MJB ADHD · Static reading view · Interactive version
Status: sourced · Content checked 2026-10-06
Six steps — make, store, release, clear, break down, self-tune. Simple parts; the complexity is in regulation, timing and how the steps interact.
Think of a supply chain. A factory makes the product (synthesis), a warehouse stores it (vesicles), a shipping dock releases it (firing), a recycling crew collects what is left (transporters), a disposal service breaks down the excess (enzymes), and a manager watches demand and adjusts output (autoreceptors).
| Step | Main part | What can vary |
|---|---|---|
| Make | Tyrosine hydroxylase | Rate, regulation by demand |
| Store | VMAT2 | Capacity and leakage |
| Release | Vesicle fusion; amphetamine reverse transport | Amount per signal |
| Clear | DAT, NET | Speed of recapture |
| Break down | MAO, COMT | Speed of disposal |
| Self-tune | D2 autoreceptors; adaptation | Feedback strength over time |
Amphetamines release catecholamines by redistributing them from vesicles to the cell fluid and reversing plasma-membrane transporters, alongside effects on uptake, exocytosis, synthesis and metabolism.
R8Why "bottleneck" is a useful word — and where it misleads. In any chain, output is limited by the slowest step. That makes it tempting to look for one broken step in ADHD. The evidence points instead to many small differences spread across steps and across brain regions, adding up.
A "component bottleneck" framing — ADHD as instability arising from several mildly under-performing components rather than one failure — is a useful way to think about individual differences in treatment response. It is a framework for generating testable questions, not an established model.
In prefrontal cortex, where dopamine transporters are sparse, noradrenaline transporters clear much of the dopamine, and alpha-2A receptors strengthen task-relevant signals — so attention depends on balance, not simply on "more".
R9Each medicine targets a different step: methylphenidate slows clearing; amphetamines force release and slow clearing; atomoxetine slows noradrenaline clearing; guanfacine strengthens prefrontal reading of the signal. Different steps, different timing, different side-effects — see How ADHD medicines act.
Too little and too much both impair prefrontal function — an inverted-U relationship. That is one reason doses are titrated, why the same dose can feel too strong one day and too weak another, and why "more" is not reliably "better".
Transporter levels appear to adapt to stimulant exposure, being higher in previously medicated people — the system re-tunes itself to treatment.
R6Most mechanism detail comes from cells, animals and small imaging studies. Which step matters most for any one person cannot currently be measured.