Describe the synthetic/metabolic pathways for serotonin
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)
Discuss some of the functions mediated by these neurotransmitters
General
● Hallucinations ● Behaviour ● Sleep ● Mood, emotion ● Memory ● Autonomic control ● Migraine
Discuss some of the functions mediated by these neurotransmitters
5HT and hallucinations
● 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
Discuss some of the functions mediated by these neurotransmitters
5HT and sleep
● 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
Discuss some of the functions mediated by these neurotransmitters
5HT and memory
● 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
5HT Receptors - types
● Many receptor subtypes (14 so far)
● All GPCRs except 5HT3 (ion channel)
Discuss the different classes of drugs affecting serotonin neurotransmission (and how these drugs affect function), and provide named examples
5HT Neuron
- 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
Discuss the different classes of drugs affecting serotonin neurotransmission (and how these drugs affect function), and provide named examples
5HT Transporter (SERT)
- 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
Discuss the different classes of drugs affecting serotonin neurotransmission (and how these drugs affect function), and provide named examples
Common therapeutic drugs
• 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