Serotonin

Question 1

Describe the synthetic/metabolic pathways for serotonin

Answer 1

Synthesis
Tryptophan –> (Tryptophan hydroxylase) –> 5-hydroxytrophan –> (L-aromatic amino acid decarboxylase) –> 5-hydroxytryptamine (5HT/serotonin)

Metabolism
5HT –> (monoamine oxidase) (aldehyde dehydrogenase) –> 5-hydroxyindoleacetic acid (5HIAA) (this is the metabolite)

Question 2

Discuss some of the functions mediated by these neurotransmitters

General

Answer 2

●	Hallucinations
●	Behaviour
●	Sleep
●	Mood, emotion
●	Memory
●	Autonomic control
●	Migraine

Question 3

Discuss some of the functions mediated by these neurotransmitters

5HT and hallucinations

Answer 3

● LSD - 5HT analogue (5HT2 agonist)
● Decrease in firing of 5HT brainstem neurones
● “Psychadelic” drug - popular in 60’s, 70’s
● Hallucinations (audio, visual)
● Disturbed thought process
● Other hallucinogens - DMT, psilocybin, mescaline - also act via 5HT2

Question 4

Discuss some of the functions mediated by these neurotransmitters

5HT and sleep

Answer 4

● Lesion of raphe nucleus (nucleus in brain stem that contains serotonin cell bodies) deplete 5HT - reduce sleep
● Injection of 5HT into animals can induce sleep
● However, in humans
○ 5HT precursors (tryptophan, 5-hydroxytryptophan) - do not induce sleep in people with insomnia

Question 5

Discuss some of the functions mediated by these neurotransmitters

5HT and memory

Answer 5

● 5HT receptor localisation in brain areas involved in memory (hippocampus, amygdala, cortex)
● Alzheimer’s and schizophrenic patients - decreased 5HT levels correlate with cognitive impairments
● Genetic variation 5HT2a humans - decreased performance in memory tasks
● Many 5HT drugs can improve memory

Question 6

5HT Receptors - types

Answer 6

● Many receptor subtypes (14 so far)

● All GPCRs except 5HT3 (ion channel)

Question 7

Discuss the different classes of drugs affecting serotonin neurotransmission (and how these drugs affect function), and provide named examples

5HT Neuron

Answer 7

• PCPA inhibits tryptophan hydrolase and serotonin synthesis
• Reserpine inhibits VMAT and depletes serotonin stores
• SSRI and SNRI antidepressants inhibit the serotonin transporter
• Many antipsychotic drugs inhibit 5HT2A receptors
• Odansetron is a 5HT3 antagonist
• Antimigraine triptans are 5HT1D agonists
• MAOI antidepressants inhibit MAOA
• Buspirone is a partial agonist at 5HT1A receptors

Question 8

Discuss the different classes of drugs affecting serotonin neurotransmission (and how these drugs affect function), and provide named examples

5HT Transporter (SERT)

Answer 8

• Reuptake of 5HT from synaptic cleft
• Similar structure to noradrenaline/dopamine transporters (NET/DAT)
• High levels of protein expression throughout brain (projections, nerve terminals)
• Drugs which inhibit/affect transport – can promote/prolong 5HT signalling

Drugs Affecting SERT
 - MDMA (ecstasy)
o	Competes with serotonin for transporter
o	Substrate for SERT, can release 5HT from nerve terminals
o	Agonist at 5HT2
o	Mood elevations, altered perception
o	Side effects
	Tachycardia
	Hyperthermia
	Panic
	Neurotoxicity

• Antidepressants
  o High affinity for SERT
  o Selective serotonin reuptake inhibitors (SSRIs – e.g. fluoxetine, sertraline)
  o Tricyclic antidepressants (clomipramine)
• Cocaine
  o Inhibits SERT, NET and DAT
  o Prevents reuptake of 5HT, NA, DA, so levels of these neurotransmitters in the synapse remain high

Question 9

Discuss the different classes of drugs affecting serotonin neurotransmission (and how these drugs affect function), and provide named examples

Common therapeutic drugs

Answer 9

•	Sumatriptan
o	5-HT1D agonist
o	Migraine
•	Buspirone
o	5-HT1A partial agonist
o	Anxiety
•	Clozapine
o	5HT2A/2C antagonist
o	Antipsychotic
o	Also a dopamine antagonist
•	Ondansetron
o	5-HT3 antagonist
o	Chemotherapy induced nausea and vomiting
o	Also has anxiolytic, memory enhancing functions
•	Fluoxetine
o	SERT blocker (more 5-HT in synapse)
o	SSRI
o	Depression, OCD, various anxiety disorders
o	Relatively few side effects