Neuropharmacology 3202

Serotonin / Noradrenaline
Nicole Jones
Department of Pharmacology
UNSW
n.jones@unsw.edu.au

References

Nestler, Hyman & Malenka: Molecular Pharmacology : A foundation

for clinical Neuroscience 2nd Edition (chapter 6)
Rang, Dale Ritter & Flower: Pharmacology 7th edition (chapter 33)
Katzung: Basic & clinical pharmacology 7th ed (chapter 21)
Goodman and Gilmans Pharmacology (chapter 12)

Learning Objectives
At the end of this lecture you should be able to:
Describe the synthetic / metabolic pathways
for serotonin and noradrenaline
Discuss some of the functions mediated by
these neurotransmitters
Discuss the different classes of drugs affecting
serotonin and noradrenaline
neurotransmission (and how these drugs
affect function), and provide named examples

Serotonin 5 hydroxytryptamine (5HT)

Tryptophan
Tryptophan hydroxylase
5-hydroxytryptophan
L-Aromatic amino acid decarboxylase
5-hydroxytryptamine (5HT)
Monoamine oxidase
Aldehyde dehydrogenase
5-hydroxyindoleacetic acid (5HIAA)

Serotonergic pathways

CNS roles for 5HT

Hallucinations
Behaviour
Sleep
Mood, emotion
Memory
Autonomic control
Migraine

5HT and Hallucinations

LSD (Lysergic acid diethylamide) 5HT
analogue (5HT2 agonist)
Decrease in firing of 5HT brainstem neurones
Psychadelic drug popular in 60s, 70s
Hallucinations (audio, visual)
Disturbed thought processes
Other hallucinogens DMT, psilocybin,
mescaline also act via 5HT2

5HT and Sleep

Lesion of raphe nucleus deplete 5HT reduce
sleep
Injection of 5HT into animals can induce sleep
However in humans
5HT precursors (tryptophan, 5hydroxytryptophan) do not induce sleep in
people with insomnia

5HT and Memory

5HT receptor localization in brain areas
involved in memory (hippocampus, amygdala,
cortex)
Alzheimers and schizophrenic patients
decreased 5HT levels correlate with cognitive
impairments
Genetic variation 5HT2a humans decreased
performance in memory task
Many 5HT drugs can improve memory

5HT receptors
Many receptor subtypes (14 so far). All except
5HT3 GPCRs
Ionotropic

Metabotropic

A lot of drugs affecting 5HT, not really

selective, BUT there are many used clinically
Fundamental Neuroscience Zigmond, Bloom, Landis, Roberts, Squire; Academic Press, 1999

5HT neuron

Nestler, Hyman, Malenka 2008 McGraw-Hill

5HT pharmacology and localization

Receptor

Agonist

Antagonist

Brain Localization

5HT1A

8-OH-DPAT, buspirone,
gepirone

WAY 100135, Spiperone

Methiothepin, Ergotamine

Hippocampus, septum, amygdala, dorsal raphe, cortex

5HT1B

5-CT

Methiothepin

Substantia nigra, basal ganglia

5HT1D

Sumatriptan

GR 127935

Substantia nigra, striatum, hippocampus

5HT1E

??

5HT1F

Dorsal raphe, hippocampus, cortex

5HT2A

DMT, LSD, psychadelics

5HT2B

DMT

5HT2C

DMT, MCPP

Ketanserin, cinanserin,
MDL900239

Cortex, olfactory tubercle

NOT IN BRAIN

Mesulergine, fluoxetine

Basal ganglia, choroid plexus, substantia nigra

Ondansetron, granisetron

Spinal cord, cortex, hippocampus, brain stem nuclei

GR113808

Hippocampus, nucleus accumbens, striatum, substantia

nigra

5HT5A

Methiothepin

Cortex, hippocampus, cerebelum

5HT5B

Methiothepin

Habenula, CA1 hippocampus

5HT6

Methiothepin, clozapine,
amitriptyline

Striatum, cortex, hippocampus

5HT7

Methiothepin, clozapine,
amitriptyline

Hypothalamus, thalamus, cortex, suprachiasmatic nucleus

5HT3
5HT4

Metoclopramide;

Adapted from Nestler, Hyman, Malenka 2008 McGraw-Hill

5HT transporter (SERT)

Re-uptake 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
SERT radioligand
Autoradiography in
Baboon brain sections

Szabo, et al
J Nucl Med. 2002;43:678-692.

Drugs affecting SERT

MDMA (3,4-methylenedioxy
methamphetamine - Ecstasy)
Substrate for SERT, can release 5HT from
nerve terminals, and agonist at 5HT2
Mood elevation, altered perception
Side effects: tachycardia, hyperthermia, panic,
neurotoxicity?

MDMA (5 mg/kg daily) for 4 d

at 2x intervals prior to imaging

Szabo, et al
J Nucl Med. 2002;43:678-692.

Other drugs acting at SERT

Antidepressants high affinity for SERT
Selective serotonin reuptake inhibitors (SSRIs
e.g. fluoxetine, sertraline)
tricyclic antidepressants (clomiprimine)

Cocaine inhibits SERT, NET and DAT

prevents reuptake 5HT, NA, DA, so levels of
these neurotransmitters in the synapse
remain high

Interference with the 5HT system

Activate / block receptors __________________

Inhibit synthesis: ________________________
Inhibit neuronal re-uptake: _________________
Depletion: __________________________
Inhibit metabolism: ________________________
Promote release: __________________________

Common therapeutic drugs that

affect 5HT system in CNS?
Sumatriptan: 5-HT1D agonist: migraine
Buspirone: 5-HT1A partial agonist: anxiety
Clozapine: 5HT2A/2C antagonist: antipsychotic
Ondansetron: 5-HT3 antagonist: chemotherapy
induced nausea and vomiting. Also has
anxiolytic, memory enhancing actions.
Fluoxetine: SERT blocker (more 5-HT in
synapse). Used to treat depression, OCD,
various anxiety disorders with relatively few
side effects

Serotonin syndrome
Excess synaptic level of 5-HT due to high intake of
serotonergic drugs, e.g., fluoxetine + other
antidepressant
Overstimulation of 5-HT1A and 5-HT2 receptors.
Symptoms develops within hours.
Mental effects: insomnia, confusion, hallucination,
coma.
Autonomic effects: or BP, HR, diarrhea,
fever.
Neurological effects: tremor, rigidity, hyperreflexia.

5HT in one line

Noradrenaline Synthesis
Tyrosine
Tyrosine hydroxylase
Dihydroxyphenylalanine (Dopa)
L-Aromatic amino acid
decarboxylase
Dopamine
Dopamine hydroxylase
Noradrenaline
Phenylethanolamine Nmethyltransferase
(PNMT)
Adrenaline

Noradrenaline Metabolism

Noradrenaline

Catechol-O-methyl transferase (COMT)

Monoamine oxidase (MAO)

3-methoxy-4-hydroxymandelic acid (VMA)

3-methoxy-4-hydroxyphenylglycol (MHPG)

Noradrenaline
Nestler, Hyman, Malenka 2008 McGraw-Hill

Noradrenergic pathways in brain

NA-containing Neurons
Select few brainstem nuclei
Mainly locus coereleus (LC)
Terminals widespread (cortex, hippocampus)
Used by sympathetic neurons of autonomic
nervous system
, adrenergic receptors

CNS roles for NA

Sleep
Attention
Arousal (fear, stress)
Learning, memory
Mood (depression, anxiety)
Blood pressure regulation

NA and fear, stress

LC cells respond to stressful stimuli
Yohimbine (2 antagonist) increase firing of
LC neurones, induces fear/anxiety.

Khoshbouei, H., et al., 2002. Pharmacol. Biochem. Behav. 71, 407 417.

NA - fear, stress & memory

NA and memory
NA enhances memory
antagonist Propranolol reduces memory
performance
Emotional memory in humans involves central
adrenoreceptors (possible use in PTSD?)

Van Stegeren 2008, Acta Psychologica 127; 532-541

NA and sleep/arousal
Recordings from LC neurones
Silent while asleep
Increased activity following arousal

Aston-Jones, 2005 Sleep Medicine 6 (Suppl 1) S3-7

NA pharmacology and localization

Receptor

Agonist

Antagonist

Localization

Phenylephrine
Methoxamine

Prazosin
Indoramin

Cortex, Hippocampus,
Brainstem

Clonidine

Yohimbine
Rauwolscine
Prazosin

Cortex, Brainstem,
Midbrain, Spinal cord

Isoproteronol
Terbutaline

Alprenolol
Betaxolol
Propranolol

Olfactory nucleus, cortex,

cerebellum, brainstem, spinal
cord

Procaterol
Zinterol

Propranolol

Olfactory bulb, piriform cortex,

hippocampus, cerebellum

Pindolol
Bupranolol
Propranolol

Adapted from Nestler, Hyman, Malenka 2008 McGraw-Hill

NA Neuron

Nestler, Hyman, Malenka 2008 McGraw-Hill

NA transporter (NET)
Re-uptake of NA from synaptic cleft
Similar structure to SERT, DAT
High levels of protein expression throughout
brain (projections, nerve terminals)
Drugs which inhibit/affect transport can
promote/prolong NA signalling

Drugs inhibiting NET

Antidepressants high affinity for NET
venlafaxine, reboxetine
tricyclic antidepressants (desipramine,
nortryptiline)

Cocaine inhibits NET, SERT and DAT and

prevent the reuptake of 5HT, NA, DA
Amphetamines: are taken up by transporters
(NET, SERT, DAT), and then VMAT, leading to
leakage of transmitter out of vesicles

Amphetamine actions

Interference with the NA system

Activate / block receptors __________________

Inhibit synthesis: ________________________
Inhibit neuronal re-uptake: _________________
Depletion: __________________________
Inhibit metabolism: ________________________
Promote release: __________________________

Common therapeutic drugs

that affect NA in CNS?
Antidepressants (TCAs, MAO Inhibitors,
selective noradrenaline reuptake inhibitors)
Stimulants
Methylphenidate (ADHD)
Amphetamines (ADHD, narcolepsy)

NA synthesis inhibitors
Carbidopa (Parkinsons)
Some adverse effects associated with modulating
NA system??

Summary
After this lecture (and with a bit of studying)
you should be familiar with:
Synthetic & metabolic pathways for 5HT, NA
Main 5HT/NA pathways in CNS (to help
explain function)
Their roles in CNS function (normal and
abnormal)
Therapeutic use of drugs affecting 5HT, NA