Oxidative Stress: Beta-arrestin and dynamin induced endocytosis - losing the magic

[Jabberwocky]

The normal housekeeping process of membrane remodeling is mainly managed by beta-arrestins and dynamin for the 5HT2 (serotonin) receptor.

Some evidence indicates that increased oxidative stress causes an upregulation in the binding proteins for both beta-arrestins and dynamin.

This increased activity results in increased endocytosis of receptors (basically the cell internalizes and eats the receptor).

Scientific evidence of prevention of tolerance has been observed in vivo in rodents where ascorbate (an antioxidant) is co-administered with MDMA.

Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT.


"In rats treated with a neurotoxic regimen of MDMA, the ability of a subsequent injection of MDMA to increase the extracellular concentration of 5-HT in the striatum, elicit the 5-HT behavioral syndrome, and produce hyperthermia was markedly reduced compared to the responses in control rats. The concomitant administration of ascorbic acid with the neurotoxic regimen of MDMA prevented the diminished neurochemical and behavioral responses to a subsequent injection of MDMA" (prevented tolerance)

https://www.ncbi.nlm.nih.gov/pubmed/11170222


I propose that the "loss of magic" is due to a runaway process of 5HT2 receptor internalization (endocytosis)due to upregulated beta-arrestin and dynamin binding proteins mediated by oxidative stress.

I propose that multiple gram dosage of ascorbate prior and post MDMA/MDXX [serotonergic drugs] administration will prevent such process and prevent tolerance and loss of magic

 

[Cotcha Yankinov]

Beta-arrestins are also signal transducers, rather than solely mediators of receptor homeostasis.

 

[Amml]

R-Alpha lipoic acid in combination with natural vitamin c sources and some other antioxidant substances should prevent damage from MDMA use. The advantage of R-Alpha lipoic acid is that it is able to cross the Blood-brain-barrier without problems, not like Ascorbic acid, that needs to be oxidized before to get into the brain and then reduced again into the active form. R-ALA also can reactivate natural occurring antioxidants like Ascorbic acid, glutathione, etc.
So the better choice would be R-ALA in combination with other Antioxidants like Vit C, polyphenols, etc.

 

[Cotcha Yankinov]

NAC is another great anti-oxidant, with studies showing it can help prevent oxidative stress related damage from amphetamines.

 

[Amml]

Is NAC permeable to the BBB? Because one big plus point of ALA is that it can easily pass the BBB and has antioxidative properties on it's own and also regenerates existing antioxidants.

 

[Cotcha Yankinov]

NAC certainly has effects on the central nervous system, and it enhances natural anti-oxidant defenses as well. I think either one would be a great choice, but I certainly wouldn't take too much NAC.