Topic 8: Serotonin Flashcards
What is serotonin’s effect on the gut?
90% of the 5-HT in your body is found in the gut
5-HT is a major neurotransmitter in the enteric nervous system and is released by enterochromaffin cells
5-HT stimulates peristalsis and secretion into the intestines
5-HT is massively released in response to chemical, physical, or pathological stimuli and can activate vagal afferents to signal the brain in generation of nausea & act at the area postrema (chemoreceptor trigger zone)
What are the steps of synthesis of serotonin?
dietary L-tryptophan is transported into the brain where it is converted to 5-HT by tryptophan hydroxylase (the rate limiting enzyme)
What are the steps of serotonin catabolism?
5-HT is deaminated by monoamine oxidase to 5-hydroxyindoleacetic acid in the cytoplasm of serotonergic neurons
in contrast to the catecholamines, 5-HT breakdown occurs only through MAO
How does L-Tryptophan cross the blood brain barrier?
uses transporter into the brain
same one is used by other amino acids, so might have to wait a bit
What occurs when tryptophan delpletion?
para-chlorophenylalanine (PCPA) is used in animals to rapidly deplete 5-HT
PCPA is an irreversible inhibitor of tryptophan hydroxylase: 1-2 doses depletes 5-HT by up to 90% for up to 2 weeks, prolonged effect since new protein synthesis is required
reserpine also depletes 5-HT by inhibiting VMAT
tryptophan can be depleted in humans by administering an amino acid mix devoid of tryptophan: boost of amino acids triggers protein synthesis in the liver, depleting previous supply of tryptophan, neutral amino acids compete for BBB transporters
What are serotonin releasers?
fenfluramine: prescribed for weight loss in obese patients
para-chloroamphetamine: amphetamine analogue used experimentally
3,4-methylenedioxymethamphetamine (MDMA): psychoactive recreational drug
What is Fen-Phen?
dopamine and 5-HT are directly opposed in regulating appetite
dopamine is released in response to food stimuli (smell), stimulates appetite
5-HT generated as a result of eating inhibits dopamine release, decreasing appetite
fenfluramine is a 5-HT releaser
phentermine suppresses appetite through effects on catecholamines (psychostimulant similar to amphetamine)
Fen-Phen came into use in the 1990’s as an off-label prescription for obesity
co-treatment avoided drowsiness and adverse mood effects associated with fenfluramine
Why was Fen-Phen controversial?
Fen-Phen was never FDA approved for weight loss (off-label use)
several studies published in 1996-7 linked long term Fen-Phen use with severe adverse consequences
heart valve abnormalities
primary pulmonary hypertension - increased blood pressure between heart and lungs - often fatal
both fenfluramine (Pondimin) and dexfenfluramine (Redux) removed from clinical use in late 1997
What is the serotonin transporter (SERT)?
responsible for inactivation of 5-HT signaling by reuptake
similar to DAT, NET: many drugs have effects at all three (e.g., cocaine and amphetamines, antidepressants)
SERT also found in lungs, placenta, and platelets: SERT pumps systemic 5-HT into platelets, functions in clotting cascades as a vasoconstrictor
What are some examples of drugs that target SERT?
TCA antidepressants (non-selective for SERT, NET)
SSRI antidepressants (selective for SERT)
SNRI antidepressants (non-selective SERT, NET)
SNDRI antidepressants (SERT ~ NET > DAT)
psychoactive drugs (non-selective for SERT, NET, DAT)
