The buspirone challenge test clearly distinguishes ME/CFS patients from healthy controls: why is it not being developed and deployed?

It all seems very complicated but the lived experience input makes me think that focusing on D2 receptors for a bit might be no bad thing and that prolactin might even be relevant in itself. Certainly, the sort of fluctuation over hours that we see with neuroendocrine signals seems potentially very relevant.

It also makes me think that studying perturbation of the system is the key to getting answers. The body's biochemistry seems to be very good at presenting us with happy homeostasis most of the time but clearly this is masking something badly wrong somewhere.
 
Jonathan Edwards said:
It all seems very complicated but the lived experience input makes me think that focusing on D2 receptors for a bit might be no bad thing and that prolactin might even be relevant in itself. Certainly, the sort of fluctuation over hours that we see with neuroendocrine signals seems potentially very relevant.

It also makes me think that studying perturbation of the system is the key to getting answers. The body's biochemistry seems to be very good at presenting us with happy homeostasis most of the time but clearly this is masking something badly wrong somewhere.
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The beauty and the beast of neuroscience, possibilities for connections seem almost infinite for this receptor alone. D2 also seem to have a more inhibitory influence on glutamate and even directly on the AMPA or NMDA receptors.

https://www.cell.com/trends/neurosciences/abstract/S0166-2236(07)00069-0

This is just an old meta-analysis I found but there are many papers out there about D2 and glutamate, also newer ones, for example this one about a migraine model in rats, where D2 receptors seem to have an effect on AMPA trafficking. I don't know about the reliability of a rat model for migraine, but I thought it's interesting to see that they consider the D2 receptor a potential target for migraine treatments.
https://link.springer.com/article/10.1186/s10194-022-01469-x

In any way it's surely interesting that there's research going on about D2 receptors in other conditions.
I don't quite understand though why they mostly seem to use quinpirole as a D2 agonist instead of cabergoline despite quinpirole being a D2 and D3 agonist and cabergoline as far as I can see solely targets D2.
 
Jonathan Edwards said:
It all seems very complicated but the lived experience input makes me think that focusing on D2 receptors for a bit might be no bad thing and that prolactin might even be relevant in itself. Certainly, the sort of fluctuation over hours that we see with neuroendocrine signals seems potentially very relevant.

It also makes me think that studying perturbation of the system is the key to getting answers. The body's biochemistry seems to be very good at presenting us with happy homeostasis most of the time but clearly this is masking something badly wrong somewhere.
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There are, after all, specific genes for D2 receptors – does the fact that these have not yet turned up in genome sequencing suggest anything?

Does this make it unlikely that they play an important role in ME, or does it simply mean that the mere presence or density of these receptors can hardly play a role in ME, and it would have to be something that influences these receptors or is influenced by them?
 
Silip said:
I don't quite understand though why they mostly seem to use quinpirole as a D2 agonist instead of cabergoline despite quinpirole being a D2 and D3 agonist and cabergoline as far as I can see solely targets D2.
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Probably because prolonged use was linked to heart valve fibrosis. The EMA recommended a max dose of 3mg a day and regular heart echos (Link). That's why it fell out of favor in Parkinson's, where the dose is much higher than for Prolactinoma.

Also it seems that Cabergoline binds to D3 as well (and the heart valve risk is because of a 5-HT receptor), so it's also not a clean D2 drug.
 
Silip said:
There are, after all, specific genes for D2 receptors – does the fact that these have not yet turned up in genome sequencing suggest anything?
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My thought was more that D2 receptor pathways might lead us to what is the specific pathway problem. As you say, the absence of genetic hits for D2 might well mean that shifts in receptor density and efficiency don't matter much because the feedback loops will work the same anyway (if they didn't the result might be severe problems with brain development since the receptor is so widespread).

It would be good if the D2 pathways lead the story to some more specific transmitter/hormone like orexin. If they don't, working out which pathway is crucial may be hard but doing something new in science always seems hard until you work out how to do it.
 
Lorazepam can also trigger a Prolactin response (The effects of the nonselective benzodiazepine lorazepam [....] on plasma prolactin levels).

It appears to be a bit tricky, because in vitro GABA should inhibit prolactin release at the lactotrophs but in vivo we see a rise.

Also note that many pwME say that lorazepam is an effective symptom/PEM relief for them (me included).

So, I think this might be an interesting test to do in combination with buspirone challenge. I imagine reduced/normal/increased response to Lorazepam could tell us something about the involved pathways.

Apologies, if this has already been here. This thread is sometimes hard to keep up with.
 
I am wondering about the nausea impact from buspirone. Sharper records a score of "29mn" for CFS cases using a 10cm visual analogue scale. I amnot sure if mn means mean or is a misprint for mm. It looks as if on average people graded nausea ~3 out of 10, which I reckon is acceptable as long as they have been warned that they might feel some nausea.

Any thoughts?
 
Turtle said:
I still use ropinirol for nerve pain, 1 1/2 year now. It still works when taken before bedtime, 4 mg. That can also cause nausea when I don't lie down in time. I was offered gabapentin, but declined because my brainfog is already bad.
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Did you notice any effects on your ME/CFS except less nerve pain?

I wonder if this discussion around Cabergoline and other D2 agents would be more on-topic in the Dopamine modifying agents thread
 
Jonathan Edwards said:
I am wondering about the nausea impact from buspirone.
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Yeah I assumed that meant 3/10 as well. Though Sharpe was the only one to report a number, none of the studies gave me the impression that the nausea was terribly severe.

Maybe the fact that patients are fasted for the test could be increasing risk of nausea? Looks like of the old studies, Bakheit, Richardson and Majeed fasted patients overnight, and Sharpe had patients fast for 4 hours. I guess there's not much we can do about that though.
 
fst said:
Did you notice any effects on your ME/CFS except less nerve pain?

I wonder if this discussion around Cabergoline and other D2 agents would be more on-topic in the Dopamine modifying agents thread
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That might be a good idea to relocate it to that thread. I would have posted my comment about cabergoline and other information on the D2 receptor there, but as I said I couldn’t find this or any other thread on dopamine after a quick search before posting.
 
I am beginning to think that there are numerous signs of paradoxical hormonal dysfunction. Empty CRH neurons but normal cortisol levels; low vasopressin levels but normal aldosterone; normal prolactin levels but prone to spikes or drops during exercise.
Of course, these observations need to be confirmed, but could all this point to a single underlying dysfunctional mechanism?
I then wonder whether a paradoxical pattern might not also be found in glutamatergic and GABAergic regulation?
Or perhaps the behaviour of hormones is sufficient to cause mess signals in other neural areas and to disturb the dynamic responses going on with normal activities.
Or perhaps none of the above, but it is intriguing.
 
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