serotonergic neurons are primarily located along the midline of the brainstem, particularly in
clusters known as the raphe nuclei.
- The dorsal raphe nucleus (DRN) and the median raphe nucleus (MRN) are of particular
interest, as they give rise to most of the serotonergic bers in the forebrain.
- Virtually all forebrain regions receive serotonergic innervation, including the neocortex,
striatum, thalamus, hypothalamus, and limbic system structures like the hippocampus,
amygdala, and septal area.
- Serotonergic bers innervating speci c brain areas are not uniformly distributed, as illustrated
by dense bers at the cortical surface (layer 1) and sparse bers within the white matter and
major cell layers of the hippocampus.
- The distribution pattern suggests that serotonergic inputs target dendrites rather than cell
bodies within certain brain regions.
The ring of dorsal raphe serotonergic neurons varies with behavioral states
- Serotonergic neurons in the dorsal raphe nucleus (DRN) exhibit distinct ring patterns
correlated with di erent behavioral states in cats.
- During wakefulness, DRN neurons re at a slow but regular rate (tonic ring), while in slow-
wave sleep (non-REM sleep), their ring slows down and becomes more irregular.
- DRN neurons are almost completely inactive during rapid-eye-movement (REM) sleep.
- Studies in mice suggest that tonic ring of DRN neurons promotes sleep (non-REM sleep),
while burst ring favors wakefulness.
- Recent research using genetic manipulations and optogenetic activation indicates that
di erent subsystems of serotonergic neurons within the DRN may mediate these e ects.
- Subsystems of serotonergic neurons within the DRN di er in neurochemical characteristics,
inputs, and outputs, potentially explaining the di erential e ects of tonic and burst ring.
There is a large family of serotonin receptors, most of which are metabotropic
- There are at least 14 subtypes of serotonin (5-HT) receptors identi ed by pharmacologists.
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Serotonin
Serotonin Synthesis, Release, and Inactivation
Serotonin synthesis is regulated by enzymatic activity and precursor availability
- Serotonin was discovered and isolated initially from the bloodstream, not the brain.
- Its name, serotonin, comes from "sero" (serum) and "tonin" (vascular tone).
- Serotonin is synthesized from the amino acid tryptophan.
- Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by the enzyme tryptophan
hydroxylase (TPH).
- 5-HTP is further converted to serotonin (5-HT) by aromatic amino acid decarboxylase (AADC).
- There are two forms of the TPH gene: TPH1 and TPH2.
- TPH2 is expressed by serotonergic neurons, while TPH1 is expressed by non-neuronal cells
like enterochroma n cells in the gut.
- The conversion of tryptophan to 5-HTP is the rate-limiting step in serotonin synthesis, similar
to the conversion of tyrosine to DOPA in dopamine synthesis.
- TPH is speci c to serotonergic neurons, similar to tyrosine hydroxylase in catecholamine
synthesis.
- AADC is the same for both catecholamines and serotonin.
- Telotristat inhibits both TPH1 and TPH2 and is used to treat carcinoid syndrome by reducing
peripheral serotonin levels without crossing the blood-brain barrier.
Tryptophan Metabolic Pathways and Their Functional Consequences
- Tryptophan is essential and must be obtained from the diet since humans cannot synthesize
it.
- Over 95% of ingested tryptophan is metabolized into kynurenine rather than serotonin.
- Manipulating tryptophan availability a ects serotonin synthesis.
- Large doses of tryptophan or 5-HTP stimulate serotonin synthesis more e ectively than
tryptophan alone.
- The ratio of tryptophan to other amino acids in the bloodstream a ects its entry into the brain
and subsequent serotonin synthesis.
- Meals high in carbohydrates but low in protein increase brain tryptophan and serotonin levels
due to insulin's e ect on amino acid uptake.
- Pharmacological depletion methods like acute tryptophan depletion (ATD) reduce brain
serotonin levels and are used in research.
- Elevating tryptophan availability through supplementation or dietary changes may enhance
cognitive functions, mood, and sleep.
- Reducing brain serotonin levels using ATD impairs memory consolidation and can induce a
negative cognitive bias.
- ATD e ects on patients with major depression suggest serotonin's role in mood regulation.
- The kynurenine pathway metabolizes tryptophan into kynurenine, in uenced by stress and
in ammation, and is implicated in psychiatric disorders and neurodegenerative diseases.
Similar processes regulate storage, release, and inactivation of serotonin and the
catecholamines
- Serotonergic neurons use vesicular monoamine transporter 2 (VMAT2) to transport serotonin
(5-HT) into synaptic vesicles, protecting it from enzymatic breakdown.
fl ff fi ffffi ff ff fl ff
, 2 of 8
- Serotonergic autoreceptors, particularly the 5-HT1A subtype, regulate 5-HT release by
inhibiting ring of serotonergic neurons.
- Some serotonergic neurons lack autoreceptors and re more rapidly.
- Release of 5-HT can be stimulated by drugs like para-chloroamphetamine, fen uramine, and
MDMA, a ecting the serotonergic system.
- Inactivation of 5-HT involves reuptake via the 5-HT transporter (SERT), targeted by drugs like
SSRIs (selective serotonin reuptake inhibitors).
- Mutant mice lacking functional SERT exhibit behavioral and physiological abnormalities due
to chronic enhancement of serotonergic activity.
- 5-HT is metabolized by monoamine oxidase-A (MAO-A) to yield 5-hydroxyindoleacetic acid
(5-HIAA), used as a measure of serotonergic neuron activity.
Basic Features of the Serotonergic System: Anatomical
Organization, Cell Firing, and Receptor Families
The serotonergic system originates in the brainstem and projects to all forebrain
areas
- Swedish researchers mapped the distribution of serotonin (5-HT) neurons in the CNS using
experimental techniques similar to those used for catecholamine systems.
- Serotonergic neurons are primarily located along the midline of the brainstem, particularly in
clusters known as the raphe nuclei.
- The dorsal raphe nucleus (DRN) and the median raphe nucleus (MRN) are of particular
interest, as they give rise to most of the serotonergic bers in the forebrain.
- Virtually all forebrain regions receive serotonergic innervation, including the neocortex,
striatum, thalamus, hypothalamus, and limbic system structures like the hippocampus,
amygdala, and septal area.
- Serotonergic bers innervating speci c brain areas are not uniformly distributed, as illustrated
by dense bers at the cortical surface (layer 1) and sparse bers within the white matter and
major cell layers of the hippocampus.
- The distribution pattern suggests that serotonergic inputs target dendrites rather than cell
bodies within certain brain regions.
The ring of dorsal raphe serotonergic neurons varies with behavioral states
- Serotonergic neurons in the dorsal raphe nucleus (DRN) exhibit distinct ring patterns
correlated with di erent behavioral states in cats.
- During wakefulness, DRN neurons re at a slow but regular rate (tonic ring), while in slow-
wave sleep (non-REM sleep), their ring slows down and becomes more irregular.
- DRN neurons are almost completely inactive during rapid-eye-movement (REM) sleep.
- Studies in mice suggest that tonic ring of DRN neurons promotes sleep (non-REM sleep),
while burst ring favors wakefulness.
- Recent research using genetic manipulations and optogenetic activation indicates that
di erent subsystems of serotonergic neurons within the DRN may mediate these e ects.
- Subsystems of serotonergic neurons within the DRN di er in neurochemical characteristics,
inputs, and outputs, potentially explaining the di erential e ects of tonic and burst ring.
There is a large family of serotonin receptors, most of which are metabotropic
- There are at least 14 subtypes of serotonin (5-HT) receptors identi ed by pharmacologists.
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