Serotonin

Question 1

Describe where serotonin is mostly found

Answer 1

• 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)

Question 2

Describe serotonin synthesis and catabolism

Answer 2

Dietary L-tryptophan is transported into the brain where it is converted to 5-HT by tryptophan hydroxylase (the rate limiting enzyme).
5-HT is deaminated by monoamine oxidase to 5-hydroxyindoleacetic acid in the cytoplasm of seratonergic neurons
In contrast to the catecholamines, 5-HT breakdown occurs only through MAO.

Question 3

Describe tryptophan depletion

Answer 3

• 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

Question 4

Describe 5 HT releasers

Answer 4

• Fenfluramine
• Prescribed for weight loss in obese patients
• Some substituted amphetamines * Para-chloroamphetamine
• Amphetamine analogue used experimentally
• 3,4-methylenedioxymethamphetamine (MDMA)
• Psychoactiverecreationaldrug(Ecstasy)

Question 5

Describe fen-phen

Answer 5

• 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 supresses 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

Question 6

Describe the effects of Fen-Phen

Answer 6

• 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

Question 7

Describe 5-HT transporters

Answer 7

• Responsible for inactivation of 5-HT signalling 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

Question 8

How is SERT a popular drug target?

Answer 8

• TCA antidepressants (non-selective for SERT, NET)
• Imipramine
• SSRIantidepressants(selectiveforSERT)
• Fluoxetine
• SNRI antidepressants (non-selective for SERT, NET)
• Venlafaxine
• SNDRI antidepressants (SERT ~ NET > DAT)
• Psychoactive drugs (non-selective for SERT, NET, DAT)
• Cocaine, amphetamines, MDMA