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Possible dopamineric neurotoxic effects of alcohol caused by salsolinol?

A

Amml

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Jul 21, 2016
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I looked up for the chemical "Salsolinol", which is a potent natural dopamineric neurotoxin and occurs in chocolate in very small amounts (5 micrograms/g) and is even produced endogenous by the addition of pyruvate or formal-/acetaldehyde to dopamine, but usually only in very small amounts.

My question is: When you drink alcohol, it is metabolized to acetaldehyde in quite large amounts, and acetaldehyde should also occur in the brain then and actually react with Dopamine to Methylsalsolinol and therefore cause neurotoxic effects to dopamineric neurons. Could my theory be right?
 
It has been sugested previously that salsolinol may contribute to alcohol-induced neurotoxicity, but it remains to be conclusively established that it actually plays a role.
 
AS IF thats the only toxin produced by alcohol use...

im curious about it being present in chocolate tho, how did that come about. if anything i wonder if it does affect dopamine now, because high consumption of chocolate really dulls me out
 
I think it is somehow metabolized before it reaches the blood brain barrier, and even then the brain has some neuroprotective substances to prevent damage, but I'm not sure about that.
 
cayman sez:
Salsolinol is a metabolite of ethanol produced by the condensation of dopamine with acetaldehyde in the brain. It is thought to contribute to some aspects of alcohol’s addictive properties in part through its ability to stimulate dopaminergic neurons in the posterior ventral tegmental area of the brain.
Click to expand...

As far as ingesting it directly, I don't think it would survive first pass metabolism. Usually most cachetol compounds (benzene diol) are too polar / too easily oxidised to quinones / too easily conjugated to sulfates, sugars etc. to make it from the gut into the brain. (side note: the absolute worst of these are stuff like the flavonoids and cachetins... this is why Rhodiola rosacea extracts are not a pharmacologically effective MAOI in vivo.) By analogy, oral dopamine is effectively useless - and even IV dopamine does not cross the BBB as well as you would expect, leading it to have mostly only peripheral effects on heart rate/blood pressure instead of anything rewarding (or nauseating!). Same with epinephrine.

So in order for this compound to produce any central effects, I would imagine it would require to be manufactured on the "inside" of the BBB. That's not actually a far fetched idea either, given that ethanol/acetaldehyde can easily make it past BBB and the presence of large stores of dopamine in e.g. motor neurons in the brain. So even if salsolinol has a short half life, it's conceivable that it could be generated quickly enough during alcohol intoxication to produce some effects before fading away entirely.
 
What about ones that form with seretonin?

It looks like O-desmethyltetrahydroharmaline
 
sekio what is that about rhodiola being useless in vivo? ive taken that stuff, and i did not find it to be just a talk. it has some serious MAOI effects
 
I think that depends largely on the structure, for example on oral administration:
5-HT: No CNS activity
5-HTP: CNS active, but only about 10% or less reaches the BBB
5,7-dihydroxy-tryptamine: Potent serotogenic neurotoxin
Psilocin/4-Aco-DMT: Oral active
DMT: Oral inactive

There are just small structural differences and derivates of Serotonin, but they all work different, I believe it's the same with other chemicals.
 
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Amml said:
I think that depends largely on the structure, for example on oral administration:
5-HT: No CNS activity
5-HTP: CNS active, but only about 10% or less reaches the BBB
5,7-dihydroxy-tryptophane (5-HTP with a second hydroxyl group): Potent serotogenic neurotoxin
Psilocin/4-Aco-DMT: Oral active
DMT: Oral inactive

There are just small structural differences and derivates of Serotonin, but they all work different, I believe it's the same with other chemicals.
Click to expand...
It is actually 5,7-dihydroxytryptamine that you are thinking of. It is taken up by SERT into serotonergic terminals and then causes oxidative stress.
 
from where does one gets exposed to 5,7-dihydroxytryptamine?
 
IIRC the strongest MAOI compound in Rhodiola rosea extract, rosavin, only has an affinity of about ~10 uM ( = 4.28 microgram / mL = 4.28 milligrams / liter), comparable to piperine from black pepper. When you factor in that rosavin is a molecule consisting mostly by mass of polar sugar groups, its hydrophilic nature will mean it has difficulty penetrating into any fatty tissues (or through BBB w/o active transport) and is likely going to be subject to extensive metabolism too (lots of enzymes in the body work to pull sugar groups off of each other and smaller molecules, both of which would lead to inactivation of rosavin) I would imagine that any pharmacological effects of Rhodiola ext. are unlikely to be mediated by MAOI alone...
 
I think it's possible that some substances cause CNS-Effects even if they only work peripheral. For example Turmeric powder can significantly improve cognitive function for 6 hours when taken orally. As far as I remember they only used normal Turmeric powder (1g), which is known to nearly be none adsorbed and shows no detectable blood curcumin levels. Maybe some substances can influence Neurotransmitter production or work though periphreral antioxidative effects, that also influences indirectly brain function.
P.S.: The "study" had no sources mentioned, so I'm sorry that I couldn't find further information on it.
 
There are also regions like the paraventricular nucleus for example that are not really behind the BBB.
 
Isn't the BBB more a combination of different cell types that function as a barrier?
 
Correct, especially endothelial cells in the presence of astrocytes. The takeaway is that the BBB is not static but rather dynamic and imperfect, but reactions to supplementing GABA and 5-HTP could be explained by regions that are not behind the BBB rather than slight leakage of those molecules through the BBB.
 
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