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Author Topic: Why can certain (dopamine) receptors upregulate in an irreversible manner (TD) ?  (Read 5692 times)

Offline Chip (OP)

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from r/neuro


Why can certain dopamine receptors upregulate in an irreversible manner?

Dopamine is a neurotransmitter important for movement, motivation, concentration and cognition.

It has been long known that antipsychotics can induce Tardive Dyskinesia (TD) through upregulation of dopamine receptors. TD is mainly characterized by involuntarily muscle contractions (dopamine hypersensitivity in the substantia niagra), but also with sleep problems and effects on cognition (dopamine hypersensitivity in other areas of the brain).

TD is, in most cases, a permanent illness which cannot be treated at all. From this reason, it seems that the dopamine receptors upregulated by the antipsychotic medication the patient has taken are permanently upregulated. The sensitivity to dopamine seems to permanently increase with every dose of a dopamine antagonist.

Why is it permanent ?

Caffeine is an adenosine receptor antagonist, and it upregulates adenosine receptors as a result. But this is not permanent. The adenosine system is completely normalized after a few months of abstaining from Caffeine (or a few weeks, depending on how much it was upregulated).

Opioid antagonists upregulate opioid receptors and thus increase sensitivity to endorphins, but this is not permanent as well. It's a temporary change.

Dopamine antagonists seem to upregulate dopamine receptors PERMANENTLY. Why are most of the dopamine receptors upregulated by dopamine antagonists never downregulate?

TL;DR: Dopamine antagonists cause a permanent upregulation of certain dopamine receptors, which do not downregulate even after years of abstaining. Why can dopamine sensitivity permanently increase, while other systems cannot be permanently sensitized?

The actual reason is unknown. Speculating, this effect is likely related to the clinical population who receive antipsychotic drug treatment.

People who are given antipsychotics like chlorpromazineWiki probably have a genetic abnormality that increases dopamine receptor expression, and giving them potent dopamine receptor antagonists like chlorpromazine are effective for a shot-while to treat their symptoms. Soon however, their homeostatic systems kick-in to compensate for the dopamine block by ramping up receptor expression. This has the unfortunate side effect of eliciting neurons that already produce too much dopamine receptors to further increase their receptor levels. Thus, Tardive dyskinesia may result from neuroleptic-induced dopamine supersensitivity.

If that wasn't bad enough, tardive dyskinesiaWiki is often misdiagnosed as a mental illness rather than a neurological disorder, and as a result patients are prescribed even more neuroleptic drugs (together these neuroleptics can greatly inhibit CYP enzymes for which they are a substrate, and hence can prevent their own metabolism).

All of these things put together drastically increases the probability that the patient will develop a severe and disabling case of Tardive dyskinesia.


Upregulation of dopamine D3, not D2, receptors correlates with tardive dyskinesia in a primate model

source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807122/

Abstract

Background

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to centrally-active dopamine D2 receptor antagonists, including antipsychotic drugs and metoclopramide. The classical dopamine D2 receptor supersensitivity hypothesis in TD, which stemmed from rodent studies, lacks strong support in humans.

Conclusions

These results suggest for the first time that upregulated striatal D3 receptors correlate with TD in non-human primates, adding new insights to the dopamine receptor supersensitivity hypothesis. The D3 receptor could provide a novel target for drug intervention in human TD.

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