5ht receptors

Question 1

Overall structure

Answer 1

1. Intro
2. 5HT1A receptor
3. 5HT1A role in depression
4. Desensitisation
5. Buspirone
6. SSRIs
7. Pindolol
8. Other treatments
9. Conlcusions

Question 2

Intro

Answer 2

1. Anxiety and mood disorders affect millions of people in the UK every year costing large amounts to the economy.
2. There are many limitations with existing antidepressants requiring persistent and vigorous treatment and even then, only 70% enter remission.
3. All of the antidepressants currently in use have been shown to be more efficacious than placebo but only a few are found to be more acceptable than placebo due to side effects.
4. The safety and onset time as well as withdrawal effects are further limitations of existing antidepressants.
5. Therefore, there is a need to identify new therapeutic targets to improve treatments and 5-ht1a receptors may be an effective approach

Question 3

5HT1A mechanisms pt 1

Answer 3

1. The serotonergic system originates from neurons in the raphe nuclei and project widely to various areas in the brain involved in the regulation of mood.
2. There are seven major families of 5HT receptors which are located in different areas and are involved in a variety of physiological processes.
3. 5-HT1A receptors are a subtype which are either located presynaptically in the raphe nuclei somatodendritically on 5-HT neurons (autoreceptors) or post-synaptically on non-5HT neurons (heteroreceptors).
4. 5HT-1A receptors are Gi/Go coupled and when they are activated the alpha subunit dissociates from the g-protein and inhibits adenylyl cyclase, which inhibits cAMP and the phosphorylation of PKA.
5. The beta and gamma subunits also dissociate and are responsible for closing calcium channels and opening potassium channels.

Question 4

5HT1A receptor pt 2

Answer 4

1. The 5HT1a autoreceptors are coupled to calcium channels and their activation results in the closure of these channels which reduces calcium mediated exocytosis of the neurotransmitter and reduces transmitter release.
2. These autoreceptors function physiologically as a negative feedback mechanism that regulates 5-HT release
3. their activation by excess 5HT results in a decrease in the firing of the 5HT neuron and subsequently reduces the synthesis, turnover, and release of 5-HT from nerve terminals in projection areas.
4. 5HT1A heteroreceptors however, are coupled to potassium channels and their activation results in their opening and potassium leaving the cell down the concentration gradient, eliciting a slow hyperpolarisation of the nerve they are located on.
5. Post-synaptic 5-HT1A heteroceptors are widely distributed in forebrain regions that receive serotonergic input including the cortex, hippocampus and amygdala, regulating their firing.

Question 5

5HT1A receptor role

Answer 5

1. involved in the regulation of mood and anxiety and as a result have been the target of various mood disorder treatments such as the anxiolytic buspirone.
2. Lemonde et al 2003
3. Moreover, a further study by Lemonde et al 2004,
4. Furthermore, using PET imaging Drevets et al 1999,
5. These studies all indicate the importance of these receptors in both mood regulation and response to treatment and therefore their potential importance in treatments for anxiety and depression.

Question 6

Lemonde et al 1

Answer 6

1. 2003
2. identified that the individuals with major depression were twice as likely to have the C(-1019)G polymorphism of the 5-HT1AR promoter gene.

Question 7

lemonde et al 2

Answer 7

1. 2004
2. found that those with the same single nucleotide polymorphism were less likely to respond to antidepressant treatments such as fluoxetine.

Question 8

Drevets et al

Answer 8

1. using PET imaging Drevets et al 1999, found that 5HT1A binding potential was significantly reduced in patients with major depression in both the midbrain raphe and the corticolimbic areas.

Question 9

Desensitisation

Answer 9

1. Sustained exposure to an agonist result in the desensitisation of 5HT1A receptors.
2. Desensitisation is the agonist-induced loss of function which occurs when a receptor has been activated by an agonist leaving it non-functional for a period of time and unable to be activated if exposed to the agonist again.
3. This process is thought to be related to the therapeutic effects of SSRIs and buspirone.

Question 10

Buspirone

Answer 10

1. partial agonist of both post and pre-synaptic 5-HT1A receptors.
2. It has reduced side effects compared to benzodiazipines and a better safety profile,
3. however it has a short half-life requiring frequent dosing and a delayed onset of therapeutic action.
4. The activation of the heteroreceptors results in the hyperpolarisation and therefore inhibition of the fore-brain neurons e.g. glutamatergic nerves.
5. This process therefore reduces the excitability of these neurons which produces an anxiolytic effect.
6. Buspirone selectively turns up the 5HT1A response as systemic application also activates the autoreceptors which reduces the firing of the 5-HT neuron reducing transmitter release.
7. Buspirones have a delayed therapeutic effect which is thought to be the result of the increased activation of the autoreceptors which decreases the 5-HT neuron firing.
8. After a few weeks these autoreceptors are thought to be desensitised and normal firing is resumed, further increasing the activation of heteroreceptors allowing the full therapeutic effect to be achieved.
9. Interestingly, the effect of desensitisation is only seen in the 5HT1A autoreceptors.
10. But is known that injecting buspirone directly into the amygdala of mice is enough to get anxiolytic effects so may not involve actions in the pre-synaptic receptors at all.

Question 11

SSRIs

Answer 11

1. Selective serotonin reuptake inhibitors (SSRIs) bind to 5-HT transporters, blocking their action acutely leading to increased levels of 5HT in the synapse and somatodendritcally.
2. This will activate 5HT autoreceptors leading to a transient decrease in the firing rate of neurons, but as the autoreceptors desensitise due to prolonged exposure to 5-HT, the firing rate will recover resulting in enhanced synaptic 5HT levels.
3. Similarly, to buspirone, the transient decrease in 5HT neuron firing bought about by autoreceptor function is one reason why SSRIs are thought to have a delayed therapeutic response.

Question 12

Pindolol

Answer 12

1. The action of desensitisation therefore led to the idea that if the desensitisation process could be accelerated or bypassed by selectively antagonising the 5HT1A autoreceptors or using a selective post-synaptic agonist the onset of therapeutic action may be faster.
2. Pindolol (a 5HT1AR antagonist) binds preferentially to autoreceptors and so blocks their activation preventing the transient decrease in 5HT neuron firing.
3. This preferential binding was seen by Martinez et al 2001
4. It has therefore been investigated as something to use alongside certain anti-depressants to increase their onset time and augment their effect.
5. However, there has been a large variability in results.
6. A study by Blier et al 1997
7. Similarly, Bordet et al 1998,
8. In contrast, Berman et al 1999
9. Factors such as the different depression criteria, whether it was the patients first depressive episode, the length of the depressive episode and timing of pindolol application all seemed to contribute to the variability.
10. Furthermore, disparities in the patient’s such as decreased differentiation in affinity between autoreceptors and heteroreceptors, differences in 5HT1A receptors reserve and gene expression would also be expected to influence the effectiveness of pindolol to act as an augmenter.
11. It is also unknown how it affects the desensitisation of other 5HT autoreceptors such as the 5HT1B which if not blocked may reduce firing of the 5HT neuron anyway.

Question 13

Martinez et al 2001

Answer 13

This preferential binding was seen by Martinez et al 2001, using PET scanning to look at receptor occupancy after applications of pindolol and found occupancy of the receptors in the raphe nucleus was significantly higher than elsewhere.

Question 14

Blier et al

Answer 14

1. 1997
2. found that application of pindolol alongside buspirone to patients with MDD reduced depressive symptoms significantly in the majority of patients, this effect was much larger than application of buspirone alone.

Question 15

Bordet

Answer 15

1. 1998
2. carried out a Double-Blind, Placebo-Controlled Trial which found a significant acceleration in response with Paroxetine and pindolol compared to paroxetine alone.

Question 16

Berman et al

Answer 16

1. In contrast, in a double-blind placebo-controlled trial Berman et al 1999
2. found no accelerated or augmented anti-depression response with concurrent application of pindolol and fluoxetine

Question 17

Other treatments

Answer 17

1. Despite these uncertainties, further developments of antidepressants using this idea have led to compounds which combine various autoreceptors antagonists with an SSRI.
2. One example of this is SB‐649915 which is a 5HT transporter inhibitor as well as an antagonist at both 5HT1A and 1B receptors (1B are also suggested to be involved in SSRI delayed therapeutic effect).
3. Starr et al 2007
4. Vilazodone is a serotonin partial agonist reuptake inhibitor (SPARI), it has selective affinity for the 5HT1A receptor.
5. In a double-blind, placebo-controlled trial, Kahn et al 2011
6. Similar results were found by Rickels et al 2009,
7. There are various other antidepressants which have been developed using these ideas such as Vortioxetine which is a multi-modal drug which is an SSRI, an agonist of 5-HT1A, an antagonist of the 5-HT3 and 5-HT7 receptors, a partial agonist of 5-HT1B.

Question 18

Starr et al

Answer 18

1. 2007
2. showed SB‐649915 significantly increased the onset of anxiolytic effects compared to paroxetine in the high light social interaction test.

Question 19

Kahn et al 2011

Answer 19

1. In a double-blind, placebo-controlled trial, Kahn et al 2011 found that vilazodone was shown to be significantly more efficacious than placebo with similar efficacies to other anti-depressants.

Question 20

Rickels et al

Answer 20

1. Similar results were found by Rickels et al 2009
2. who also found that Vilazodone appeared to have a better side effect profile with fewer sexual side effects and no evidence of weight gain.

Question 21

Conclusion

Answer 21

1. Overall, the 5HT1A receptors have been identified as playing an important role in many antidepressants’ mode of action with the potential delayed therapeutic effects corresponding to the time taken for desensitisation of autoreceptors.
2. This idea has laid the foundation for the development of novel therapeutic strategies to improve the side effects and onset time of the medications currently in use.