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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
Vesicular Packaging
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Vesicular monoamine transporter (VMAT)
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VMAT1 found in adrenal medulla
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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
Reserpine
5mg kg-1
Plus DOPA
200mg kg-1
(Carlssen et al 1957)
MAO Mono amine oxidase; COMT catechol-O-methyltransferase
MOA
inhibitors
Eg Phenelzine,
tranylcypromine
COMT
inhibitors
Entacapone
Tolcapone
DAT; 5-HTT
(or SERT), NAT,
NET
Transport blocking drugs: Cocaine - DA, - NE, - 5HTT
Reboxetine -NE; tricyclic antidepressants –NE, -5HTT
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)
Receptor types: Dopamine

Dopamine
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5 subtypes D1 – D5
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D1, D5 similar
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D2, D3, D4 separate family

D1 and D2 most common

Found in: striatum (basal ganglia) and nucleus
accumbens (limbic)
D1, D2 have opposite effects: activate different G proteins (Gs, Gi)
Also, D2 activates G protein that opens K+ gates
Dopamine Pathways I

NIGROSTRIATAL DA PATHWAY

substantia nigra
(mesencephalon)
basal ganglia
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Role in movement
control
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Parkinsonism
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Antipsychoticinduced extrapyramidal side
effects
Dopamine
Pathways II

Midbrain (VTA10) near
substantia nigra
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MESOCORTICAL


MESOLIMBIC
 cerebral cortex (esp.
frontal cortex)
 limbic system (esp.
limbic cortex, nucleus
accumbens, amygdala,
hippocampus
Underlies reward
system
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
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2 similar to DA D2 receptor effect (commonly an
autoreceptor)

1 operates through phosphoinositide 2nd messenger
system  Ca2+ influx within postsynaptic cell (Gq)
The Locus Coeruleus
LC and Vigilance
Aston
Jones 1985
Effect of 1 and  adrenergic agonists injected
into the rat medial septum on time spent awake
Berridge et al 2003)
LC
2 receptor: effect blocked by 2 antagonist
(eg yohimbine) and mimicked when 2 agonist
(eg clonidine) replaces NE
(Wellman et al 1992)
Serotinin:
5-hydroxytryptamine (5-HT)

“Serotonergic neurones”
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Same VMAT2
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VMAT2 blocker reserpine
depletes 5HT
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Serotonergic autoreceptors
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Somatodendritic 5-HT1A
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Terminal autoreceptors 5HT1B or 5-HT1D
More similarities……..
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Release directly stimulated by
amphetamine-type drugs
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Para-chloramphetamine
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fenfluoramine
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3,4-methylenedioxymethamphetamine
(MDMA – ecstasy)
5-HT uptake also similar

5-HT transporter
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Key site of drug uptake
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eg Fluoxetine (Prozac)
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Antidepressant
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Selective serotonin reuptake inhibitors (SSRIs)

nb MDMA and cocaine interact with 5-HTT, but
not selective (also influence DA transporter)
Catabolism
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DA, NE metabolised by MAO and COMT
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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
“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
5-HT receptors: horrible!

15 subtypes, so far
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Including:
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5-HT1 large family: 5-HT1A, 5-HT1B……etc
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Smaller 5-HT2 family 5-HT2A, 5-HT2B……etc :
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Plus 5-HT3, 5-HT4, 5HT5, 5-HT6, 5-HT7
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All metabotropic (class II), except
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5-HT3 – excitatory ionotropic receptor
5-HT1A Receptor: hippocampus,
septum, amygdala, raphe nuclei
(Gi) inhibits adenylate cyclase (cAMP
Opens K+ channels

Receptor agonists
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Buspirone, ipasapirone, 8-hydroxy-2-(di-npropylamino) tetralin (8-OH-DPAT)
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Hyperphagia (5-HT tends to reduce appetite)
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Reduced anxiety
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Hypothermia
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Inhibits motivation to drink alcohol
5-HT2A Receptor: large numbers in cerebral
cortex, also striatum, nucleus accumbens
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(Gq) activates phosphoinositide 2nd messenger system
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Agonists
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1-(2,5 dimethoxy-4-iodophenyl)-2-aminopropane (DOI)
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Hallucinogenic (cf Lysergic acid diethylamide; LSD)
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Head twitch response in rats/mice
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Measure of 5-HT2A receptor stimulation
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Antagonists: ketanserin, ritanserin
Acetyl Choline
HC-3 hemicholinium
AChE blocked by (eg)
Physostigmine,
Neostigmine
Insecticides (malathion)
Nerve gas (sarin, soman)
Ach central pathways
Note: basal forebrain cholinergic system (BFCS)
Ach Receptors

Two families

Nicotinic


Ionotropic, 5 subunits,
Muscarinic
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Metabotropic
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M1 – M5
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Agonists: (parasympathomimetic) eg pilocarpine

Antagonists: (parasympatholytic) eg atropine,
scopolamine
Glutamate: excitatory amino acid
Glutamate receptors
(and kainate)
MGluR1- MGluR8
Phencyclidine, ketamine
Roles

AMPA (selective agonist:  amino 3 hydroxy
5 methyl 4 isoxazole proprionic acid) – rapid
excitation
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NMDA (N-methyl-D-aspartate)


Learning, memory, cognitive ability
MGluR1


Normal locomotor activity, motor co-ordination,
learning
Normal cerebellum control of motor function
High levels of glutamate are neurotoxic

Depolarisation-induced excitotoxicity
Gamma Amino Butyric Acid
GABA Receptors

GABAA
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Ionotropic: opens chloride channels

Classic agonist = muscimol
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Macroscopia
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Hyperthermia
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Pupil dilation
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Elevation of mood
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Difficulties with concentration
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Anorexia
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Catalepsy,
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hallucinations
GABAA Antagonist
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Bicuculline – best known competitive
antagonist
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Convulsant
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Pentylenetetrazol, picrotoxin
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Non competitive convulsants
GABAA sensitivity to CNS
depressant drugs

Benzodiazepines (BDZs), barbiturates,
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Potentiates the action of GABA on GABAA
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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
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