2. Serotonin and Noradrenaline

Neuropharmacology 3202 Serotonin / Noradrenaline

Nicole Jones Department of Pharmacology

UNSW [email protected]

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 Gilman’s Pharmacology (chapter 12)

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

Learning Objectives

Serotonin – 5 hydroxytryptamine (5HT)

Tryptophan

5-hydroxytryptophan

5-hydroxytryptamine (5HT)

5-hydroxyindoleacetic acid (5HIAA)

Tryptophan hydroxylase L-Aromatic amino acid decarboxylase Monoamine oxidase Aldehyde dehydrogenase

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 60’s, 70’s • 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, 5-

hydroxytryptophan) – do not induce sleep in people with insomnia

5HT and Memory

• 5HT receptor localization 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 task

• Many 5HT drugs can improve memory

5HT receptors • Many receptor subtypes (14 so far). All except

5HT3 – GPCRs

• 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

Ionotropic Metabotropic

5HT neuron

Nestler, Hyman, Malenka 2008– McGraw-Hill

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 Ketanserin, cinanserin, MDL900239

Cortex, olfactory tubercle

5HT2B DMT NOT IN BRAIN

5HT2C DMT, MCPP Mesulergine, fluoxetine Basal ganglia, choroid plexus, substantia nigra

5HT3 Ondansetron, granisetron Spinal cord, cortex, hippocampus, brain stem nuclei

5HT4 Metoclopramide; 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

5HT pharmacology and localization

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

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

SERT radioligand Autoradiography in Baboon brain sections

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?

J Nucl Med. 2002;43:678-692. Szabo, et al MDMA (5 mg/kg daily) for 4 d

at 2x intervals prior to imaging

• 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

Other drugs acting at SERT

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 hydroxylase L-Aromatic amino acid decarboxylase Dopamine β hydroxylase Phenylethanolamine – N-methyltransferase (PNMT)

Tyrosine

Dihydroxyphenylalanine (Dopa)

Dopamine

Noradrenaline

Adrenaline

Noradrenaline Metabolism

Noradrenaline Monoamine oxidase (MAO) Catechol-O-methyl transferase (COMT) •3-methoxy-4-hydroxy-

mandelic acid (VMA) •3-methoxy-4-hydroxy- phenylglycol (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 • α, β 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 (α2 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 • β antagonist – Propranolol – reduces memory

performance • Emotional memory in humans involves central

β 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

Receptor Agonist Antagonist Localization

α1 Phenylephrine Methoxamine

Prazosin Indoramin

Cortex, Hippocampus, Brainstem

α2

Clonidine Yohimbine Rauwolscine Prazosin

Cortex, Brainstem, Midbrain, Spinal cord

β1 Isoproteronol Terbutaline

Alprenolol Betaxolol Propranolol

Olfactory nucleus, cortex, cerebellum, brainstem, spinal cord

β2

Procaterol Zinterol

Propranolol Olfactory bulb, piriform cortex, hippocampus, cerebellum

β3

Pindolol Bupranolol Propranolol

NA pharmacology and localization

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

• 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

Drugs inhibiting NET

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 (Parkinson’s)

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