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Re: What do TRD patients take without an MAIO

Posted by linkadge on December 9, 2019, at 17:15:19

In reply to Re: What do TRD patients take without an MAIO linkadge, posted by undopaminergic on December 9, 2019, at 9:14:33

>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:

Right. There is the possibility of amphetamine (and related substances) as being directly neurotoxic (in a manner that substances like MTPP are). Anything that leads to excessive glutamate function, in theory can be neurotoxic.

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).

>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. Complicating the picture is the action of the presynaptic dopamine autoreceptor system. Cocaine can actually calm hyperactive mice in a similar fashion to Ritalin. This may be via stimulation of dopamine autoreceptors. Amphetamine too may lower dopamine release (in ADHD) via TAAR1's interaction with presynaptic dopamine autoreceptors. TAAR1 agonsits actually reduce dopamine release. Hence the anti-hyperkinetic effects of amphetamines may have nothing to do with their direct actions on the dopamine transporter.

>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 don't know the relative potency of amphetamines vs. cocaine for sigma receptors, 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. The neurotrophic effects (and cognitive enhancing effects of amphetamines) may be via sigma-1 receptors. There is an increased propensity for schizohprenics to use amphetamines. 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.

https://en.wikipedia.org/wiki/Sigma_receptor

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

What were we originally talking about :)

Linkadge



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