Catecholamines

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Catecholamines

• Stored in vesicles
• Release tightly controlled
• Presynaptic receptors
• Activators include
• NE (?2), DA (D2), Ach, prostaglandins, other
  amines, glutamate and/or endorphins
• Autoreceptors important target for antidepressant
  drugs eg mirtazapine
• Amphetamines can stimulate release of stored
  catecholamines
• Behavioural activation

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Vesicular Packaging

• Vesicular monoamine transporter (VMAT)
• VMAT1 found in adrenal medulla
• VMAT2 found in brain
• Both blocked by reserpine
• Elevated intracellular breakdown of DA and NEebox
• Low levels in brain
• Sedation in animals, depressive symptoms in
  humans

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Reserpine 5mg kg-1
Plus DOPA 200mg kg-1
(Carlssen et al 1957)
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MAO Mono amine oxidase COMT catechol-O-methyltran
sferase
MOA inhibitors
COMT inhibitors
Eg Phenelzine, tranylcypromine
Entacapone Tolcapone
DAT 5-HTT (or SERT), NAT, NET
Transport blocking drugs Cocaine - DA, - NE, -
5HTT Reboxetine -NE tricyclic antidepressants
NE, -5HTT
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Post Synaptic Catecholamine Receptors

• Class 2 Metabotropic GPCR
• Open ion channels and/or influence metabolism by
  2nd messenger system
• Receptors may down-regulate in presence of
  antidepressant drugs which inhibit re-uptake (eg
  maprotilene, bupropion)

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Receptor types Dopamine

• Dopamine
• 5 subtypes D1 D5
• D1, D5 similar
• D2, D3, D4 separate family
• D1 and D2 most common
• Found in striatum (basal ganglia) and nucleus
  accumbens (limbic)

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D1, D2 have opposite effects activate different
G proteins (Gs, Gi) Also, D2 activates G protein
that opens K gates
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Dopamine Pathways I

• substantia nigra (mesencephalon)
• ?basal ganglia
• Role in movement control
• Parkinsonism
• Antipsychotic-induced extra-pyramidal side
  effects

NIGROSTRIATAL DA PATHWAY
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Dopamine Pathways II

• Midbrain (VTA10) near substantia nigra
• ? cerebral cortex (esp. frontal cortex)
• ? limbic system (esp. limbic cortex, nucleus
  accumbens, amygdala, hippocampus
• Underlies reward system

MESOCORTICAL
MESOLIMBIC
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Noradrenaline Receptor Types

• Norepinephrine (and epinephrine) exert effects
  via two primary types ?, ? adrenoreceptors
• each has two subtypes ?1, ?2 ?1, ?2
• ?1, ?2 similar to DA D1 receptor effect
• ?2 similar to DA D2 receptor effect (commonly an
  autoreceptor)
• ?1 operates through phosphoinositide 2nd
  messenger system ? Ca2 influx within
  postsynaptic cell (Gq)

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The Locus Coeruleus
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LC and Vigilance
Aston Jones 1985
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Effect of ?1 and ? adrenergic agonists injected
into the rat medial septum on time spent awake
Berridge et al 2003)
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?2 receptor effect blocked by ?2 antagonist (eg
yohimbine) and mimicked when ?2 agonist (eg
clonidine) replaces NE
LC
(Wellman et al 1992)
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Serotinin 5-hydroxytryptamine (5-HT)

• Serotonergic neurones
• Same VMAT2
• VMAT2 blocker reserpine depletes 5HT
• Serotonergic autoreceptors
• Somatodendritic 5-HT1A
• Terminal autoreceptors 5-HT1B or 5-HT1D

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More similarities..

• Release directly stimulated by amphetamine-type
  drugs
• Para-chloramphetamine
• fenfluoramine
• 3,4-methylenedioxymethamphetamine (MDMA
  ecstasy)

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5-HT uptake also similar

• 5-HT transporter
• Key site of drug uptake
• eg Fluoxetine (Prozac)
• Antidepressant
• Selective serotonin reuptake inhibitors (SSRIs)
• nb MDMA and cocaine interact with 5-HTT, but not
  selective (also influence DA transporter)

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Catabolism

• DA, NE metabolised by MAO and COMT
• 5-HT not a catecholamine, therefore COMT not
  effective
• MAO 5-HT ? 5-hydroxyindoleacetic acid
  (5-HIAA)
• Brain or CSF 5-HIAA used as a measure of
  serotonergic activity

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B 1-8 The Raphe Nuclei in midbrain and
pons Major source of seroternergic fibres B7
Dorsal Raphe B8 median Raphe To all forebrain
neocortex, striatum, nucleus accumbens, thalamus,
hypothalmus, and limbic structures hippocampus,
amygdala, septal area
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5-HT receptors horrible!

• 15 subtypes, so far
• Including
• 5-HT1 large family 5-HT1A, 5-HT1Betc
• Smaller 5-HT2 family 5-HT2A, 5-HT2Betc
• Plus 5-HT3, 5-HT4, 5HT5, 5-HT6, 5-HT7
• All metabotropic (class II), except
• 5-HT3 excitatory ionotropic receptor

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5-HT1A Receptor hippocampus, septum, amygdala,
raphe nuclei

• (Gi) inhibits adenylate cyclase (cAMP?
• Opens K channels
• Receptor agonists
• Buspirone, ipasapirone, 8-hydroxy-2-(di-n-propylam
  ino) tetralin (8-OH-DPAT)
• Hyperphagia (5-HT tends to reduce appetite)
• Reduced anxiety
• Hypothermia
• Inhibits motivation to drink alcohol

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5-HT2A Receptor large numbers in cerebral
cortex, also striatum, nucleus accumbens

• (Gq) activates phosphoinositide 2nd messenger
  system
• Agonists
• 1-(2,5 dimethoxy-4-iodophenyl)-2-aminopropane
  (DOI)
• Hallucinogenic (cf Lysergic acid diethylamide
  LSD)
• Head twitch response in rats/mice
• Measure of 5-HT2A receptor stimulation
• Antagonists ketanserin, ritanserin

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Acetyl Choline
HC-3 hemicholinium
AChE blocked by (eg) Physostigmine,
Neostigmine Insecticides (malathion) Nerve gas
(sarin, soman)
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Ach central pathways
Note basal forebrain cholinergic system (BFCS)
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Ach Receptors

• Two families
• Nicotinic
• Ionotropic, 5 subunits,
• Muscarinic
• Metabotropic
• M1 M5
• Agonists (parasympathomimetic) eg pilocarpine
• Antagonists (parasympatholytic) eg atropine,
  scopolamine

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Glutamate excitatory amino acid
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Glutamate receptors
(and kainate)
MGluR1- MGluR8
Phencyclidine, ketamine
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Roles

• AMPA (selective agonist ? amino 3 hydroxy 5
  methyl 4 isoxazole proprionic acid) rapid
  excitation
• Normal locomotor activity, motor co-ordination,
  learning
• NMDA (N-methyl-D-aspartate)
• Learning, memory, cognitive ability
• MGluR1
• Normal cerebellum control of motor function
• High levels of glutamate are neurotoxic
• Depolarisation-induced excitotoxicity

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Gamma Amino Butyric Acid
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GABA Receptors

• GABAA
• Ionotropic opens chloride channels
• Classic agonist muscimol
• Macroscopia
• Hyperthermia
• Pupil dilation
• Elevation of mood
• Difficulties with concentration
• Anorexia
• Catalepsy,
• hallucinations

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GABAA Antagonist

• Bicuculline best known competitive antagonist
• Convulsant
• Pentylenetetrazol, picrotoxin
• Non competitive convulsants

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GABAA sensitivity to CNS depressant drugs

• Benzodiazepines (BDZs), barbiturates,
• Potentiates the action of GABA on GABAA
• Receptors on GABAA for other ligands
• Eg BDZ (diazepam valium) sensitises the
  receptor to GABA
• BDZs cannot activate the GABAA receptor on their
  own
• No effect in the absence of GABA

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GABAB

• Metabotropic receptor
• Inhibition of cAMP
• K opening
• GABAB agonists/antagonists have no effect on
  GABAA
• GABAB activated by selective agonist baclofen
  (Lioresal)
• Muscle relaxant, anti-spastic agent