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NSC 243
Serotonin
5-HT staining of dorsal and
median raphe nuclei
Functional Roles of 5-HT
• General tone of NS
– Repetitive activities like grooming activate 5-HT
neurons
• 5-HT stimulates CRH (corticotropin-releasing
hormone) release from hypothalamus
• 5-HT has negative effects on the ability of light to
reset the circadian clock
• 5-HT activation decreases food consumption and
drugs that inhibit 5-HT stimulate food intake
– Effect on satiety
Serotonin synthesis
Synthesis takes place in the
terminal
Stimulation induced regulation
of 5-HT production
Increasing tryptophan
increases 5-HT release
Effect of egg protein diet on
tryptophan:LNAA ratio
British Journal of Nutrition (2011), 105, 611–617
Inactivation of 5-HT signal
SERT
Serotonin inactivation is a target of
many pharmaceuticals
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Serotonin transporters
Inhibition of SERT
• Tricyclic antidepressants like
imipramine, SSRI’s like prozac
• Inhibit SERT, increase 5-HT levels
• Effects take weeks to develop
– Compensatory changes?
Transient regulation of
monoamine transporters
Regulation by phosphorylation
• Model:
– Depolarization triggers 5-HT release, Na+
influx
– Disruption of Na+ gradient disrupts
transport, allows 5-HT to diffuse away
– Phosphorylation by PKC also decreases
SERT activity in absence of high 5-HT
– Low 5-HT levels lead to decreased levels
of SERT and SERT activity (& vice versa)
• Cell surface localization?
Regulation of 5-HT release
• Tryptophan availability
• Firing rate of neuron (pretty constant)
• Autoreceptors
– Somatodendritic
– Terminal
Effect of 5-HT autoreceptors
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Regulation of 5-HT release
• Autoreceptors
– Somatodendritic
– “activity modulating”
– Terminal
– “release modulating”
• Drug effects: tryptophan, SSRI, MAO inhibitors
• Meant to increase 5-HT; actually can inhibit
raphe firing via autoreceptors!
Regulation of 5-HT release
• Effects of Drugs: Amph, Ecstasy (MDMA),
and fenfluramine
– Reverse SERT, block vesicular transport
– Destroy dorsal raphe terminals (not median)
– Tax energy: disrupt ion gradients
– Non-exocytotic, non-Ca2+ dependent
Toxic effects of MDMA
Activity of pre-synaptic
autoreceptor 5HT1A on firing
Release of CA
• Ca2+ dependent
exocytosis (DBH
release)
• Release at
varicosities
Volume transmission
Sites of preferential volume
release of 5-HT
• Dorsal Raphe
• SN? Protected by glial sheaths
surrounding synapses, so not in practice
• SERT located far from synapses in these
regions, allows for distance transmission
• Explains why receptors are often nonjunctional