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Re: What do TRD patients take without an MAIO linkadge

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:
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.





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