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Re: Amphetamine for schizohprenia? linkadge

Posted by undopaminergic on July 1, 2021, at 7:25:48

In reply to Re: Amphetamine for schizohprenia? undopaminergic, posted by linkadge on June 28, 2021, at 14:42:10

> Exactly. Interestingly, mice lacking the TAAR1 receptor, become significantly more stimulated by amphetamine than normal mice. This indicates that activating TAAR1 by amphetamine offsets some of the 'stimulant' effects of amphetamines.

I've read that amphetamines reverse the direction of the dopamine transporter, and, as far as I understand it, also the vesicular monoamine transporter. Do you know if these actions have anything to do with agonism at the TAAR1?

> TAAR1 agonists seem like a very interesting target. In mice, they have antidepressant and antipsychotic effects. However, the antidopamingic effects are very region specific. (i.e. the don't induce cataplexy).

Incidentally, the so-called typical antipsychotics do cause cataplexy, or is it catalepsy? Clozapine does not, even at very high doses, but is considered the gold standard for this class of drugs.

I think a possible explanation as to why TAAR1 agonist do not cause these psychomotor reactions, is that there is a ceiling to their effect, or in other words, their dose-response curve flattens with higher doses.

> In animal models of ADHD, there is actually dopamine overactivity. In those responding to amphetamine, the TAAR1 system may be intact (and perhaps upregulated) and, like you say, the brain is responding with more of an antidopaminergic effect. Of note, antipsychotics are also occasionally used for ADHD, and they apparently work too (although less so for cognition). If ADHD was low dopamine, then they should make things worse.

Yes, but methylphenidate (and cocaine) help too (of course not in all subjects), and it is not a TAAR1 agonist.

You also need to consider the possible involvement of dopamine autoreceptors.

> This may be true too for schizophrenics. Perhaps, in a certain dose range, amphetamines may actually be doing something positive. I remember reading reports of 'bipolar' patients having clear 'antimanic' effects from stimulants.

I find that although methylphenidate (and ethylphenidate) stimulates me more than it calms me, it improves my self-control.

> Perhaps there is a deficiency of endogenous TAAR1 agonists in ADHD (PEA, tryptamine, octopamine, tyramine, thyroid metabolites etc).

Incidentally, selegiline helps in a substantial percent of cases, and one of its primary effects is to increase PEA through inhibition of the metabolism thereof.

Also, I think in addition to reducing the rate of spontaneous firing of dopamine neurons, TAAR1 agonists also increase the amount of dopamine released per firing. Thus each "pulse" is more powerful than in the absence of the TAAR1 agonism. This could be a partial explanation of why these agents help in ADHD. In other words, they may increase the signal to noise ratio.





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