Posted by undopaminergic on December 9, 2019, at 9:14:33
In reply to Re: What do TRD patients take without an MAIO » undopaminergic, posted by linkadge on December 6, 2019, at 18:15:25
> Cocaine and amphetamine work in different ways to elevate dopamine levels.
>Of course. I hesitate to call myself an expert, because the more I learn, the more I realise there is so much more to learn, but at least relatively speaking, stimulants are one of my areas of expertise.
> It may not be the elevation in dopamine levels (per se) that leads to neurotoxicity.
>No, it is not the elevated dopamine *itself* that is neurotoxic. Rather, it is the metabolism thereof, which leads to oxidative stress. But now, stumbling across this article:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870191/
I realise it is more complex than I had thought. See, that's what I meant when I said the more I learn, the more I realise how much more there is to learn.> Cocaine works as more of a monoamine reuptake inhibitor ...
>Of course. There may be less important actions as well, including modestly increased dopamine release. As a matter of fact, you called my attention to this in a debate many years ago!
> whereas amphetamine causes the transport to work in reverse (forcing more dopamine out of the presynaptic neuron).
>Of course.
> Interestingly, cocaine (or Ritalin) can actually block the neurotoxic effects of amphetamines!.
>Yes, it is interesting, but it follows from the fact that amphetamines need the DAT (dopamine transporter) in order to produce their effects, and cocaine inhibits that transporter.
> But, combining the two (can) produce a synergistic elevation in dopamine.
>"can" is the keyword. This is complex, and I don't have a good understanding of it.
> Also, dopamine agonists (like Mirapex) can be neuroprotective.
>Yes, but these agonists are not identical to dopamine; their metabolism does not produce oxidative stress. Indeed pramipexole (Sifrol; Mirapex?) has been show to have antioxidant properties.
> There may be something else going on with amphetamine because ...
>Many things, it seems, including increased release of glutamate; see the article I referenced above.
> it has other targets (i.e. sigma receptors, and TAAR1 receptors). Sigma agonism (in a certain dose range) can be neurotrophic but at higher doses can be neurotoxic. The sigma actions of amphetamine may be more involved in the neurotoxicity than dopamine elevations.
>I did not know amphetamines modulate sigma. Cocaine definitely does, and it is apparently associated with the seizures sometimes resulting from cocaine overdose. Although cocaine seems to be a more potent sigma-agonist (amph. do not produce seizures), it does not produce the same neurotoxicity as the amphetamines.
> Another interesting tidbit is that caffeine raises dopamine but is neuroprotective (and can prevent Parkinson like dopamine receptor decline).
>Yes (I knew about the DA elevation but not the neuroprotection), and caffeine-like stimulants (primarily adenosine-receptor antagonists) have been researched as a treatment for Parkinson's.
I have personal (first-hand) experience with this. At some point, cocaine-like stimulants (in my case, ethylphenidate and desoxypipradrol) alone seemed to lose most of their effects, but when combined with ~ 500-1000 mg of caffeine, I get excellent effects. Severely nootropic!
> But, I really don't know as I am not an expert.
>You are certainly one of the more well-informed people I've met regarding these issues.
-undopaminergic
poster:undopaminergic
thread:1106750
URL: http://www.dr-bob.org/babble/20191019/msgs/1107121.html