SB L1 - Monoamines 2 - 5HT1A Flashcards
What type of receptors are 5HT1AR?
GPCR
What is the presynaptic action of 5HT1AR activation?
Closes calcium channels to reduce transmitter release (autoreceptor)
What is the postsynaptic action of 5 HT 1aR activation?
opens potassium channes eliciting slow hyperpolarisation - (this has an inhibitory effect on transmission)
What is the pharma action of SSRIs?
Inhibit 5HT reuptake via SERT
Note: not all agonists are full or partial agonists and pre and post synaptic sites
…..
What happens if you administer buspirone in the forebrain region?
anxiolytic response - so anxiolytic effects are partially mediated through activation of this receptor
how fast does buspirone create response?
~2 weeks
it’s thought to be as fast acting as BZs
Where are 5HT1A receptors localised (broadly according to SB diagram)
Pre-synaptic in the Raphe nuclei
Post-synaptic in forebrain regions such as the hippocampus
What is the effect of buspirone (5HT ag) on the 5HT system overall
Activates the 5HT1A receptor - this inhibits and slows firing therefore reducing the amount of neurotransmitter released. The overall effect is less activation of the 5HT receptors, more activation of the 5HT1A receptors.
Desensitisation occurs. Activates the 5HT1A receptors but over time they desensitise and the normal rate of brain firing is restablished.
Firing rate of neurons recover and
What is the effect of buspirone (5HT ag) on the 5HT system:
a) short term
b) long term
a) short term - firing rate decreases
b) long term - number of auto receptors in the cell body reduces so firing of 5HT neurones returns to normal. There is an increase in transmission as there is endogenous Ag + ag
What is desensitisation
receptors become inactive so when you put the agonist on again some receptors are not available to signal, therefore you get a much smaller response.
Over time the reduced 5HT release is normalised
Which 5HT receptors don’t get desensitised
s
Which 5HT receptors don’t get desensitised
postsynaptic
what could be a reason for the delay in response of antidepressants?
desensitisation
what could be a reason for the delay in response of antidepressants?
desensitisation
Buspirone has a good anxiolytic profile but lack of efficacy for ……..
efficacy of the other azapirones?
ref?
depression
gepirone, ipsapirone, flesinoxan some clinical efficacy for anxiety/depression
(Blier & Ward, 2003)
presynaptic receptors in ……. desensitize
postsynaptic receptors in the ……… do not
raphe desensitise
hippocampal receptors do not
The azapirones are full ag at ……….. and partial ag at ……..
full ag at 5HT1 autoreceptors
generally partial ag at the post synaptic 5HT1a receptors
The azapirones are full ag at ……….. and partial ag at ……..
full ag at 5HT1 autoreceptors
generally partial ag at the post synaptic 5HT1a receptors
How could we use pindolol to improve antidepressant effect
speed up desensitisation
What is pindolol
5HT1A antagonist - preferentially blocks pre-synaptic raphe receptors.
So you don’t get the inhibitory effects and slowing of firing of pre-synaptic neurones
Evidence for use on pindolol:
(2) + 2 refs
SSRIs + pindolol speeds up onset of antidepressant effects
Seagrave & Nathan, 2005
Evidence for use on pindolol:
(2) + 2 refs
- SSRIs + pindolol speeds up onset of antidepressant effects
(Seagrave & Nathan, 2005) - SB-649915 a dual 1A/1B receptor antagonist and SSRI (Watson & Dawson, 2007)
Reasons proposed for the speed up of onset with pindolol and SSRIs?
but….
Occupancy of 1A receptors by antagonist when 5HT levels are elevated
Desensitisation of other autoreceptors e.g. 5HT 1B may circumvent this stratagy
