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A mechanism for ADHD stimulant medication tolerance has now been found. See http://neurosciencenews.com/adhd-medication-patient-brains-adapt-dat/.

Here's the thing though: what exactly is the "signal" that the body uses to interpret whether or not it needs to upregulate the amount of DAT (dopamine transporter) that exist? Is it a dopamine-based signal that somehow then gets carried to a transcription factor that gets carried to the nucleus for additional transcription?

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First the boring (but most important part) looking at the study:

It is important to critique the study design FIRST to see what kind of information we can actually obtain from this study. This is a meta-analysis of cross-sectional studies (meaning there is no record of change over time) that include a variety of age ranges of ADHD patients (some on treatment, some not) who were compared with age, gender and IQ-matched non-ADHD people to measure DAT levels in the stratum measured with PET and SPECT.

What they found:

There were very heterogeneous results from all the studies, there was no statistically significant difference between DAT in ADHD and normal (note that they use the word "trends"). The only thing statistically significant that they found was that there was a wide spread of DAT in the ADHD population, and that exposure to treatment accounted for half of this spread (variance).

What can we say about this?

This is not a very conclusive study, but studies like this are often necessary to merit doing higher resource intensive studies. This study did not reach statistical significance in it's primary outcome, and on further search was able to only find a single outcome of significance. My summary of this would be: maybe this could represent a method of medication tolerance.

To answer your question If hypothetically this was the cause and I had to make up a possible method of transcription control, I would say something similar to your answer. I would guess there is some transcription factor that is inhibited by dopamine in the cell. When there isn't dopamine (b/c it is being blocked from returning), it would somehow become active and start transcribing the gene for DAT.

Disclaimer I am not a neurobiologist, this is my opinion after reading the article. Feel free to add to my comments

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