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

[ScoutB]

While I'm at it, I've had this somewhat-relevant paper open in a tab for a while:
Occupancy of Dopamine D3 and D2 Receptors by Buspirone: A [11C]-(+)-PHNO PET Study in Humans

They gave people a radioligand that binds to dopamine receptors, as well as various doses of buspirone. Then they measured how buspirone competed with the radioligand for dopamine receptors.

(DRD2 = dopamine receptor D2, DRD3 = dopamine receptor D3)

[..] findings suggest [buspirone] has high in vitro affinity for dopamine receptor D3.

No study has explored the occupancy of DRD3 by buspirone in humans. Here, we used positron emission tomography (PET) and the D3-preferring probe, [11C]-(+)-PHNO, to test the hypothesis that buspirone will occupy (i.e. decrease [11C]-(+)-PHNO binding) the DRD3 more readily than the DRD2. Eight healthy participants underwent [11C]-(+)-PHNO scans after single oral dose administration of placebo and 30, 60, and 120 mg of buspirone in a single-blind within-subjects design.

Two of their results might be of interest for us.
(1) Prolactin release correlated to dopamine receptor occupancy by buspirone:

[11C]-(+)-PHNO binding in DRD2- and DRD3-rich areas was decreased by the highest (60–120 mg), but not the lowest (30 mg), doses of buspirone. The maximal occupancy obtained was ~25% in both areas. Plasma levels of prolactin (a DRD2 marker) correlated with percentage occupancy after orally administered buspirone.

(2) in vitro buspirone is much more selective for D3 than D2 (which is interesting because prolactin release is controlled by D2 receptors). However, this study found that in vivo the D2 vs D3 selectivity of buspirone seems to be more equally balanced:

The in vitro data indicate a twofold affinity and an 11-fold functional selectivity [of buspirone] for DRD3 over 5HT1A, and 70-fold affinity over DRD2 (Kula et al, 1994), with metabolites of buspirone also binding with higher affinity to DRD3 relative to DRD2 (Bergman et al, 2013).

Our data indicate for the first time that acute doses of buspirone can occupy DRD2 and DRD3 in human subjects. This occupancy was in the same range for the DRD2 vs DRD3 and the maximum occupancy achieved during acute single-dose regimen was modest with the doses of buspirone tested.

 

[hotblack]

Thanks @ScoutB that’s really useful.

DecodeME Locuszoom for DRD2 which I guess you could say maybe shows a little hump in the area but nothing significant. And not even a blip on DRD1, 3 or 4.

 

[hotblack]

Some other bits from reading

From the Wikipedia page for prolactin

Prolactin also acts in a cytokine-like manner and as an important regulator of the immune system. It has important cell cycle-related functions as a growth-, differentiating- and anti-apoptotic factor. As a growth factor, binding to cytokine-like receptors, it influences hematopoiesis and angiogenesis and is involved in the regulation of blood clotting through several pathways. The hormone acts in endocrine, autocrine, and paracrine manners through the prolactin receptor and numerous cytokine receptors.

Pituitary prolactin secretion is regulated by endocrine neurons in the hypothalamus. The most important of these are the neurosecretory tuberoinfundibulum (TIDA) neurons of the arcuate nucleus that secrete dopamine (a.k.a. prolactin inhibitory hormone) to act on the D2 receptorsof lactotrophs, causing inhibition of prolactin secretion. Thyrotropin-releasing hormone has a stimulatory effect on prolactin release, although prolactin is the only anterior pituitary hormone whose principal control is inhibitory.

increased serum concentrations of prolactin during pregnancy cause enlargement of the mammary glands and prepare for milk production, which normally starts when levels of progesterone fall by the end of pregnancy

In general, dopamine inhibits prolactin, but this process has feedback mechanisms.

Prolactin also stimulates proliferation of oligodendrocyte precursor cells. These cells differentiate into oligodendrocytes, the cells responsible for the formation of myelin coatings on axons in the central nervous system.

Prolactin follows diurnal and ovulatory cycles. Prolactin levels peak during REM sleep and in the early morning. Many mammals experience a seasonal cycle

During pregnancy, high circulating concentrations of estrogen and progesterone increase prolactin levels by 10- to 20-fold.

Levels can rise after exercise, high-protein meals, minor surgical procedures, following epileptic seizures or due to physical or emotional stress.

A lot to unpick and things may not be a clear single directional effect, but the relationship to dopamine and variation with sleep/wake and menstrual cycles aa well as changes in pregnancy given the reports we have on changes in me/cfs symptoms seems interesting.

 

[hotblack]

And on the receptor

Prolactin receptors are present in the mammillary glands, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin and areas of the central nervous system. When prolactin binds to the receptor, it causes it to dimerize with another prolactin receptor. This results in the activation of Janus kinase 2, a tyrosine kinase that initiates the JAK-STAT pathway. Activation also results in the activation of mitogen-activated protein kinases and Src kinase.

A bit more from the dedicated Wikipedia page

The PRLR is a class 1 cytokine receptor that uses messenger pathways to control cell proliferation, migration, intracellular ion concentration and inhibit programmed cell death (apoptosis). PRLRs also have functions in the second messenger cascades, including:

• JAK-STAT pathway – the STAT protein family has been shown to have a key transduction role in cytokine receptor signalling; this pathway is initiated following the activation of PRLRs. Although there have been 4 STAT proteins identified as transducer molecules of PRLR, STAT5 is recognised as the most important transducer of PRLR isoforms, with a role in inhibiting the regulation of gene transcription.

 

[hotblack]

It seems that elevated prolactin is unlikely to be our problem (see https://en.wikipedia.org/wiki/Hyperprolactinaemia) but the way in which it and dopamine interact with effects on GABA in another of these finely balanced and regulated systems does seem enticing somehow.

If there were a problem somewhere with dopamine receptors or function of cells like the eMSNs/eSPNs you can see how this whole loop could easily spin out or be nudged in one direction or another.

 

[ChronicallyOverIt]

Ah you guys are already talking about the dopamine connection!

When I ran LDN my prolactin went really high, during this time I found this paper with monkey prolactin on naltrexone:

Behavioural and endocrine effects of naltrexone in male talapoin monkeys - PubMed

The effect of treating captive male talapoin monkeys with naltrexone hydrochloride (500 micrograms/kg intra-muscular injection twice daily) was studied both in socially living and singly caged animals. The behaviour of the group males and endocrine changes in all treated animals were monitored...

pubmed.ncbi.nlm.nih.gov

 

[ScoutB]

Good to have this info here.

Another datapoint in support of hyperprolactinaemia not being our problem: if I recall correctly, several of these buspirone challenge studies also checked prolactin before the challenge and found it was the same between pwME and controls. But maybe having little spikes of prolactin all the time that are larger than usual has its own set of consequences.

I'm also very curious about the other direction -- if the (claimed) buspirone sensitivity says something about the D2 receptors that could in turn tell us about something happening upstream with dopamine.

 

[bobbler]

Some other bits from reading

From the Wikipedia page for prolactin













A lot to unpick and things may not be a clear single directional effect, but the relationship to dopamine and variation with sleep/wake and menstrual cycles aa well as changes in pregnancy given the reports we have on changes in me/cfs symptoms seems interesting.

Yes this is very interesting stuff thanks @hotblack

In general, dopamine inhibits prolactin, but this process has feedback mechanisms.

Alongside the buspirone potentially being dopamine-related effect in causing the prolactin in the above ME/CFS research makes it interesting.

 

[SugarSquared]

With the WE&ME funding opportunity, I think it would be a good time to see if we can get a researcher interested in doing a study on this.

Has anyone contacted Fluge & Mella? Any other ideas of who would be a good fit? It seems buspirone challenge studies have dropped off in popularity, but maybe we can contact the last people who did one? @forestglip, did you ever get any more responses to your emails?

 

[forestglip]

@forestglip, did you ever get any more responses to your emails?

A couple more, but one didn't respond when I asked if I could copy what they said, and the other specifically asked that I don't copy their response. But it's really not anything much different from what the other researchers said. No one said they believed it wasn't a real finding. It just kind of fizzled out, I think mainly because it wasn't clear where to go from there.

 

[ScoutB]

Yea I’ve been meaning to think more about this.

I wonder if some of the researchers who’ve done brain scans recently (especially the long covid dopamine one) would have any interest or ideas about what could be going on, or how it could be investigated further.

 

[ChronicallyOverIt]

I’ve been exploring options here in BC Canada as a group here did a brain scan study. I will update when I get a bit more understanding of how the previous study came to be, and if there is still a framework to do biomedical research on ME here. Things seem to have fizzled a bit on that front. It will take time though.

 

[ChronicallyOverIt]

Would anyone be able to help me with what I would call an "elevator pitch". Basically a short paragraph(s) summary on what was missed, implications, and what could be measured potentially in the future? Very very preliminary I am trying to put out feelers to see if there is interest and I think this would help a lot. It doesn't have to be perfect at all.

AI summary:
The buspirone challenge reliably distinguishes ME/CFS patients through abnormal prolactin spikes, but past research overlooked that this response is likely driven by buspirone’s occupancy of Dopamine D2 receptors rather than just serotonin. Future diagnostics must pivot to measuring upstream D2 receptor dysfunction and the resulting dopamine-prolactin feedback loops that may drive systemic immune crashes. This specific neuroendocrine pathway provides a highly actionable target for the DecodeME study: by cross-referencing this dopamine-prolactin hypothesis with DecodeME's massive GWAS dataset, researchers can hunt for specific genetic variants (SNPs) linked to D2 receptor function or neuroendocrine signaling, bridging the gap between a proven physiological anomaly and its root genetic causes to accelerate the discovery of targeted biomarkers and treatments.

 

[Jonathan Edwards]

Would anyone be able to help me with what I would call an "elevator pitch".

I would be happy to contribute but am trying to get my head around another project or two at present. I will try to keep this in mind.

 

[ChronicallyOverIt]

I would be happy to contribute but am trying to get my head around another project or two at present. I will try to keep this in mind.

I don’t think right now this is super time sensitive, so focus on those, I’m working on making connections. I can reach out again if it does become time sensitive. It’s more in the case I make the right connection I want to be able to clearly summarize why this is valuable. Just trying to get my ducks in a row.

 

[Utsikt]

From a layman so take it for what it’s worth:

The buspirone challenge reliably distinguishes ME/CFS patients through abnormal prolactin spikes, but past research overlooked that this response is likely driven by buspirone’s occupancy of Dopamine D2 receptors rather than just serotonin.

Are the findings robust enough to say «reliably»?

Future diagnostics must pivot to measuring upstream D2 receptor dysfunction and the resulting dopamine-prolactin feedback loops that may drive systemic immune crashes.

What are «future diagnostics»?

Why «must» they do it? Would it be better to say that it’s promising or that more research is warranted?

What are «systemic immune crashes»?

This specific neuroendocrine pathway provides a highly actionable target for the DecodeME study: by cross-referencing this dopamine-prolactin hypothesis with DecodeME's massive GWAS dataset, researchers can hunt for specific genetic variants (SNPs) linked to D2 receptor function or neuroendocrine signaling, bridging the gap between a proven physiological anomaly and its root genetic causes to accelerate the discovery of targeted biomarkers and treatments.

Maybe add «and upcoming WGS (SequenceME)» after the mention of DecodeME?

Is it «proven»?

For once I think «biomarker» might be warranted, but perhaps «accelerate the discovery of actionable pathological abnormalities, ultimately leading to much needed treatments» is better?

If you’re planning on cold approaches to outsiders to ME/CFS, you might also need a short intro like:
ME/CFS is a highly disabling and often lifelong syndrome affecting about one in every two hundred people. There are no available treatments and no reliable understanding of the pathology.