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5HT2C, reward, and motivated behavior

5ht2c serotonin antidepressants motivation anhedonia

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#1 StevesPetMacaque

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Posted 17 June 2020 - 07:57 PM


Direct dopamine agonists and reuptake inhibitors are not targeted to increase dopamine in respose to particular environmental stimuli, but rather provoke a generally stimulating effect. This is usually undesirable (though often the "lesser of two evils" when compared to no treatment at all!). However, an alternative exists: some receptors act to inhibit or enhance the release of dopamine into the synaptic cleft. In particular, both 5HT2C and KOR activation inhibit dopamine release in brain areas associated with goal-oriented behavior. KOR antagonists are covered extensively in another thread, so I'd like to start a little discussion about 5HT2C here. Unfortunately, at the moment, I can't find the exact paper that most piqued my interest in this direction, but it basically showed that mice who were administered 5HT2C agonists shifted their pattern of activity to low-cost, low-reward strategies, whereas with a 5HT2C inverse agonist, they pursued high-cost, high-reward ones.
Nevertheless, here are several related papers:
 
However, this effect can be a double-edged sword; hedonic compounds are more enticing with decreased 5HT2C activity:
 
I believe that a combination of long-acting KOR antagonism + 5HT2C inverse agonism + a balanced amount of dopamine reuptake enhancement (one wants strong dopaminergic pulses, not a steady-state "flood") would be the most effective pharmacological treatment for those (such as myself) who struggle with long-term planning and the pursuit of novel, challenging activities (vs getting stuck in a rut).


#2 ibtisam_midlet

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Posted 18 June 2020 - 12:14 AM

As of my experience with ht2c antagonist,they don't increase motivation for other things then food and maybe drugs consumption

This is must likely because ht2c receptors increase dopamine and noradrenaline in just the area of brain they are located. Which is. Regulate just food and drugs consumption.

https://en.m.wikiped...5-HT2C_receptor
https://en.m.wikiped.../wiki/Serotonin

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#3 StevesPetMacaque

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Posted 19 June 2020 - 07:31 PM

As of my experience with ht2c antagonist,they don't increase motivation for other things then food and maybe drugs consumption
 

 

That is somewhat surprising. Do you mind if I ask which antagonist you used? All of the publicly available ones have activity at many receptors; in particular, dopamine antagonism from some atypical antipsychotics could very much override the 5HT2C effects.

 

I did even more reading after your comment, and found a couple more encouraging results. There were several studies like this one that imply 5HT2C blockade will improve SSRI-induced apathy by restoring dopaminergic activity.

And this study suggests that blocking 5HT2C enhances NMDA-mediated motor neuron depolarization - if there is a more fundamentally biological way to express motivation than having your thoughts turn into stronger signals to your muscles, I am not sure what it would be.



#4 ibtisam_midlet

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Posted 19 June 2020 - 08:44 PM

Do you mind if I ask which antagonist you used?

 

this is my experience:

firstly I'm always putted on 75mg anafranil which is selective balanced serotonin noradrenaline reuptake inhibitor

https://en.wikipedia...ki/Clomipramine

one time my doctor prescript me amitriptyline as a replacement for anafranil which is primary strong HT2C antagonist and also balanced SNRI with some anticholinagic effect

https://en.wikipedia...i/Amitriptyline

 

i have ADHD and live alone so I'm cooking to my self 2 times a day, when switched to amitriptyline i started feeling I'm hungry so started cooking in 8:00am then cooking again in 12:00 which lead to cooking again in the night it was 3 time a day which is unusual because i normally lazy to cook

 

i started getting fantasies about how is so delicious to eat that meal etc..

 

after 2 days i decided to stop amitriptyline do to dry mouth side effect because of its anticolinagic effect

then my appetite restored as what is usually be.

this effect was so noticeable

 

add to that the anti psychotic olanzpine is strong HT2C antagonist which is the cause why she product profound weight gain in some cases.

https://en.wikipedia...wiki/Olanzapine

 

it's all linked to the reward system

when she reward you for gambling you will be addicted to gamble and the receptor linked to this is dopamine 3

https://en.wikipedia...wiki/Ropinirole

 

when she reward you for eating you will be fat and the receptor linked to this is HT2C

 

she always lead to motivation.


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#5 StevesPetMacaque

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Posted 20 June 2020 - 01:47 AM

Thanks for the detailed reply! At least cooking is a complex behavior - not quite the same as sitting on the couch and eating potato chips.

Amitriptyline and Olanzapine are both potent inverse agonists at the H1 receptor, with affinities up to 10x higher for that receptor than 5HT2C. This is also strongly linked to weight gain (though of course 5HT2C has a link, too).

My hope is that a cleaner 5HT2C inverse agonist will produce clearer motivational effects, especially without the histamine antagonism / inverse agonism, but I would be OK with it if part of the motivation was for food.



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#6 ibtisam_midlet

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Posted 30 June 2020 - 11:23 PM

theres a drug called cyproheptadine its well-known HT2C antagonist used as appetite increaser

you can search for it in wikipedia







Also tagged with one or more of these keywords: 5ht2c, serotonin, antidepressants, motivation, anhedonia

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