Fluoxetine - serotonin system Flashcards
5-hydroxytryptamine
5-HT or serotonin
90% of serotonin found in…
gut
enterochromatin cells
10% of 5-HT found in…
CNS (mainly mid-brain)
biosynthesis of serotonin
tryptophan –> 5-hydroxytryptophan –> 5-hydroxytryptamine
5-HT in diet
tryptophan found in meat and dairy products
degradation of 5-HT
monoamine oxide enzyme
enzyme in 5-HT biosynthesis
tryptophan hydroxylase
how are serotonin receptors classified
by their pharmacology and their signal transduction mechanisms
how many 5-HT receptor subtypes
7
which 5-HT receptor is an autoreceptor
5-HT1
main function of fluoxetine
SSRI
blocks serotonin transporter
SSRI stands for
serotonin selective re-uptake inhibitor
SERT
serotonin transporter
sodium-dependent
importance of SERTs
recover neurotransmitter
if you block SERTs
you increase bioavailability of serotonin in the synaptic cleft
clinical uses of SSRIs
treat disorders such as depression, general anxiety, OCD, PTSD, social anxiety, bulimia
common side effects of SSRIs
nausea
vomiting
constipation
diarrhoea
time delay in serotonin release
therapeutic effect of SSRI not seen until several weeks later
then significant increase in serotonin seen
why is there a time delay in serotonin release
inhibitory pre-synaptic receptors
auto-receptor decreases 5-HT release however eventually decreases with more treatment
once desensitised then increase in 5-HT seen
clinical use of 5-HT modulators
treatment of migraines
mechanism of migraine treatment by 5-HT modulator
5-HT receptor agonists induce vasoconstriction in cerebrovascular smooth muscle
they do this by inhibiting release of vasoactive peptides
cause of migraine
cranial vasodilation
examples of 5-HT receptor agonist
triptans
ergot alkaloids
lorcaserin
5-HT 2C receptor agonist
activation of the receptor suppresses appetite –> potential obesity therapy?
why are rats mostly used in evalutating depressive behaviours in pre-clinical studies
they are better than mice as they are less anxious around humans
2 tests used to evaluate depressive like behaviours in animals
forced swim test
sucrose preference test
process of forced swim test
rats in container full of water
swim around until they become immobile –> state of despair
more time in immobility –> more depressive rat
what is measured in forced swim test
time spent immobile
latency (time until 1st immobility reached)
effect of antidepressants on forced swim test
rat spends less time immobile and more time swimming
3 methods to induce stress upon a rodent
restraint
early-life
intruder mechanism
tubes in sucrose preference test
tube A = water
tube B = water + sucrose
method of sucrose preference test
if the rodent is more depressed it will have less preference for sucrose
if a stressed animal is given an anti-depressant, its sucrose preference will icnrease
rats self-administration of cocaine
rats with cocaine press lever more for more cocaine
effect of fluoxetine on self administration of cocaine
rats with fluoxetine have less reinforcement
progressive ratio test
number of times you have to press the lever for the reward increases each time
break point in progressive ratio test
when the reward isnt worth the effort of pressing the lever that many times
the greater the breakpoint
the more motivation the animal has
effect of cocaine on breakpoint
animal never reaches breakpoint
increased reinforcement
rats keep pressing lever until exhaustion
which 5-HT receptor is not a 7TM GPCR
5-HT3
ligand for 5-HT3
cation channel
Na+
K+
another factor that contributes to serotonin related diseases
polymorphisms in the 5-HT receptors
5-HT1 signalling pathways
Gi/o
decreases cAMP
main functions of 5-HT1 signalling
neuronal inhibition behaviour sleep feeding thermoregulation anxiety
5-HT2 signalling pathways
Gq
effects of 5-HT2 signalling
increased IP3 and DAG and Ca2+
main function of 5-HT3 and 5-HT4
neuronal excitation
5-HT3 receptor type
ligand gated ion channel
5-HT4 signalling pathway
Gs
increased cAMP
stimulatory
which 5-HT receptors signal via Gs
5-HT4
5-HT5
5-HT6
5-HT7
transporter to get 5-HT into vesicles
VMAT
fluoxetine treats
major depressive disorder
bulimia nervosa
5-HT2 receptor antagonist used to treat hypertension
ketanserin
5-HT3 receptor antagonists prevent nausea and vomiting
ondansetron
tropisetron
where are 5-HT2C receptors often located
POMC neurons in hypothalamus
what is the POMC
pro-opiomelanocortin neurons
Prader-Willi Syndrome
genetic form of obesity
reduced expression of 5-HT2C receptor
specific types of animals used to evaluate depressive-like behaviours in pre-clinical drug studies
mice
Wistar rats
Sprague Dawley rats
Long-Evans rats
squirrel monkeys
rhesus monkeys
potentiation of which 5-HT receptor modulates exploratory behaviour of rodents
5-HT5A
which 5-HT receptor is found in vascular smooth muscle
5-HT1A
