4-FA: Dopaminergic Neurotoxicity?

[atrollappears]

Hey, I was wondering if anyone with a better knowledge of neurochemistry than me has looked into, or at least thought about, the likelihood that 4-FA causes damage to dopaminergic cells in the striatum similarly to (meth)amphetamine. We know 4-FA does not deplete serotonin, but what does that say about it's likelihood to deplete dopamine? And if it is likely to do so, then to what extent?

Thus far, I've been inclined to think that it would be relatively safe also in this respect. I figure that as it doesn't seem to be oxidized with para-hydroxylation, and so does not form metabolites that are responsible for 5-HT toxicity, the absence of that initial step likely blocks the formation of oxidative byproducts that may account for DA toxicity in other amphetamines. But, is the formation of such metabolites a necessary step in DA toxicity? If so, is para-hydroxylation a necessary step in the formation of such metabolites?

Just think, if it doesn't display monoaminergic neurotoxicity (or 5-HT2B agonism) then it could be used as a "safer" amphetamine, probably substituting adequately for most of amphetamine's therapeutic and recreational uses.

 

[ebola?]

What characteristics make methamphetamine more dopaminergically neurotoxic than unsubstituted amphetamine (beyond increased potency due to increased lipophilicity allowing greater penetration of the BBB and increased potency due to increased receptor affinity)? That might be a good start. Then we could ask whether structural facets of 4-fluoro-amp suggest relevant pharmacological properties similar to meth-amp.

but what does that say about it's likelihood to deplete dopamine? And if it is likely to do so, then to what extent?

Mmmm...we have to remember to keep our indicators straight from what they measure. What physiological processes does depletion of dopamine point to? This can point to a variety of things, including cellular death, inhibition of tyrosine hydroxylase, etc. (would it also say anything about axon pruning? It doesn't seem like it would...)

ebola

 

[atrollappears]

Mmmm...we have to remember to keep our indicators straight from what they measure. What physiological processes does depletion of dopamine point to? This can point to a variety of things, including cellular death, inhibition of tyrosine hydroxylase, etc. (would it also say anything about axon pruning? It doesn't seem like it would...)

Well, DA depletion from amphetamines seems to point to a pathway, requiring calcium influx and (probably) oxidation, which is not directly the result of DA release. This is evidenced by the existence of non-neurotoxic DA releasers (such as 2-AI, the aminorex family sans dimethyl, even MDMA as far as the striatum is concerned), and the fact that neurotoxicity can be blocked by NMDA antagonists and reduced by antioxidants.

The neurotoxic releasing agents are separable from non-neurotoxic releasing agents in that the neurotoxic ones are amphetamines, as opposed to aminoindanes, aminorexes, or even (it appears) many cathinones. So, why would this happen? It's possible to attribute it to some pharmacological action which is specific to strict amphetamines, or to the metabolic behavior of amphetamines. Now, the evidence seems to say that in serotonergic neurotoxicity, which in many ways is similar to DAergic (i.e. is blocked by antioxidants and NMDA antagonists, results from only or mostly strict amphetamines, depends on hyperthermia), the metabolic products of amphetamines are to blame. See: http://www.sciencedirect.com/science/article/pii/S0014299997000447 and 4-FA itself, http://www.sciencedirect.com/science/article/pii/0028390875900994

But, I don't think any metabolites of (meth)amphetamine have been found which deplete DA similar to the parent compounds. And, DAergic neurotoxicity does not behave exactly the same as 5-HTergic; I think 5-HTergic spares cell bodies while DAergic does not, and antioxidants don't completely block DA depletion. And, to complicate matters further, what the hell is going on here?: http://www.sciencedirect.com/science/article/pii/009130579190106C

Edit: I forget, actually, if it was that cathinones don't seem to deplete DA, or 5-HT. And MDMA can cause DAergic toxicity in high doses. But regardless, the point stands that DA release and DA releasing agent neurotoxicity are separable phenomena.