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Re: What do TRD patients take without an MAIO linkadge

Posted by undopaminergic on December 10, 2019, at 12:12:24

In reply to Re: What do TRD patients take without an MAIO, posted by linkadge on December 9, 2019, at 17:15:19

> Right. There is the possibility of amphetamine (and related substances) as being directly neurotoxic (in a manner that substances like MTPP are).

MPTP, which is metabolised into the MPP+ ion by MAO-B. The ion is the neurotoxic principle.

If amphetamines were neurotoxic in this manner, then cocaine would not prevent that toxicity.

> Anything that leads to excessive glutamate function, in theory can be neurotoxic.

Excitotoxic, to be specific.

> However, I've never heard of cocaine blocking the high associated with amphetamine (although I only know a few people personally that would have mixed the two), even though, it appears it can block the neurotoxicity. I would imagine, however, that cocaine would lead to increased glutamate levels (at least in some brain regions).

I don't know; as I said, this is complex. In principle, too high a dose of cocaine (or the like) would prevent amphetamines from getting taken up into the nerve terminals. There is still the possibility for the amph. to passively diffuse into the terminal, but then it would not reach much higher concentrations within than outside the terminal. So, the key would be to take a large dose amph. and a small (but not insignificant) dose of cocaine. Then there would be enough DAT function remaining for the amph. to be taken up into the terminal. At the same time, the cocaine would augment the reuptake inhibition produced by the amph. itself. Amph. is also a (modest) reversible MAOI.

> >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.
> I don't know if cocaine only blocks the transporter within the synaptic junction, or whether it also enters the presynaptic neuron and prevents the dopamine transporter function there.

The DAT is located at the membrane and can be blocked from outside or within. Cocaine does not get taken up into the terminal actively, but I believe it might enter in small quantities through passive diffusion. At least this is my understanding.

> Complicating the picture is the action of the presynaptic dopamine autoreceptor system.

Yes. Combining sulpiride with cocaine results in significantly higher extracellular dopamine elevation.

> Cocaine can actually calm hyperactive mice in a similar fashion to Ritalin. This may be via stimulation of dopamine autoreceptors.

I don't know for sure if there is something to that. While autoreceptors reduce the release (and synthesis -- I think) of dopamine, cocaine still elevates (rather than reduces) the synaptic levels thereof and the net effect is an increase in postsynaptic DA receptor stimulation.

As I understand it, it is through one of the trace amine receptors that amph. (and PEA) reduce the spontaneous firing of the presynaptic neuron.

As for calming effects, those happen in some people and in some strains of rodents, but not in others. I don't know why. It may have something to do with the particular configuration of stimulatory (D1 and D5) vs. inhibitory (D2, D3, and D4) dopamine receptors.

> Amphetamine too may lower dopamine release (in ADHD) via TAAR1's interaction with presynaptic dopamine autoreceptors. TAAR1 agonsits actually reduce dopamine release.

Yes, I am quite sure TAAR agonists do that (ie. reduce spontaneous firing of presynaptic neurons).

Do TAARs interact with the autoreceptor system, or do these receptors produce their effect independently of each other?

> Hence the anti-hyperkinetic effects of amphetamines may have nothing to do with their direct actions on the dopamine transporter.

You may be right, but I have some evidence that the calming effect happens through stimulation of postsynaptic receptors, when the synaptic dopamine concentrations are high enough. See above regarding inhibitory and stimulatory DA.

> >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.
> True, and it may depend on the degree (and location) of dopaminergic stimulation. Caffiene, adenosine antagonists, and MAO-B inhibitors are typically neuroprotective but they increase dopamine to a lesser degree than amphetamine.

I guess you mean "caffeine [and other] adenosine antagonists"? Or are you thinking of other pharmacodynamic actions of caffeine?

> I don't know the relative potency of amphetamines vs. cocaine for sigma receptors,

Well, as I recall, amphetamines do not produce seizures. So, if cocaine does (in overdose) through sigma receptors, it must be more potent.

> and there are two subtypes of sigma receptors that have different effects. Some sigma agonsits are neuroprotective (sigma-1?) and others have more neurotoxic effects.

I need to learn more about that.

> The neurotrophic effects (and cognitive enhancing effects of amphetamines) may be via sigma-1 receptors.

*Some* of the cognitive enhancing effects. Remember they primarily act via dopamine.

> There is an increased propensity for schizohprenics to use amphetamines.

Yes, but as far as I can tell, there is a combination of deficiency and excess of dopamine in schizoprenia, in different bran regions; eg. excess in limbic regions and shortage in the prefrontal cortex. The excess seems to cause positive symptoms while the shortage seems produces negative symptoms. Indeed, many of the negative symptoms are identical to Parkinsonian symptoms. If schizophrenics have increased incidence of amphetamine use, it is probably because they treat the negative symptoms.

> I have wondered if the TAAR1 agonism and sigma-1 agonism (which have antipsychotic qualities in some paradigms) may control certain psychotic symptoms (in a certain dose range). Wikipedia lists meth as a sigma agonist, but I believe I have seen this property for amphetamines as well.

Meth *is* an amphetamine. I suppose you mean amphetamine itself (unsubstituted). The reason why amphetamines is used in the plural is to cover other substances with an amphetamine structure. This can sometimes be misleading; ie. you typically mean to refer to amphetamine and methamphetamine, and not others like MDMA and MDA.


I read it. This article is rather scarce given how much there is to know about sigma-receptors.

> Amphetamines have other targets (like inhibition of MAO-A) which may exert some anticonvulsant effect.

I didn't know MAO inhibition had anticonvulsant effects.

> Fenfluramine (amphetamine derivative) has anticonvulsant effects (which may be related to 5-ht2c agonism). It has been used with some success for Dravet syndrome.


> I believe amphetamines can interact with 5-ht2c as well, which might mediate with anorexigenic and anticonvulsant properties. Or, as you mention, sigma receptors could be involved.

I don't recall seeing that mentioned (5-HT2x actions of amph.).

> What were we originally talking about :)

Judging by the title, it was something about treatment-resistant depression.





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