The short version
This is a map of how one dopamine-releasing nerve cell in the brain makes, stores and releases dopamine, and of what then happens to the dopamine. Each box is a step, a supporting ingredient, a feedback brake or a related pathway. The biology of each step is well established (Tier A). Whether a weak step explains ADHD in any particular person is an open question (Tier D), and the map does not answer it.
How to use it. Select any box to read about it in the panel below the map. Selecting a box only changes what you are reading. It does not measure, test or change anything, and it cannot tell you whether you have ADHD or which medicine might suit you.
The map
Solid arrow: next step in the sequenceDotted: cofactor or energy supportDashed: feedback (a brake)Thin: related pathway, for context
Every step as text
Main line: inside a brain dopamine cell
Tyrosine supply
Step · The starting material, from the blood.
- What happens
- Tyrosine, an amino acid, is the starting material for dopamine. It comes from protein in food, and the body can also make it from another amino acid, phenylalanine, using the enzyme phenylalanine hydroxylase (PAH). Tier A
- Connections
- → Entry into the brain: Tyrosine in the blood is carried into the brain by LAT1. (solid arrow)
- → Outside the brain: The same starting material and enzymes are also used outside the brain. (thin line)
- ADHD research
- No established link (GEN-03). Phenylketonuria (PKU), where PAH does not work, is a separate condition.
- Limits
- This map is not diet advice. It does not show that eating more protein or taking tyrosine changes ADHD symptoms.
- Sources
- [1] Abstract
- Read more
- Related article
Entry into the brain
Step · Crossing the blood–brain barrier.
- What happens
- To reach brain nerve cells, tyrosine has to cross the blood–brain barrier. It uses LAT1 (gene SLC7A5), a carrier for large neutral amino acids, and competes for it with other amino acids of that type, such as phenylalanine. Tier A
- Connections
- → Tyrosine to L-DOPA: Tyrosine inside the brain is the starting material for tyrosine hydroxylase. (solid arrow)
- ← Tyrosine supply: Tyrosine in the blood is carried into the brain by LAT1. (solid arrow)
- ADHD research
- Open research question, not established (GEN-03). Tier D
- Limits
- The LAT1 statement comes from the discussion section of a rat and mouse study and describes the transporter's general role.
- Sources
- [2] Discussion; [1] Biochemical markers for assessment of metabolic control; Functional effect of Phe-free L-amino acid supplements
- Read more
- Related article
Tyrosine to L-DOPA
Step · Rate-limiting step, by tyrosine hydroxylase.
- What happens
- The enzyme tyrosine hydroxylase (TH) converts tyrosine to L-DOPA. It is the rate-limiting step: the slowest, most tightly controlled step in making dopamine and the other catecholamines. Tier A
- Needs
- BH4 (tetrahydrobiopterin), oxygen, and iron held in the enzyme.
- Connections
- → L-DOPA to dopamine: Tyrosine hydroxylase's product, L-DOPA, is converted to dopamine by AADC. (solid arrow)
- ← Entry into the brain: Tyrosine inside the brain is the starting material for tyrosine hydroxylase. (solid arrow)
- ← BH4 helper molecule: Tyrosine hydroxylase needs BH4 to work. (dotted line)
- ← Autoreceptor feedback: Autoreceptor activity reduces dopamine synthesis. (dashed line)
- ← L-DOPA to dopamine: Dopamine and other catecholamines inhibit tyrosine hydroxylase (end-product feedback). (dashed line)
- ADHD research
- None established (GEN-03). None of the 27 regions in the 2023 genome-wide study lists TH within 50 kb (GEN-12).
- Medicines that act here
- Levodopa, used mainly for Parkinson's disease, supplies L-DOPA directly and so does not depend on this step (GEN-03). For understanding only; not a treatment guide.
- Limits
- “Rate-limiting” describes how much dopamine is made. How strongly dopamine signals also depends on packaging, release, receptors and clearance.
- Sources
- [3] Abstract
- Read more
- Related article
L-DOPA to dopamine
Step · Conversion by AADC.
- What happens
- The enzyme aromatic L-amino acid decarboxylase (AADC, gene DDC) converts L-DOPA to dopamine. Tier A
- Needs
- PLP (pyridoxal phosphate), the active form of vitamin B6.
- Connections
- → Packaging into vesicles: Newly made dopamine is loaded into vesicles by VMAT2. (solid arrow)
- → Tyrosine to L-DOPA: Dopamine and other catecholamines inhibit tyrosine hydroxylase (end-product feedback). (dashed line)
- ← Tyrosine to L-DOPA: Tyrosine hydroxylase's product, L-DOPA, is converted to dopamine by AADC. (solid arrow)
- ← Vitamin B6 (PLP): AADC needs PLP to work. (dotted line)
- ADHD research
- None established (GEN-03). None of the 27 regions in the 2023 genome-wide study lists DDC within 50 kb (GEN-12).
- Limits
- AADC deficiency is a rare inherited condition. It is mentioned to show that this step matters, not as an explanation of ADHD.
- Sources
- [3] Introduction; [4] Abstract; Lumbar puncture
- Read more
- Related article
Packaging into vesicles
Step · Loaded into storage sacs by VMAT2.
- What happens
- VMAT2 (gene SLC18A2) loads dopamine from inside the cell into vesicles, the small sacs that store it ready for release. Tier A
- Needs
- A proton gradient across the vesicle wall, built by the vesicle's proton pump.
- Connections
- → Release: Filled vesicles release dopamine when calcium enters the nerve ending. (solid arrow)
- → Noradrenaline branch: In noradrenaline cells, dopamine inside vesicles is converted to noradrenaline by DBH. (thin line)
- ← L-DOPA to dopamine: Newly made dopamine is loaded into vesicles by VMAT2. (solid arrow)
- ← Vesicle proton pump: VMAT2 uses the proton gradient built by the vesicle's proton pump. (dotted line)
- ADHD research
- One small platelet study (GEN-03 rates this Tier C). None of the 27 regions in the 2023 genome-wide study lists SLC18A2 within 50 kb (GEN-12). Tier C
- Medicines that act here
- Amphetamine inhibits VMAT2, which releases dopamine from vesicle storage. Methylphenidate is reported to redistribute VMAT2. For understanding only; not a treatment guide.
- Limits
- After release, vesicles are recycled and refilled; that cycle is not drawn as a separate step.
- Sources
- [5] Abstract; [6] Amphetamine; Methylphenidate; [7] Figure 2 legend
- Read more
- Related article
Release
Step · Calcium triggers vesicles to release dopamine.
- What happens
- When an electrical signal reaches the nerve ending, calcium flows in and triggers vesicles to fuse with the cell membrane, releasing dopamine into the gap between cells. Tier A
- Connections
- → Receptors: Released dopamine binds receptors on nearby cells. (solid arrow)
- → Reuptake: Released dopamine is carried back into the releasing cell, mainly by DAT in the striatum. (solid arrow)
- → Breakdown: Released dopamine is broken down by MAO and COMT. (solid arrow)
- → Autoreceptor feedback: Released dopamine also binds D2 autoreceptors on the releasing cell. (solid arrow)
- ← Packaging into vesicles: Filled vesicles release dopamine when calcium enters the nerve ending. (solid arrow)
- ← Autoreceptor feedback: Autoreceptor activity reduces dopamine release. (dashed line)
- ADHD research
- No specific link stated on this site.
- Medicines that act here
- Amphetamine can also move dopamine out of the cell by making the transporter DAT run in reverse (see Reuptake). For understanding only; not a treatment guide.
- Limits
- Release is adjusted moment to moment by the cell's activity and by autoreceptor feedback.
- Sources
- [7] Abstract
- Read more
- Related article
Supports: cofactors and energy
BH4 helper molecule
Support (cofactor or energy) · Cofactor for tyrosine hydroxylase.
- What happens
- Tetrahydrobiopterin (BH4) is a helper molecule (cofactor) that tyrosine hydroxylase needs. BH4 has its own rate-limiting step, made by the enzyme GTP cyclohydrolase I (GCH1). Tier A
- Connections
- → Tyrosine to L-DOPA: Tyrosine hydroxylase needs BH4 to work. (dotted line)
- ADHD research
- None established. GCH1 conditions are movement disorders (see GEN-06).
- Limits
- A support link, not a step in the sequence.
- Sources
- [3] Abstract
- Read more
- Related article
Vitamin B6 (PLP)
Support (cofactor or energy) · Cofactor for AADC.
- What happens
- Pyridoxal phosphate (PLP), the active form of vitamin B6, is the cofactor AADC needs to convert L-DOPA to dopamine. Tier A
- Connections
- → L-DOPA to dopamine: AADC needs PLP to work. (dotted line)
- ADHD research
- None established.
- Limits
- A support link, not a step. This map does not give supplement advice.
- Sources
- [4] Lumbar puncture
- Read more
- Related article
Vesicle proton pump
Support (cofactor or energy) · Builds the gradient VMAT2 uses.
- What happens
- A pump in the vesicle wall, the vesicular proton ATPase (V-ATPase), uses ATP to push protons into the vesicle, making it acidic and charged inside. Vesicle transporters, including VMAT2, use this gradient to load their transmitter. Tier A
- Needs
- ATP.
- Connections
- → Packaging into vesicles: VMAT2 uses the proton gradient built by the vesicle's proton pump. (dotted line)
- ← Energy (ATP): The proton pump uses ATP. (dotted line)
- ADHD research
- None established.
- Limits
- The pump is not driven directly by the mitochondria's own proton gradient; energy supply matters through ATP (GEN-03).
- Sources
- [8] Abstract; Vesicular Synergy of VNTs
- Read more
- Related article
Energy (ATP)
Support (cofactor or energy) · Powers the proton pump.
- What happens
- ATP is the cell's energy currency. The vesicle's proton pump is an ATPase: it uses ATP to do its work. Tier A
- Connections
- → Vesicle proton pump: The proton pump uses ATP. (dotted line)
- ADHD research
- None established.
- Limits
- This is not a measure of anyone's energy, tiredness or “battery level”.
- Sources
- [8] Abstract
- Read more
- Related article
After release
Receptors
Step · Dopamine binds receptors on nearby cells.
- What happens
- Released dopamine binds dopamine receptors on nearby cells. There are five types, D1 to D5, grouped as D1-like (D1 and D5) and D2-like (D2, D3 and D4). Tier A
- Connections
- ← Release: Released dopamine binds receptors on nearby cells. (solid arrow)
- ADHD research
- Older candidate-gene studies reported signals for DRD4 and DRD5, with heterogeneity, before genome-wide studies (GEN-03). None of the 27 regions in the 2023 genome-wide study lists DRD4 or DRD5 within 50 kb.
- Medicines that act here
- Some medicines act directly on dopamine receptors, such as drugs for Parkinson's disease and antipsychotics. For understanding only; not a treatment guide.
- Limits
- Receptor signalling inside the receiving cell is not drawn.
- Sources
- [9] Dopamine D2-autoreceptors – Location and Behavioral Function; [10] Abstract; [11] as cited on GEN-03; [12] Table 1
- Read more
- Related article
Reuptake
Step · DAT carries dopamine back into the cell.
- What happens
- After release, the dopamine transporter (DAT, gene SLC6A3) carries dopamine back into the releasing cell. In the striatum this is the main way released dopamine is cleared. In the frontal cortex DAT is sparse: mouse studies found that dopamine there is taken up mainly by the noradrenaline transporter (NET, gene SLC6A2). Tier A
- Connections
- ← Release: Released dopamine is carried back into the releasing cell, mainly by DAT in the striatum. (solid arrow)
- ADHD research
- Candidate-gene signal for DAT1 (SLC6A3), with heterogeneity (GEN-03). None of the 27 regions in the 2023 genome-wide study lists SLC6A3 within 50 kb (GEN-12).
- Medicines that act here
- Methylphenidate inhibits DAT and NET. Amphetamine also inhibits these transporters and can make DAT run in reverse, moving dopamine out of the cell. For understanding only; not a treatment guide.
- Limits
- The frontal-cortex finding comes from mouse studies; how closely it applies to people is less certain. How much dopamine taken back up is reused is not drawn, because it was not separately source-checked.
- Sources
- [9] 2) Regulation of Uptake; [13] Abstract; [6] Methylphenidate; Amphetamine; [11] as cited on GEN-03
- Read more
- Related article
Breakdown
Step · MAO and COMT break dopamine down.
- What happens
- Dopamine is broken down by two enzyme families, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). In the mouse frontal cortex, COMT accounts for about half of dopamine clearance. Tier A
- Connections
- ← Release: Released dopamine is broken down by MAO and COMT. (solid arrow)
- ADHD research
- No ADHD link is stated for MAO or COMT on GEN-03. None of the 27 regions in the 2023 genome-wide study lists COMT, MAOA or MAOB within 50 kb.
- Medicines that act here
- Amphetamine is reported to inhibit monoamine oxidase activity. For understanding only; not a treatment guide.
- Limits
- The regional figure comes from a mouse study.
- Sources
- [14] Abstract; [6] Abstract
- Read more
- Related article
Autoreceptor feedback
Feedback · A brake on the releasing cell.
- What happens
- Some released dopamine binds D2-type autoreceptors on the releasing cell itself. They act as a brake: feedback that controls the cell's firing and how much dopamine it makes, releases and takes back up. Tier A
- Connections
- → Tyrosine to L-DOPA: Autoreceptor activity reduces dopamine synthesis. (dashed line)
- → Release: Autoreceptor activity reduces dopamine release. (dashed line)
- ← Release: Released dopamine also binds D2 autoreceptors on the releasing cell. (solid arrow)
- ADHD research
- No specific link stated on this site.
- Limits
- Feedback keeps the system within a working range. It is not a fixed personal set-point.
- Sources
- [9] Abstract; Introduction
- Read more
- Related article
Related pathways, for context
Noradrenaline branch
Related pathway (context) · One extra step in noradrenaline cells.
- What happens
- In noradrenaline-releasing nerve cells there is one extra step. Inside vesicles, the enzyme dopamine β-hydroxylase (DBH) converts dopamine to noradrenaline. This happens in the brain, in nerves elsewhere in the body, and in the adrenal gland. Tier A
- Connections
- ← Packaging into vesicles: In noradrenaline cells, dopamine inside vesicles is converted to noradrenaline by DBH. (thin line)
- ADHD research
- ADHD stimulant medicines act on the noradrenaline transporter (NET) as well as DAT.
- Medicines that act here
- Methylphenidate and amphetamine both inhibit NET. For understanding only; not a treatment guide.
- Limits
- Shown for context. This page does not map the noradrenaline system in detail. DBH's own cofactors are not listed because they were not source-checked for this page.
- Sources
- [15] Introduction; [3] Introduction; [6] Abstract
- Read more
- Related article
Outside the brain
Related pathway (context) · The same enzymes work elsewhere.
- What happens
- Tyrosine hydroxylase also works outside the brain, for example in the adrenal gland, which makes adrenaline. Levodopa taken as a medicine is mostly broken down in the body before it reaches the brain, mainly by AADC, so it is given with a peripheral AADC inhibitor such as carbidopa or benserazide. Tier A
- Connections
- ← Tyrosine supply: The same starting material and enzymes are also used outside the brain. (thin line)
- ADHD research
- Not an ADHD finding; shown so that the brain line is not read as a universal rule.
- Medicines that act here
- Carbidopa and benserazide block AADC outside the brain so that more levodopa reaches it. For understanding only; not a treatment guide.
- Limits
- “Entry into the brain, then conversion” is the order for brain dopamine cells only, not for the adrenal gland or other nerves.
- Sources
- [3] Introduction; [16] Abstract; Pharmacokinetic and pharmacodynamic challenges
- Read more
- Related article
What genetic studies do and do not show here
None of the genes on this map is listed within 50 kb of any of the 27 regions reported by the 2023 genome-wide study (GEN-12). Older candidate-gene studies reported signals for DAT1, DRD4 and DRD5, with heterogeneity between studies (GEN-03). An association with a region of DNA is not the same as a candidate gene, and neither is a proven causal mechanism (GEN-02).
Where medicines act
Methylphenidate mainly inhibits the dopamine and noradrenaline transporters. Amphetamine also inhibits them, can make them run in reverse, and inhibits VMAT2. These notes explain why the medicines are discussed with this pathway. They are not a guide to choosing or changing treatment, which is a decision for a prescriber.
Limits and what is left out
- The map is a teaching model of one cell type. Real signalling varies between brain regions and from moment to moment.
- Region-specific clearance figures come from mouse studies.
- No part of the map describes any individual's biology, levels or treatment.
- Reuptake to repackaging (DAT → VMAT2). No checked source stated it explicitly. Add when a source is located and quoted.
- Cofactors of dopamine β-hydroxylase (vitamin C, copper). Not source-checked for this page.
Sources
Each source was read for the specific statement it supports. The location is given beside each citation, and the full claim-to-source register is kept with the page's source files.
- van Wegberg AMJ et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 2017;12(1):162. DOI · PMID 29025426 (checked: full text)
- Wittmann G, Mohácsik P, Balkhi MY, Gereben B, Lechan RM. Endotoxin-induced inflammation down-regulates L-type amino acid transporter 1 (LAT1) expression at the blood-brain barrier of male rats and mice. Fluids Barriers CNS 2015;12:21. DOI · PMID 26337286 (checked: full text)
- Daubner SC, Le T, Wang S. Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys 2011;508(1):1-12. DOI · PMID 21176768 (checked: full text)
- Wassenberg T et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis 2017;12(1):12. DOI · PMID 28100251 (checked: full text)
- German CL, Baladi MG, McFadden LM, Hanson GR, Fleckenstein AE. Regulation of the dopamine and vesicular monoamine transporters: pharmacological targets and implications for disease. Pharmacol Rev 2015;67(4):1005-1024. DOI · PMID 26408528 (checked: abstract)
- Faraone SV. The pharmacology of amphetamine and methylphenidate: relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev 2018;87:255-270. DOI · PMID 29428394 (checked: full text)
- Südhof TC. Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron 2013;80(3):675-690. DOI · PMID 24183019 (checked: full text)
- Münster-Wandowski A, Zander JF, Richter K, Ahnert-Hilger G. Co-existence of functionally different vesicular neurotransmitter transporters. Front Synaptic Neurosci 2016;8:4. DOI · PMID 26909036 (checked: full text)
- Ford CP. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience 2014;282:13-22. DOI · PMID 24463000 (checked: full text)
- Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 2011;63(1):182-217. DOI · PMID 21303898 (checked: abstract)
- Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 2009;126(1):51-90. DOI · PMID 19506906 (checked: as summarised on GEN-03; not re-read for this page)
- Demontis D et al. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nat Genet 2023;55(2):198-208. DOI · PMID 36702997 (checked: Table 1 and author manuscript)
- Morón JA, Brockington A, Wise RA, Rocha BA, Hope BT. Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 2002;22(2):389-395. DOI · PMID 11784783 (checked: abstract)
- Käenmäki M et al. Quantitative role of COMT in dopamine clearance in the prefrontal cortex of freely moving mice. J Neurochem 2010;114(6):1745-1755. DOI · PMID 20626558 (checked: abstract)
- Wassenberg T et al. Clinical presentation and long-term follow-up of dopamine beta hydroxylase deficiency. J Inherit Metab Dis 2021;44(3):554-565. DOI · PMID 33034372 (checked: full text)
- Tambasco N, Romoli M, Calabresi P. Levodopa in Parkinson's disease: current status and future developments. Curr Neuropharmacol 2018;16(8):1239-1252. DOI · PMID 28494719 (checked: full text)