catecholamines stored in vesicles release tightly controlled presynaptic receptors activators...
Post on 19-Dec-2015
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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
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
DAT; 5-HTT (or SERT), NAT, NET
MAO Mono amine oxidase; COMT catechol-O-methyltransferase
MOA inhibitors
Transport blocking drugs: Cocaine - DA, - NE, - 5HTT
Reboxetine -NE; tricyclic antidepressants –NE, -5HTT
Eg Phenelzine,
tranylcypromine
COMT inhibitors
Entacapone
Tolcapone
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
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)
D1, D2 have opposite effects: activate different G proteins (Gs, Gi)
Also, D2 activates G protein that opens K+ gates
Dopamine Pathways I substantia nigra
(mesencephalon)
basal ganglia
Role in movement
control
Parkinsonism
Antipsychotic-induced
extra-pyramidal side
effects
NIGROSTRIATAL DA PATHWAY
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
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)
Effect of 1 and adrenergic agonists injected into the rat medial septum on time spent awake
Berridge et al 2003)
(Wellman et al 1992)
LC2 receptor: effect blocked by 2 antagonist (eg
yohimbine) and mimicked when 2 agonist (eg
clonidine) replaces NE
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
More similarities……..
Release directly stimulated by
amphetamine-type drugs Para-chloramphetamine
fenfluoramine
3,4-methylenedioxymethamphetamine
(MDMA – ecstasy)
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)
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
“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
Including:
5-HT1 large family: 5-HT1A, 5-HT1B……etc
Smaller 5-HT2 family 5-HT2A, 5-HT2B……etc :
Plus 5-HT3, 5-HT4, 5HT5, 5-HT6, 5-HT7
All metabotropic (class II), except
5-HT3 – excitatory ionotropic receptor
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-propylamino) tetralin (8-
OH-DPAT)
Hyperphagia (5-HT tends to reduce appetite)
Reduced anxiety
Hypothermia
Inhibits motivation to drink alcohol
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
Acetyl CholineHC-3 hemicholinium
AChE blocked by (eg)
Physostigmine, Neostigmine
Insecticides (malathion)
Nerve gas (sarin, soman)
Ach Receptors
Two families
Nicotinic Ionotropic, 5 subunits,
Muscarinic Metabotropic
M1 – M5
Agonists: (parasympathomimetic) eg pilocarpine
Antagonists: (parasympatholytic) eg atropine,
scopolamine
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
GABA Receptors GABAA
Ionotropic: opens chloride channels Classic agonist = muscimol
Macroscopia Hyperthermia Pupil dilation Elevation of mood Difficulties with concentration Anorexia Catalepsy, hallucinations
GABAA Antagonist
Bicuculline – best known competitive
antagonist
Convulsant
Pentylenetetrazol, picrotoxin
Non competitive convulsants
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