SB L1 - Monoamines 2 - 5HT1A

Question 1

What type of receptors are 5HT1AR?

Answer 1

GPCR

Question 2

What is the presynaptic action of 5HT1AR activation?

Answer 2

Closes calcium channels to reduce transmitter release (autoreceptor)

Question 3

What is the postsynaptic action of 5 HT 1aR activation?

Answer 3

opens potassium channes eliciting slow hyperpolarisation - (this has an inhibitory effect on transmission)

Question 4

What is the pharma action of SSRIs?

Answer 4

Inhibit 5HT reuptake via SERT

Question 5

Note: not all agonists are full or partial agonists and pre and post synaptic sites

Answer 5

…..

Question 6

What happens if you administer buspirone in the forebrain region?

Answer 6

anxiolytic response - so anxiolytic effects are partially mediated through activation of this receptor

Question 7

how fast does buspirone create response?

Answer 7

~2 weeks

it’s thought to be as fast acting as BZs

Question 8

Where are 5HT1A receptors localised (broadly according to SB diagram)

Answer 8

Pre-synaptic in the Raphe nuclei

Post-synaptic in forebrain regions such as the hippocampus

Question 9

What is the effect of buspirone (5HT ag) on the 5HT system overall

Answer 9

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

Question 10

What is the effect of buspirone (5HT ag) on the 5HT system:

a) short term
b) long term

Answer 10

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

Question 11

What is desensitisation

Answer 11

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

Question 12

Which 5HT receptors don’t get desensitised

Answer 12

s

Question 13

Which 5HT receptors don’t get desensitised

Answer 13

postsynaptic

Question 14

what could be a reason for the delay in response of antidepressants?

Answer 14

desensitisation

Question 15

what could be a reason for the delay in response of antidepressants?

Answer 15

desensitisation

Question 16

Buspirone has a good anxiolytic profile but lack of efficacy for ……..
efficacy of the other azapirones?

ref?

Answer 16

depression

gepirone, ipsapirone, flesinoxan some clinical efficacy for anxiety/depression

(Blier & Ward, 2003)

Question 17

presynaptic receptors in ……. desensitize

postsynaptic receptors in the ……… do not

Answer 17

raphe desensitise

hippocampal receptors do not

Question 18

The azapirones are full ag at ……….. and partial ag at ……..

Answer 18

full ag at 5HT1 autoreceptors

generally partial ag at the post synaptic 5HT1a receptors

Question 19

The azapirones are full ag at ……….. and partial ag at ……..

Answer 19

full ag at 5HT1 autoreceptors

generally partial ag at the post synaptic 5HT1a receptors

Question 20

How could we use pindolol to improve antidepressant effect

Answer 20

speed up desensitisation

Question 21

What is pindolol

Answer 21

5HT1A antagonist - preferentially blocks pre-synaptic raphe receptors.

So you don’t get the inhibitory effects and slowing of firing of pre-synaptic neurones

Question 22

Evidence for use on pindolol:

(2) + 2 refs

Answer 22

SSRIs + pindolol speeds up onset of antidepressant effects

Seagrave & Nathan, 2005

Question 23

Evidence for use on pindolol:

(2) + 2 refs

Answer 23

1. SSRIs + pindolol speeds up onset of antidepressant effects
   (Seagrave & Nathan, 2005)
2. SB-649915 a dual 1A/1B receptor antagonist and SSRI (Watson & Dawson, 2007)

Question 24

Reasons proposed for the speed up of onset with pindolol and SSRIs?

but….

Answer 24

Occupancy of 1A receptors by antagonist when 5HT levels are elevated

Desensitisation of other autoreceptors e.g. 5HT 1B may circumvent this stratagy