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Dopamine/Serotonin antagonists?


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#1 Lallante

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Posted 26 April 2010 - 12:50 PM


Apologies, but this is a crosspost from the medicine forum - it sat there for a week or more with no replies, and I want to see if the inhabitants of this forum can do any better:

After reading this fascinating thread:
http://www.imminst.o...showtopic=18073
which involves using low doses of Naltrexon at night to artificially up-regulate opioid receptors in the brain (and thus naturally be more sensitive to opioids during the day in response).

I was wondering if the same concept (antagonist at night to create natural agonism during the day) could be used in relation to serotonin or dopamine.

So, brains of Imminst, I pose to you the following questions:
1) What serotonin receptor antagonists are there with minimal side effects and shortish halflife (6-8 hours or so max, or you wouldnt get any benefits)?
2) What dopamine receptor antagonists are there with minimal side effects and shortish halflife?
3) Would this work in the same way as using Naltrexon did to opioid receptors (eg force them to gain higher sensitivity to naturally-produced opioids)
4) What would be the likely effects on you the next day?
5) Any thought as to long term risks (or benefits?)
6) Any hormonal effects?


Apologies if this is the mechanism by which something commonly used already acts and Im just being thick.

#2 KimberCT

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Posted 26 April 2010 - 01:43 PM

I think monoamine receptors are more about balance. Hyperactivity in these systems would be more associated with a disease state rather than increased wellbeing.

But... to answer a couple of your questions...

1) Cyproheptadine, although 5-HT2 receptors down regulate in the pretense of antagonists/inverse agonists
6) D2 antagonists increase prolactin

I was also under the impression that LDN worked, not by upregulating opioid receptors, but instead by causing a larger release of natural opioids in the early morning hours.

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#3 FunkOdyssey

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Posted 26 April 2010 - 01:46 PM

I was also under the impression that LDN worked, not by upregulating opioid receptors, but instead by causing a larger release of natural opioids in the early morning hours.


It does both.

#4 Animal

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Posted 26 April 2010 - 10:43 PM

This wouldn't work in the same way at all. Catecholamine and monoamine receptors are far more readily regulated to compensate for variations in activity and ligand saturation, they have to be since catecholamines are both neuromodulators and hormones, and they are the primary facilitators of sympathetic nervous system functionality including physiological indicators of physical activity. While monoamines are heavily involved in gastrointestinal functionality, reproductive capability and in fibrogenesis.

This is aside from their direct activity at the synaptic cleft, in neuronal action potential transduction. Thus having a huge effect on behaviour and perception.

Opioids on the other hand are primarily indicated in analgesia (as everyone knows) , mood and systemic secondary sedation. Physiologically their role is far less immediate, and endogeneously the levels of opioid tend to fluctuate over time, as opposed to spontaneously, so there is less demand for immediate regulatory response. They do not function directly as neurotransmitters, but are neuromodulators, especially influencing the GABA dynamic. In theory you could survive without endorphins entirely, but you wouldn't be very functional.

Too much dopamine; Hypertensive crisis. Too much serotonin; Serotonin syndrome. Too much opioid activity; respiratory depression. In terms of molar concentrations, opioid levels have to be far higher then the other two ligands in order to trigger a potentially terminal physiological response.

Basically what I'm saying is that DA and 5-HT behave in completely different ways to opioids, and it is a gross oversimplification to believe that they can be manipulated in the same way that opioids can.

Saying that, receptor up-regulation is still a tertiary response to a moderate decrease in DA or 5-HT ardency, and increased sensitivity can be enabled though a somewhat similar mechanism with a different dynamic.

Neuroleptics are DA antagonists, but their MOA tends to increase the activity of tyrosine hydroxylase, rather then receptor density, and so they will typically not facilitate the response you want, at least not at typical dosing levels. With prolonged low dose exposure however they can act in a way that would be enabling to an increase in dopamine sensitivity.

Sulbutiamine induces an increase in the density of D1 dopamine receptors in the prefrontal cortex due to a reduction in the release of dopamine. But because it has a positively charged thiazole moiety it can only be transported across the plasma membrane of dopaminergic neurons by high affinity carriers, what this means, especially in the brain because of it's anion activity, is that the rate of transport tends to fluctuate. So that you get an oscillation of dopamine release in the cortex, over a prolonged period (a few weeks) this oscillation will be compensated for through reactionary changes in endogenous dopamine production. The net result being the sulbutiamine's effectiveness will become negligible, and you'll be left with a dystonic dopaminergic system.

With regards to dopamine, agonists (particularly D1) are your best bet, but they are difficult to procure.

Serotonin on the other hand already has a novel sensitization agent in the form of Tianeptine (Stablon), a beautiful molecule which not only facilitates an increase in the density of serotonin receptors, it also increases activity of dopamine in the striatum, thus increasing the explicit activity of spiny GABA-ergic projection neurons, giving rise to anxiolysis and mood enhancement (through the increase in GABA-B). Tianeptine also enhances the affinity of the D2 and D3 dopamine receptors for their ligand through minor conformational changes, once again improving your feelings of well-being markedly.

So options are:

Dopamine - Sub theraputic doses of a neuroleptic (I recommend sulpride) OR weekly cycling of sulbutiamine with a dopamine precursor such as L-Tyrosine.

Serotonin - Tianeptine!!! There are others, but what's the point when you already have the perfect substance. :)

Edited by Animal, 26 April 2010 - 10:49 PM.

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#5 Charmion

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Posted 26 April 2010 - 11:20 PM

Mon Dieu! Animal, do you have a Ph.D. or something? How long have you been studying this stuff?

#6 kassem23

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Posted 26 April 2010 - 11:39 PM

Mon Dieu! Animal, do you have a Ph.D. or something? How long have you been studying this stuff?


I was thinking the exact same thing. Great stuff, animal. I really hope you are a neuroscientist or something because thats a hell of a lot of knowledge about advanced mechanisms :)

#7 Lallante

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Posted 27 April 2010 - 12:05 AM

Wow Animal, that is incredible. It sounds like you have some experience with Tianeptine. Would it be a useful stack component for a healthy person? (hell, from the way you describe it - does it have recreational uses??)

#8 Animal

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Posted 27 April 2010 - 12:15 AM

Mon Dieu! Animal, do you have a Ph.D. or something? How long have you been studying this stuff?


:) Well I'm actually in the final year of studying for my doctorate in molecular and genomic biology, with a specialisation in viral engineering and gene therapy. My thesis is titled 'Epigenetic Manipulation of Hominid Neurogenetic Phylogeny' hehe, just wanted to write that down, sounds so cool, but it is relevant because it has implications in what I wrote in that previous post. I guess I've been studying biology as a specialisation for 10 years now, and I work as a scientist anyway, contracted by my university.

If you can believe it I'm not actually a good student, not in my attitude towards the education system anyway, it's my intense interest in the subject as a whole, and I suppose a natural ability, that has got me this far whilst maintaining such a high standard.

Usually I don't bother writing out such detailed posts, but it just kept flowing, you know how it is sometimes. Plus I have a personal passion towards the pursuit of the ideal that humans should not be slaves to their neurochemical predilections, we should be in control!
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#9 haha

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Posted 27 April 2010 - 12:30 AM

http://www.endocytosis.org/Adaptors/ i think these subunits are the opoids and nalteroxone doesnt block the sigma, just an idea to its mechansium of action. Sorry shouldnt have broughtup as will change subject

#10 Animal

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Posted 27 April 2010 - 01:05 AM

Wow Animal, that is incredible. It sounds like you have some experience with Tianeptine. Would it be a useful stack component for a healthy person? (hell, from the way you describe it - does it have recreational uses??)


This is a difficult question to answer. What exactly is healthy? Can you be more then healthy?

Tianeptine is unique, it has both immediate and long term mood enhancing, anxiolytic and potentially nootropic effects. In terms of immediate effects you will get a mild but sustained stimulant sensation, coupled with subtle but noticeable secondary and tertiary dopaminergic mood enhancement. This is due to it's relatively rapid conformational modulation of D2 and D3 peripheral receptors.

The true effectiveness of tianeptine only becomes apparent after at least two weeks of thrice daily consistent dosing. This is when the anxiolytic and pronounced mood enhancing effects will begin to be expressed. This is partially due to central modulation of D2, D3 receptors. But more contributory is the increase in 5-HT generic receptor density and the dopaminergic facilitated transduction of GABA-ergic projection. The latter of which, through indirect mechanisms still under investigation, (this is the real magic of tianeptine) also increases the D1 ligand-receptor binding affinity. This includes a substantial (relative 0.1) quantitative increase in the configuration integral dynamic through a change in the partial constant: Beta:= variable 1/Kb*T Where K is the Boltzmann constant and T is the thermodynamic temperature. LOL, it's hard to write equations in BB code, but hopefully any mathematicians out there will see what I'm getting at.

The fantastic thing about tianeptine is that it is rapid acting, has almost no side effects and you don't develop tolerance to it, if anything the effectiveness just improves with time. It is also neuroprotective, since there is a reduction in DA catabolism and hence reduced reactive oxygen species produced during normal neurological metabolism.

I do have direct experience with the substance I used it to self medicate a mood disorder. I took it for approximately 6 weeks, before I had to perform an effectively non-existent but not particularly unpleasant taper, due to a delivery delay. I haven't been back on it yet because in the mean time I'm experimenting with a different pharmaceutical and I don't want to confound the results. While I was on it I loved it, the immediate effects are certainly subtle, I suffer from dysthymia (currently managed very effectively) and what I noticed from the first day, after the second dose, it that I was laughing more easily, I felt so at ease with whatever I was currently doing, and while I didn't feel stimulated in the traditional sense, there was this odd underlying clarity that made it easy to devote my energy towards whatever I chose. Now I know this wasn't placebo because at the time I hadn't been expecting any immediate effects at all, I kept a diary though this allowed me to make effective comparisons.

As time continued I noticed the effects becoming more and more substantial, such that after about a month I felt fantastic. Not in the sense of I was high or euphoric, just that everything felt so easy in terms of application of thought and attention, my socialisation dynamic had become so much more enjoyable, I remember feeling this odd calm that would seem to cushion any negative feelings. If anything about the substance was addictive it was that sensation, not a high, but a barrier effectively preventing any lows. Then there was the constant enthusiasm I had, and the ease with which I would become excited.

I am certainly going to begin taking it again at an appropriate time. As for whether you should take it if you're healthy, well that is a personal choice. I don't see why you would want to become dependent on a substance when your well-being is perfectly satisfactory to begin with, mine certainly isn't. It would certainly have a 'positive' effect on you, the only issue is that the therapeutic dose (3*12.5mg/day) is mandatory, since it has a fairly short half-life and you need to maintain 24hr coverage. So it's not like you can take a reduced dosage. Personally, unless you have an issue with mood/motivation/energy that you feel affects your quality of life I can't really recommend it.
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#11 Thorsten3

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Posted 27 April 2010 - 10:02 PM

Wow Animal, that is incredible. It sounds like you have some experience with Tianeptine. Would it be a useful stack component for a healthy person? (hell, from the way you describe it - does it have recreational uses??)


This is a difficult question to answer. What exactly is healthy? Can you be more then healthy?

Tianeptine is unique, it has both immediate and long term mood enhancing, anxiolytic and potentially nootropic effects. In terms of immediate effects you will get a mild but sustained stimulant sensation, coupled with subtle but noticeable secondary and tertiary dopaminergic mood enhancement. This is due to it's relatively rapid conformational modulation of D2 and D3 peripheral receptors.

The true effectiveness of tianeptine only becomes apparent after at least two weeks of thrice daily consistent dosing. This is when the anxiolytic and pronounced mood enhancing effects will begin to be expressed. This is partially due to central modulation of D2, D3 receptors. But more contributory is the increase in 5-HT generic receptor density and the dopaminergic facilitated transduction of GABA-ergic projection. The latter of which, through indirect mechanisms still under investigation, (this is the real magic of tianeptine) also increases the D1 ligand-receptor binding affinity. This includes a substantial (relative 0.1) quantitative increase in the configuration integral dynamic through a change in the partial constant: Beta:= variable 1/Kb*T Where K is the Boltzmann constant and T is the thermodynamic temperature. LOL, it's hard to write equations in BB code, but hopefully any mathematicians out there will see what I'm getting at.

The fantastic thing about tianeptine is that it is rapid acting, has almost no side effects and you don't develop tolerance to it, if anything the effectiveness just improves with time. It is also neuroprotective, since there is a reduction in DA catabolism and hence reduced reactive oxygen species produced during normal neurological metabolism.

I do have direct experience with the substance I used it to self medicate a mood disorder. I took it for approximately 6 weeks, before I had to perform an effectively non-existent but not particularly unpleasant taper, due to a delivery delay. I haven't been back on it yet because in the mean time I'm experimenting with a different pharmaceutical and I don't want to confound the results. While I was on it I loved it, the immediate effects are certainly subtle, I suffer from dysthymia (currently managed very effectively) and what I noticed from the first day, after the second dose, it that I was laughing more easily, I felt so at ease with whatever I was currently doing, and while I didn't feel stimulated in the traditional sense, there was this odd underlying clarity that made it easy to devote my energy towards whatever I chose. Now I know this wasn't placebo because at the time I hadn't been expecting any immediate effects at all, I kept a diary though this allowed me to make effective comparisons.

As time continued I noticed the effects becoming more and more substantial, such that after about a month I felt fantastic. Not in the sense of I was high or euphoric, just that everything felt so easy in terms of application of thought and attention, my socialisation dynamic had become so much more enjoyable, I remember feeling this odd calm that would seem to cushion any negative feelings. If anything about the substance was addictive it was that sensation, not a high, but a barrier effectively preventing any lows. Then there was the constant enthusiasm I had, and the ease with which I would become excited.

I am certainly going to begin taking it again at an appropriate time. As for whether you should take it if you're healthy, well that is a personal choice. I don't see why you would want to become dependent on a substance when your well-being is perfectly satisfactory to begin with, mine certainly isn't. It would certainly have a 'positive' effect on you, the only issue is that the therapeutic dose (3*12.5mg/day) is mandatory, since it has a fairly short half-life and you need to maintain 24hr coverage. So it's not like you can take a reduced dosage. Personally, unless you have an issue with mood/motivation/energy that you feel affects your quality of life I can't really recommend it.


Nice info animal stablon has always been on my 'to do' list. Your account has re-ignited my interest in this med. I'm currently persuing a DA agonist in the name of trivastal to see if this complements memantine which I currently take. Mementine is a top notch drug for me but it doesn't nail my anhedonia 100%. I think stablon could be an interesting companion.

#12 Animal

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Posted 28 April 2010 - 12:46 AM

Nice info animal stablon has always been on my 'to do' list. Your account has re-ignited my interest in this med. I'm currently persuing a DA agonist in the name of trivastal to see if this complements memantine which I currently take. Mementine is a top notch drug for me but it doesn't nail my anhedonia 100%. I think stablon could be an interesting companion.


Let me know when you get around to experimenting with it. Ideally I would like another individual to begin a 3*12.5mg daily regime at the same time as me, and log it in a thread, that way we can make direct comparisons between our experiences. :p

#13 haha

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Posted 28 April 2010 - 04:38 AM

I would recommend that you have a real familiar understand of any monamine you mess with, the science may promuglate false info regarding there effects to the layman, like agonist activity on 5-ht1a maybe implicated in schiozphrenia, when its always shouted out to be the best thing. Is this why stablon has success? Also monamine receptors will often leave the cell membrane is response to agonist and antagonist for extended peroids, therefore you may get the opposite effect from what you desire.

#14 Lallante

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Posted 28 April 2010 - 07:09 AM

Wow Animal, that is incredible. It sounds like you have some experience with Tianeptine. Would it be a useful stack component for a healthy person? (hell, from the way you describe it - does it have recreational uses??)


This is a difficult question to answer. What exactly is healthy? Can you be more then healthy?

Tianeptine is unique, it has both immediate and long term mood enhancing, anxiolytic and potentially nootropic effects. In terms of immediate effects you will get a mild but sustained stimulant sensation, coupled with subtle but noticeable secondary and tertiary dopaminergic mood enhancement. This is due to it's relatively rapid conformational modulation of D2 and D3 peripheral receptors.

The true effectiveness of tianeptine only becomes apparent after at least two weeks of thrice daily consistent dosing. This is when the anxiolytic and pronounced mood enhancing effects will begin to be expressed. This is partially due to central modulation of D2, D3 receptors. But more contributory is the increase in 5-HT generic receptor density and the dopaminergic facilitated transduction of GABA-ergic projection. The latter of which, through indirect mechanisms still under investigation, (this is the real magic of tianeptine) also increases the D1 ligand-receptor binding affinity. This includes a substantial (relative 0.1) quantitative increase in the configuration integral dynamic through a change in the partial constant: Beta:= variable 1/Kb*T Where K is the Boltzmann constant and T is the thermodynamic temperature. LOL, it's hard to write equations in BB code, but hopefully any mathematicians out there will see what I'm getting at.

The fantastic thing about tianeptine is that it is rapid acting, has almost no side effects and you don't develop tolerance to it, if anything the effectiveness just improves with time. It is also neuroprotective, since there is a reduction in DA catabolism and hence reduced reactive oxygen species produced during normal neurological metabolism.

I do have direct experience with the substance I used it to self medicate a mood disorder. I took it for approximately 6 weeks, before I had to perform an effectively non-existent but not particularly unpleasant taper, due to a delivery delay. I haven't been back on it yet because in the mean time I'm experimenting with a different pharmaceutical and I don't want to confound the results. While I was on it I loved it, the immediate effects are certainly subtle, I suffer from dysthymia (currently managed very effectively) and what I noticed from the first day, after the second dose, it that I was laughing more easily, I felt so at ease with whatever I was currently doing, and while I didn't feel stimulated in the traditional sense, there was this odd underlying clarity that made it easy to devote my energy towards whatever I chose. Now I know this wasn't placebo because at the time I hadn't been expecting any immediate effects at all, I kept a diary though this allowed me to make effective comparisons.

As time continued I noticed the effects becoming more and more substantial, such that after about a month I felt fantastic. Not in the sense of I was high or euphoric, just that everything felt so easy in terms of application of thought and attention, my socialisation dynamic had become so much more enjoyable, I remember feeling this odd calm that would seem to cushion any negative feelings. If anything about the substance was addictive it was that sensation, not a high, but a barrier effectively preventing any lows. Then there was the constant enthusiasm I had, and the ease with which I would become excited.

I am certainly going to begin taking it again at an appropriate time. As for whether you should take it if you're healthy, well that is a personal choice. I don't see why you would want to become dependent on a substance when your well-being is perfectly satisfactory to begin with, mine certainly isn't. It would certainly have a 'positive' effect on you, the only issue is that the therapeutic dose (3*12.5mg/day) is mandatory, since it has a fairly short half-life and you need to maintain 24hr coverage. So it's not like you can take a reduced dosage. Personally, unless you have an issue with mood/motivation/energy that you feel affects your quality of life I can't really recommend it.



Fantastic information thanks. I don't have any problems with dependence or willpower (lords knows I've given it my best shot!), so may give it a go with your caveats in mind. I am a very 'controlled' person in that I can alter my mood almost at will and easily sideline (ignore, turn off) chemically induced mood and cognition changes ('sober up'). I also don't really get anxious, over-excited etc so all in all I think I could make good use of this for a short cycle.


Playtime!

#15 haha

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Posted 28 April 2010 - 07:40 AM

That sounds really interesting, i like your write up, did you notice any nootropic effects maybe above and beyond the those mediated through improved mood.
Do you believe an indirect antagonist effect on 5-ht1a maybe mediating the benefical effects and causing the d2/d1 one like effects? Because i think 5-ht1a directly opposes D1/D2. It brings to mind other more illicit mood enhancers.

#16 Matthew M

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Posted 12 July 2010 - 06:57 PM

FWIW, I just started Stablon 25mg 3x a day about 4 days ago and it has been a life changer. For the better part of the last 8 years I abused Anabolic steroids (to the tune of >2gs of inj/week), MDMA, and stimulants. I had a very serious case of hypertension and ADHD coming on and I didn't like where I was heading. I did a little research and came up with a cocktail of my own to reset my metabolism and get my endogenous hormone levels back in working order.

I recently started the following for repairing my adrenals, detoxing estrogen, and improving insulin resistance.

(365 I take a multi vitamin, extra Vit B3, Vitacost DHA/EPA fish oil, coconut oil and BCAAs).

25iu of HMG/day
25mg of stablon 3x a day
.25mg of HGH 176-191 fragment 3x a day
20mg anavar in the morning
and 30iu of PG-CL 3x a day


First thing on empty stomach

600mg NA-R-ALA
2000mg ALCAR
Pantethine (for adrenals)
Holy Basil (when I get headaches)

1 hour later

1 1/2 scoops of Optimum Nutrition Whey
50 grams of glutamine (substitute for carbs)
2 caps of Source Naturals calcium D glucarate for estro detox
100mg DIM

with Bfast 1 1/2 hours later

pantethine
300mg NA-R-ALA
Fenugreek Seed

I am also on a multi vitamin, extra Vit B3, Vitacost DHA/EPA fish oil, coconut oil and BCAAs.


25iu of HMG/day
25mg of stablon 3x a day
.25mg of HGH 176-191 fragment 3x a day
20mg anavar in the morning
and 30iu of PG-CL 3x a day

Notes:
--Calcium d glucarate is making me excrete a ton of mucus. I am heading to GNC to pick up a methyl donor
--HGH frag is already tightening the loose skin on my stomach from losing 140lbs in high school (I'm 27 now)
--The stablon has made me a little silly. I feel like I'm on a light dose of laughing gas all day.
--Pectoral skinfolds are down measurably in less than a week. No more itching nipples either.
-- The PG-CL is something else. Within minutes of injecting I start sweating and within 25-30 minutes I am on the toilet emptying everything.
It almost seems to reset my metabolism. When I inject it into muscle that muscle gets a massive pump and stays pumped for hours.
-- My vision coming into this protocol was very good, it is incredible now. I see every detail of everything now.

I will report back periodically within the next week.

#17 Matthew M

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Posted 23 August 2010 - 08:19 PM

This stack is unbelievable. I am back. Wow, wow wow, stablon is amazing. I had to increase to 4x 25mg/day. The HGH effect is pronounced, my skin fold measurements are down immensely and the skin on my face has improve noticeably. Before this stack I had my total t levels checked and they were 150ng/dl. That is horrible for a 27 year old male. Will have bloodwork taken in 2 months. I am ecstatic. Will report back.

#18 Charmion

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Posted 21 October 2010 - 01:57 AM

This wouldn't work in the same way at all. Catecholamine and monoamine receptors are far more readily regulated to compensate for variations in activity and ligand saturation, they have to be since catecholamines are both neuromodulators and hormones, and they are the primary facilitators of sympathetic nervous system functionality including physiological indicators of physical activity. While monoamines are heavily involved in gastrointestinal functionality, reproductive capability and in fibrogenesis.

This is aside from their direct activity at the synaptic cleft, in neuronal action potential transduction. Thus having a huge effect on behaviour and perception.

Opioids on the other hand are primarily indicated in analgesia (as everyone knows) , mood and systemic secondary sedation. Physiologically their role is far less immediate, and endogeneously the levels of opioid tend to fluctuate over time, as opposed to spontaneously, so there is less demand for immediate regulatory response. They do not function directly as neurotransmitters, but are neuromodulators, especially influencing the GABA dynamic. In theory you could survive without endorphins entirely, but you wouldn't be very functional.

Too much dopamine; Hypertensive crisis. Too much serotonin; Serotonin syndrome. Too much opioid activity; respiratory depression. In terms of molar concentrations, opioid levels have to be far higher then the other two ligands in order to trigger a potentially terminal physiological response.

Basically what I'm saying is that DA and 5-HT behave in completely different ways to opioids, and it is a gross oversimplification to believe that they can be manipulated in the same way that opioids can.

Saying that, receptor up-regulation is still a tertiary response to a moderate decrease in DA or 5-HT ardency, and increased sensitivity can be enabled though a somewhat similar mechanism with a different dynamic.

Neuroleptics are DA antagonists, but their MOA tends to increase the activity of tyrosine hydroxylase, rather then receptor density, and so they will typically not facilitate the response you want, at least not at typical dosing levels. With prolonged low dose exposure however they can act in a way that would be enabling to an increase in dopamine sensitivity.

Sulbutiamine induces an increase in the density of D1 dopamine receptors in the prefrontal cortex due to a reduction in the release of dopamine. But because it has a positively charged thiazole moiety it can only be transported across the plasma membrane of dopaminergic neurons by high affinity carriers, what this means, especially in the brain because of it's anion activity, is that the rate of transport tends to fluctuate. So that you get an oscillation of dopamine release in the cortex, over a prolonged period (a few weeks) this oscillation will be compensated for through reactionary changes in endogenous dopamine production. The net result being the sulbutiamine's effectiveness will become negligible, and you'll be left with a dystonic dopaminergic system.

With regards to dopamine, agonists (particularly D1) are your best bet, but they are difficult to procure.

Serotonin on the other hand already has a novel sensitization agent in the form of Tianeptine (Stablon), a beautiful molecule which not only facilitates an increase in the density of serotonin receptors, it also increases activity of dopamine in the striatum, thus increasing the explicit activity of spiny GABA-ergic projection neurons, giving rise to anxiolysis and mood enhancement (through the increase in GABA-B). Tianeptine also enhances the affinity of the D2 and D3 dopamine receptors for their ligand through minor conformational changes, once again improving your feelings of well-being markedly.

So options are:

Dopamine - Sub theraputic doses of a neuroleptic (I recommend sulpride) OR weekly cycling of sulbutiamine with a dopamine precursor such as L-Tyrosine.

Serotonin - Tianeptine!!! There are others, but what's the point when you already have the perfect substance. :)


So, Animal, I'm interested in which of the options you believe to be better for Dopamine? Would you think the Sulpiride or the sulbutiamine/tyrosine combo is the better way to go. I ask because before this you said that "The net result being the sulbutiamine's effectiveness will become negligible, and you'll be left with a dystonic dopaminergic system." Nobody wants a dystonic dopaminergic system. So, would sulbutiamine still have this dystonic effect when cycled with tyrosine?

And...when you say weekly cycling, you mean do the sulbutiamine for one week, then switch to the tyrosine for one week; or, to have the whole cycle done within a week, i.e., three days tyrosine/four days sulbutiamine?
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#19 JLL

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Posted 21 October 2010 - 05:04 PM

That tianeptine stuff is pretty damn expensive at that dosage. Where do you get it from?

#20 Animal

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Posted 21 October 2010 - 09:40 PM

So, Animal, I'm interested in which of the options you believe to be better for Dopamine? Would you think the Sulpiride or the sulbutiamine/tyrosine combo is the better way to go. I ask because before this you said that "The net result being the sulbutiamine's effectiveness will become negligible, and you'll be left with a dystonic dopaminergic system." Nobody wants a dystonic dopaminergic system. So, would sulbutiamine still have this dystonic effect when cycled with tyrosine?

And...when you say weekly cycling, you mean do the sulbutiamine for one week, then switch to the tyrosine for one week; or, to have the whole cycle done within a week, i.e., three days tyrosine/four days sulbutiamine?


Okay, so taking Sulpride or Amisulpride at sub-therapeutic doses of no more then 50mg/day will preferentially antagonise pre-synaptic inhibitory dopamine receptors, which facilitates increased dopaminergic activity without any potential for the development of tolerance. The problem is that you can't increase the dosage much beyond this since then antagonism of primary receptors will take place, which is the opposite of what you want. Therefore if the 50mg dosage is not providing you with the desired effects then you will need to combine it with some other dopaminergic agent. I would consider Amisulpride to be the more beneficial of the two since it also has a mild antagonistic activity at D1 receptors, as well as D2 and D3, while Suplpride exclusively antagonises D2 and D3 receptors. This means that the Amisulpride will have a more activating effect, but not sufficient to cause anxiety of any kind. Saying that, Sulpride is the more easily obtainable of the two, so the choice is yours.

What I'm referring to with the phrase "dystonic dopaminergic system", is the resultant decrease in overall DA synthesis and release that chronic Sulbutiamine administration will cause. In theory though this should eventually up-regulate due to the lack of direct dopaminergic effects after your body has adjusted to the novel oscillating antagonism of Sulbutiamine. But I can't imagine the process will be a pleasant one, at least not without the cocomitant use of a selective dopamine agonist at the D2 receptors.

You can cycle the Tyrosine/Sulbutiamine any way you want, as along as you have the equivalent of a week off every two weeks. But I would not advise taking them at the same time as this will just amplify the negative effects that Sulbutiamine has after discontinuation. I would actually suggest that you both cycle Tyrosine/Sulbutiamine and take a sub-therapeutic Amisulpride dose, as the narcoleptic will reduce any potential tolerance to the Sulbutiamine while having it's own beneficial effects. But I would start with the Amisulpride/Sulpride first, as you may find this is perfectly satisfactory for your needs.

Edited by Animal, 21 October 2010 - 09:40 PM.


#21 Charmion

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Posted 22 October 2010 - 05:12 AM

Okay, I believe I understand what you're saying. What you're saying, then (and please forgive me here if I'm being thick), is that the best way to up-regulate dopamine receptors is:

FIRST:
Amisulpiride, at or less than 50mg/day (would you suggest maybe starting at ~25mg and titrating upwards to 50?). Also, when to take this dose? Before sleep?
If this achieves the desired effects, stop. (If this does, theoretically, by itself achieve these effects, how long would it take? I ask because if the Amisulpiride itself was insufficient, how long would you need to wait before being sure of this and moving on to the next step?)

SECOND:
If desired effects are not achieved, keep taking the Amisulpiride daily, and begin taking Sulbutiamine for , let's say, one week, stopping and switching to Tyrosine for one week (what doses or dose ranges would you recommend for each for this purpose? I know the Sulbutiamine is probably quite straightforward, maybe take just the amount that gives you an effect; but the possible dosing for tyrosine are much more open). So, its one week sulbutiamine, one week tyrosine, and one week off, all the while taking Amisulpiride, right?

Also, would you be able to tell if this would have any permanent up-regulation effects on dopamine receptors, or would you just have to keep doing this continually?

Also, thank you for sharing your knowledge. :)

Edited by Charmion, 22 October 2010 - 05:14 AM.


#22 Charmion

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Posted 25 October 2010 - 06:20 PM

B-B-B-Bump?

#23 Kasra

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Posted 30 March 2012 - 01:26 PM

Bump for science

#24 magniloquentc0unt

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Posted 25 May 2013 - 11:45 AM

Old thread, i know, but; does anyone know if it is wise an adviceable to take tianeptine and sulbutiamine long term? Im fighting a chronic astenia, anhedonia, hypersomnia. I dont have lak of libido

#25 jurassic

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Posted 28 May 2013 - 08:30 AM

I am also very interested in some reports of experiences with tianeptine, are there any users out there? it seems quite interesting on paper, in theory, what about practical implications?

#26 magniloquentc0unt

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Posted 28 May 2013 - 08:38 AM

Its ok, nothing major. It works better than sjw but worse than fluoxetine. Altough it does not have any side effects

#27 jurassic

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Posted 28 May 2013 - 10:07 AM

are you using it for treatment of some indication or are you healthy individual? i am interested in both groups. does fluoxetine has adverse effects on you? how much do you take and how long? any nootropic properties to mention?

thanks for the reply! :)

#28 magniloquentc0unt

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Posted 28 May 2013 - 10:50 AM

as i mentioned, asthenia, anhedonia and hypersomnia are my simptoms. To that add poor concentration, lack of focus, no motivation and slight social anxiety. I wouldnt say im "ill" but life could be better. The actual diagnosis (ive been seeing a psichiatrist last half year) is Dysthimia, but we went trough ADHD (inattentive type): from this you can easily understand that i do not look sad or depressed, not even to a psichiatrist eyes, its just that inside me theres nothing going on: no excitement, interest, affect, etc. Tianeptine supposedly increases the emotional range, as opposed to SSRI, which narrow it. I am pretty sure my emotional spectrum has been narrowed by SSRIs (or MDMA, which i mention for fairness but im pretty sure thee culprit is the fluoxetine). Side effects of fluoxetine are inexistent libido and slight cognitive impairment + emotional blunting which for me manifested in being ok with whatever anyone was saying/thinking/doing (turning into a dog). Tianeptine, on the other hand, seems to be sloooooowly taking my emotional reactivity back, and it also gave me sprouts of alpha manliness. BUT: as i said, its a substance you read a lot about on the forums, but in my case was a bit of a delusion. take that with a grain of salt, methylphenidate and modafinil did nothing to me.
so, summing it up, i dont know: i was very angry at fluoxetine, but it did give me quite some energy, it was very activating, and i could follow abstract thinking easily and focus on things so good i was astonished. It was excellent at that, and also made things a lot more enjoyable, but i have the feeling it is a temporary pact with the devil id rather avoid if i was a SSRI virgin. Rather try tianeptine first: at least it has no reported permanent side effects

#29 Perception-Is-Reality

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Posted 14 June 2013 - 04:35 PM

so 50 mg of Amisulpride/day (1 dose?) and 500 mg salbutamine/bi-daily and a dopamine precursor the other day should upregulate dopamine receptors? Would this work to either make stimulants more effective at lower dosages or slow the increase of stimulant tolerance.

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#30 Nobility

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Posted 09 January 2014 - 12:09 PM

moar info please!!

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