Michael Colwell

New paper in Nature Comms @NatureComms ! If you're interested in serotonin and its influence on human behaviour, you may enjoy our new paper. We use a now-available method to increase brain serotonin that differs from conventional methods (e.g., SSRIs). nature.com/articles/s4146…

Serotonin reduces sensitivity to aversive contexts. 🧵1/10

NEW: Researchers have found increasing serotonin makes people better able to control their behaviour, particularly when exposed to negative information. More info ⬇️ ox.ac.uk/news/2024-08-0…

Serotonin changes how people learn and respond to negative information ox.ac.uk/news/2024-08-0…

Identifying dysfunctional cell types and circuits in animal models for psychiatric disorders with calcium imaging nature.com/articles/s4138…

@EllaMgdo @NatureComms Thank you!

@MichaelJColwell @NatureComms Amazing work! As a huge serotonin enthusiast in reward/aversive learning process your work is astonishing!

New paper in Nature Comms @NatureComms ! If you're interested in serotonin and its influence on human behaviour, you may enjoy our new paper. We use a now-available method to increase brain serotonin that differs from conventional methods (e.g., SSRIs). nature.com/articles/s4146…

@zenbrainest @mattbagg Thanks for sending your papers on! I will have a read tomorrow for sure. BTW I did not mean to suggest they are the same thing, but rather one supersedes the other. Would you be happy to speak over email? It's difficult to have a considered discussion re: character limits etc.

@MichaelJColwell @mattbagg pubmed.ncbi.nlm.nih.gov/11104741/ pubmed.ncbi.nlm.nih.gov/15831837/ Binding affinity ≠ functional activity. Norfen is a very potent 2C and 2B agonist!!

This is misleading as fenfluramine is metabolized quickly to norfenfluramine which is a potent 5-HT2C and 5-HT2B agonist....perhaps this is a direct fenfluramine effect? nature.com/articles/s4146…

@zenbrainest @mattbagg Interesting. Do you mind sending on a paper? Fenfluramine itself has <1% binding affinity for 5-HT2B/C vs endogenous 5-HT.

@MichaelJColwell @mattbagg I appreciate your thoughts, except norfenfluramine (which is ~30% of the mass of drug after oral fenfluramine) is a very potent 5-HT2C/2B agonist. More potent than it's actions as a 5-HT releaser!

@zenbrainest @mattbagg We used low-dose fenfluramine our study. Fenfluramine is no longer selective to serotonin at high doses, and indeed, we know the effects on VHD are dose-dependent: nature.com/articles/08010…

@mattbagg That's precisely why fenfluramine causes VHD; fen-->norfenfluramine pubmed.ncbi.nlm.nih.gov/17202450/

@zenbrainest We discuss this in quite a bit of detail in the paper. I've highlighted the specific section. Happy to discuss further.

@mattbagg Thanks! That is interesting; firing-independent release is helpful in the sense that it is less deterred by autoreceptor supersensitivity (which delays the action of SSRIs), producing a less muddied picture of temporal/spatial aspects of 5-HT signalling. But, no method is perfect

@MichaelJColwell Cool study! A potential limitation of SSRAs as a probe is their release of 5-HT is impulse independent & from every transporter. This presumably reduces temporal and spatial aspects of 5-HT signalling in ways that acute SSRIs, which boost impulse dependent release, wouldn't.

@yonicoud @NatureComms Thanks Yoni! Hope all is well in Bordeaux.

@MichaelJColwell @NatureComms Congrats Michael, very cool story!

@dr_alexharris Thank you! While not always, aversive RL is typically increased in depression, while reward RL is reduced (see rb.gy/dbsfmq). It is tempting to speculate that this drug could reduce aversive RL in MDD, but this needs testing empirically in a clinical cohort.

@MichaelJColwell This is super cool & important work! Congratulations!!! I have 2 related Q’s: 1. How do these learning & memory parameters compare to those of untreated folks with MDD & 2. What would you speculate your results would look like if you similarly increased 5HT in that population?

Our press release: ox.ac.uk/news/2024-08-0…

If you have any questions, please do drop me an email or I can reply here! Email: michael.colwell@psych.ox.ac.uk

The serotonin releasing agent fenfluramine enhances memory, reduces impulsive responses and sensitivity to negative consequences, translating work from preclinical models to humans, by Michael Colwell @SusieMurphy ://inews.co.uk/news/why-antidepressants-work-serotonin-3215154"

Thank you to @theipaper for an interesting and well-balanced take on our latest paper: inews.co.uk/news/why-antid… #serotonin