Short form 5-HTTLPR/MDMA adverse effects possible explanation

[Cotcha Yankinov]

Apparently the short form of the SERT gene has been associated with lower levels of SERT, which is hard to reconcile with the observation that MDMA abusers with the short form seem to be worse off in some regards even though the lower levels of the SERT should lead to decreased uptake of harmful molecules via the SERT (People with the short form also fair worse with tryptophan depletion, hinting that it might not have to do with uptake of harmful molecules), but I think we should ponder what might be happening between possibly fluctuating SERT levels, receptor levels, and serotonin stores, and how this might be impacting ex-MDMA users via not necessarily nerve terminal loss but rather adaptations to the acute serotonin shortage.

Overview of framework regarding my theory of increased SERT expression after auto receptor binding -

1. With serotonin efflux the serotonin binds to presynaptic receptors and facilitates re-uptake of serotonin via SERTs
2. At some later time there might be still increased SERTs and reduced serotonin concentrations, resulting in up-regulation of presynaptic receptors
3. During the next trip, there are possibly still some of the additional SERTs acquired via presynaptic autoreceptor activation and there are therefore even more SERTs available to be reversed
4. With even more SERTs available to be reversed there is even more serotonin efflux and then more pre-synaptic auto receptors and then once again more SERTs which then clear away the serotonin

Between the acute vesicular shortage that might occur at some point down the road, increased SERT clearance of serotonin, and post-synaptic receptor downregulation, there could be a shortage of serotonin signaling. Maybe serotonin is inhibiting other neurotransmitters like glutamate, and during this acute shortage there are adaptations downstream that are somewhat persistent even after normal serotonin signaling resumes.

The 5-HTTLPR short form could be aggravating the downstream compensations because due to lifelong reduced SERT levels and the possible resulting increased synaptic serotonin concentrations there could be up-regulation of receptors downstream of serotonin receptors, which would be primed to really take off after a serotonin shortage, and there might also be chronic downregulation of post-synaptic serotonin receptors, once again making a serotonin drought more drastic.

Any thoughts on this and the plausibility of anything here is welcome. I understand that typically we would expect to see less SERTs with chronic MDMA users but I'm curious if there might be increased SERTs at some point in the beginning (before there is serotonin depletion). Many people report long term comedowns after their first couple trips as well.

 

[serotonin2A]

Apparently the short form of the SERT gene has been associated with lower levels of SERT, which is hard to reconcile with the observation that MDMA abusers with the short form seem to be worse off in some regards even though the lower levels of the SERT should lead to decreased uptake of harmful molecules via the SERT (People with the short form also fair worse with tryptophan depletion, hinting that it might not have to do with uptake of harmful molecules), but I think we should ponder what might be happening between possibly fluctuating SERT levels, receptor levels, and serotonin stores, and how this might be impacting ex-MDMA users via not necessarily nerve terminal loss but rather adaptations to the acute serotonin shortage.

Overview of framework regarding my theory of increased SERT expression after auto receptor binding -

1. With serotonin efflux the serotonin binds to presynaptic receptors and facilitates re-uptake of serotonin via SERTs
2. At some later time there might be still increased SERTs and reduced serotonin concentrations, resulting in up-regulation of presynaptic receptors
3. During the next trip, there are possibly still some of the additional SERTs acquired via presynaptic autoreceptor activation and there are therefore even more SERTs available to be reversed
4. With even more SERTs available to be reversed there is even more serotonin efflux and then more pre-synaptic auto receptors and then once again more SERTs which then clear away the serotonin

Between the acute vesicular shortage that might occur at some point down the road, increased SERT clearance of serotonin, and post-synaptic receptor downregulation, there could be a shortage of serotonin signaling. Maybe serotonin is inhibiting other neurotransmitters like glutamate, and during this acute shortage there are adaptations downstream that are somewhat persistent even after normal serotonin signaling resumes.

The 5-HTTLPR short form could be aggravating the downstream compensations because due to lifelong reduced SERT levels and the possible resulting increased synaptic serotonin concentrations there could be up-regulation of receptors downstream of serotonin receptors, which would be primed to really take off after a serotonin shortage, and there might also be chronic downregulation of post-synaptic serotonin receptors, once again making a serotonin drought more drastic.

Any thoughts on this and the plausibility of anything here is welcome. I understand that typically we would expect to see less SERTs with chronic MDMA users but I'm curious if there might be increased SERTs at some point in the beginning (before there is serotonin depletion). Many people report long term comedowns after their first couple trips as well.

Is it true that 5-HT autoreceptor activation has been shown to increase SERT expression? At least with 5-HT1A and 5-HT1B, that effect doesn't seem to occur:

http://link.springer.com/article/10.1007/s00213-012-2795-9
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472085/

 

[Cotcha Yankinov]

As I recall I actually originally got the notion that pre synaptic receptors might facilitate clearance of serotonin from you smartie pants! I can't recall if there was talk of that increased clearance being due to SERT expression modulation but this study seems to hint 5-HT1B might facilitate SERT expression

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472085/

I also recall that 5-HT2B played an important protective role concerning serotonin syndrome.

I'm curious what you think about my theory of the persistent adverse effects of MDMA that some experience being related to the possible acute deficit of serotonin signaling, and that this acute deficit might be more severe in those with the short form, or that there might already be adaptations that make the serotonin deficit more apparent.

 

[Jabberwocky]

As I recall I actually originally got the notion that pre synaptic receptors might facilitate clearance of serotonin from you smartie pants! I can't recall if there was talk of that increased clearance being due to SERT expression modulation but this study seems to hint 5-HT1B might facilitate SERT expression

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472085/

I also recall that 5-HT2B played an important protective role concerning serotonin syndrome.

I'm curious what you think about my theory of the persistent adverse effects of MDMA that some experience being related to the possible acute deficit of serotonin signaling, and that this acute deficit might be more severe in those with the short form, or that there might already be adaptations that make the serotonin deficit more apparent.

Autism Spectrum has polymorphisms of gene that encodes SERT leading to very high functioning SERT -- pulls serotonin off the cleft too fast leading to chronically low serotonin available at the synape -- but high levels in the blood, -- the result:

OCD, Depression, serotonin receptor hypersensitivity


also of note: rats fed a diet deficient in tryptophan (thereby reducing serotonin synthesis by 90%) had 5HT2A receptor upregulation after 3 weeks -- I believe binding affinities may also have increased

humans studies have shown evidence of upregulation as well

"The cortisol response to tryptophan was significantly greater after ATD than after the control treatment, suggesting that ATD upregulated postsynaptic receptors. When the authors performed a similar study with an infusion of m-chlorophenylpiperazine instead of tryptophan, the results were similar, suggesting that serotonin 2A/2C receptors were upregulated."



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756112/

 

[MeDieViL]

I have yet to see evidence that mdma causes serotonin depletion, this is a marker of neurotoxiticy in rodents, also id like to see evidence of long term mdma induced damage, cognitive problems in only poly drug users is no proof, there was some evidence of mild structural damage in a study but thats been disproven.

Ive only seen reports of mdma inducing a underlying disorder, there are CONSISTENT reports of mdma inducing a few differened problems togheter which completely points to it bringing out something like shizophrenia:
Depression
Social anxiety
Cognitive difficouldties
Social anxiety, aka avpd
OCD

Often those problems are chronic and often get worse, if you have anecdotes that say otherwise, and point to some sero damage in a particular brain area, i highly doubt mdma use is gonna cause damage in differened brain areas, but well even soo you couldnt suddenly get exactly the same symptions of shizophrenia being triggered.

5ht1a and 5ht2a downregulation mostly cause mdma tolerance which is why st johns worth can reverse this, mdma has been shown to reverse sert, but if 5ht2a upregulation indeed occurs that might explain its extreme potential for PTSD, as that receptor downregulates with agonists and antagonists but either way theres no evidence it does, also 5ht2a agonism would be extremely beneficial for ocd and atypical depression.

Also taking 5htp after mdma would prolong any potential depression by inducing more downregulation.

 

[MeDieViL]

MDMA would activate the autoreceptors thus they would downregulate trough INTERNALISATION, acute rapid non long term downregulation, altough im not sure about autoreceptors, also its a fact mdma downregulates sert.

Either way of mdma depleted serotonin you wouldnt be able to get the same effect a second day of taking mdma, if taking a HIGHER dose to counter receptor downregulation, but that doesnt disprove some depletion, just disproves complete depletion.

 

[serotonin2A]

As I recall I actually originally got the notion that pre synaptic receptors might facilitate clearance of serotonin from you smartie pants! I can't recall if there was talk of that increased clearance being due to SERT expression modulation but this study seems to hint 5-HT1B might facilitate SERT expression

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472085/

I also recall that 5-HT2B played an important protective role concerning serotonin syndrome.

I'm curious what you think about my theory of the persistent adverse effects of MDMA that some experience being related to the possible acute deficit of serotonin signaling, and that this acute deficit might be more severe in those with the short form, or that there might already be adaptations that make the serotonin deficit more apparent.

I wasn't trying to imply that the effects we were discussing were due to increased SERT expression. Transporters probably don't get internalized/recycled to the membrane as quickly as receptors. I was thinking that SERT is phosphorylated (or something similar), which increases the rate of transport (Vmax).

 

[Cotcha Yankinov]

I wasn't trying to imply that the effects we were discussing were due to increased SERT expression. Transporters probably don't get internalized/recycled to the membrane as quickly as receptors. I was thinking that SERT is phosphorylated (or something similar), which increases the rate of transport (Vmax).

Okay I see... So am I to understand that the promoter region involves a basal level of expression and this expression is not dependent on the acute biology of the brain, so a variation in 5HTTLPR would not change how the SERTs are expressed under acute circumstances? Or does a promoter region have more to do with acute biology and therefore the short form might stand some chance of being involved acutely, alternatively is the 5HTTLPR not promoting the entire SERT at once but rather is promoting particulars of the SERT that might affect function and then proceed to play a role in modulating MDMA's adverse affects?

In other words, if the short form of 5HTTLPR isn't affecting the acute function of the SERT then this might narrow down the short form's contribution to MDMA adverse effects being more related to either a long term adaptation to decreased SERT clearance of serotonin or some sort of mechanism by which the short form contributes to issues that MDMA then excacerbates?

If the short form leads to increased serotonin concentrations then I wonder if the MDMA adverse effects aren't related to a reaction to the acute deficit of serotonin but instead a reaction to an overabundance of serotonin that the brain has already been putting up with before drugs, possibly stimulating glutamate via excitatory serotonin (rather than having a deficit of serotonin that inhibits glutamate). It seems that there is overlap between some of MDMA's adverse effects (In terms of long term comedowns and derealization and such) and adverse reactions to psychedelics, and as I recall some of the 5HT2A agonists effects are being partially mediated through glutamate... Some of the people I've talked to and myself had somewhat mild derealization experiences etc. from hallucinogens prior to MDMA so maybe there is some commonality between the two in the form of excess glutamate.

 

[serotonin2A]

Gene expression is definitely governed by interactions with the promoter. But gene transcription happens in the cell body. That means it can take days for newly synthesized SERT to be transported along axons to varicosities where it could then be involved in the processes you are discussing. Expression of new SERT protein doesn't happen fast enough to play a role in acute drug effects. That is why many receptors are sequestered in the cytoplasm after internalization -- they can be rapidly recycled to the cell surface if needed, without having to be synthesized.

Changing receptor/transporter expression level by altering gene transcription is a long-term regulatory process that doesn't usually occur with the same time course as acute drug effects.

 

[Cotcha Yankinov]

Gene expression is definitely governed by interactions with the promoter

So there is some mechanism by which physiology interacts with the 5HTTLPR gene, and therefore the 5HTTLPR gene is not just coding for some basal level of SERT expression? I understand that because of the time frames involved, new SERT synthesis is not relevant to a single use of MDMA, but was wondering if cumulative interactions might lead to more SERTs available in the MDMA uses down the road, especially if binged upon a couple days in a row.

But you don't think that the 5HTTLPR gene changes the functionality of the SERT, rather just the conditions under which it might be expressed? To me if there is no change in the function of the SERT, a mechanism by which the short form of 5HTTLPR could lead to more adverse effects could by:

1. With the short form there are already present adaptations that are amplified when MDMA is used

1a. The adaptations involve chronic stimulation of an excitatory serotonin that overstimulates glutamate etc., with reduced SERTs available to be reversed this might require on some level that the magnitude of the serotonin increase with MDMA is more related to the serotonin reserves and not how many SERTs are available to utilize those reserves (Unless SERT levels can be increased during a multi-day binge, which means that the short form might possibly lead to excess serotonin concerning frequent use scenarios - I know studies are finding reduced SERT expression in some instances of MDMA users but I'm not familiar with what we see in the very short term, and even if SERT levels are decreased that might add to the case that excess excitatory serotonin is contributing to MDMA adverse effects, and maybe SERT is decreased even further in MDMA users with the short form?).

1b. The adaptations involve a temporary deficit of an inhibitory serotonin that normally inhibits glutamate etc., and the short form could be amplifying this scenario via already present or somehow amplified downregulation of post-synaptic receptors, or some change of SERT expression that means there are increased SERTs available to be reversed (Under circumstances of a multi-day binge) and hence deplete serotonin, and then after they are un-reversed after MDMA is gone or if there are still more SERTs on the way that will not be reversed, those SERTs then clear more serotonin and make more apparent the already somewhat present serotonin depletion.

2. Once again with the multiday scenario, after SERT expression is increased, there are more SERTs available than usual to intake harmful molecules when serotonin concentrations are low after the binge.

So with a frequent use scenario, maybe variable expression of SERT dependent on 5HTTLPR type can lead to either an excess of excitatory serotonin (because of increased SERTs available to be reversed after a couple days), a deficit of inhibitory serotonin (possibly due to already present post-synaptic downregulation, increased SERTs available to deplete serotonin, or reduced availability of SERTs that help replenish serotonin stores such so that MAO-A is playing a bigger role in clearing serotonin but without it having a chance of being used again - I would be curious to see if many years down the road there is ever any literature on use of MAOI inhibitors post MDMA to curb an inhibitory serotonin deficit, because if you just used SSRIs when SERT levels are already reduced they won't increase serotonin concentrations as much, and if MAO-A is already clearing a lot of the serotonin at that time it might not help to use SSRIs anyways)

 

[Limpet_Chicken]

Dont forget the fact that tryptophan hydroxylase is inhibited too, leading to a short but severe 5HT depletion.

 

[WSH]

I would be curious to see if many years down the road there is ever any literature on use of MAOI inhibitors post MDMA to curb an inhibitory serotonin deficit

You would have to really make sure that the MDMA is totally cleared out of the body first, because otherwise such a study would turn very ugly very fast!