Cotcha Yankinov
Bluelight Crew
- Joined
- Jul 21, 2015
- Messages
- 2,952
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.
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.