Neurotransmitters in ADHD
The messenger substances in the brain that transmit information at chemical synapses between nerves are called neurotransmitters. Examples are dopamine, norepinephrine, serotonin, acetylcholine, GABA and glutamate. The different neurotransmitters have different tasks in the brain and overlap in their effects.
Neurotransmitters cause rapid stimulus transmission or blockade between neurons (nerve cells) through their release at the synapses. Other messenger substances, the hormones, mediate their effect slowly via the bloodstream to more distant target organs (e.g. cortisol, estradiol, insulin, testosterone, thyroxine, triiodothyronine). Some substances act simultaneously as neurotransmitters and hormones (e.g. norepinephrine, serotonin, histamine).
1. Nerve cells (neurons)
A nerve cell consists of the cell body and up to 200,000 connecting extensions to other nerve cells. Sending connections are called axons, receiving extensions dendrites. Axons can be up to 1 meter long (e.g. from nerve cells in the spinal cord to muscle cells in the fingertips).
When a neuron receives signals from other neurons that are stronger than a certain threshold, the neuron is activated. It fires an electrical impulse (the action potential) at up to 120 meters / second across the axon to the synapse. The thicker the axon, and the better sheathed (myelinated) by glial cells (in the brain oligodentrocytes, peripherally Schwann cells), the faster the electrical conduction.
2. Information flow through neurotransmitters
Neurotransmitters are formed in the nerve cells and, enclosed in vesicles, are transported mainly by the microtubules via the axons in the nerve fibers to the synapses. The transport speed in the axons varies depending on the substance and is up to 5 µm/second = approx. 40 cm / day.1
Electrical impulses from the sending cell release neurotransmitter from vesicles (storage containers for neurotransmitter) at the presynapse (the sending synapse). The vesicles release the neurotransmitter into the synaptic cleft, which is between 20 and 40 nm wide2, from which it is taken up on the other side, from the beginning of the receiving nerve (the postsynapse) by means of receptors, by which the neurotransmitter docks with them (lock-and-key principle).
Nerve cells can fire up to 500 times/second. If a sufficient amount of the receptors available for a neurotransmitter is occupied, many postsynaptic potentials are generated in the receiving cell at the postsynapse, which add up. If the action potential exceeds the required threshold, an electrical impulse is triggered, which is transported further by the axon of the receiving nerve cell.
Afterwards, the precious neurotransmitter is returned by the receptors to the synaptic cleft and from there is reabsorbed into the sending cell by transporters of the presynapse. This is that reuptake that can be inhibited by drugs. The reuptaken neurotransmitter is stored in the vesicles for next use or metabolized by degrading enzymes (e.g., dopamine and norepinephrine by monoamine oxidase and COMT).
Neurotransmitters do not pass on either only activating or inhibiting (inhibitory) information. Dopamine and serotonin are predominantly involved in the transmission of inhibitory information. But in dopamine, the D1 and D5 receptors are activating (excitatory) (they activate the enzyme adenylyl cyclase), whereas the D2, D3, and D4 receptors are inhibitory (they inhibit the enzyme adenylyl cyclase).
Optimal information transmission between brain synapses requires an optimal level of the neurotransmitters involved. Too low a neurotransmitter level leads to almost identical consequences of signal transmission disturbance as too high a neurotransmitter level (inverted-U theory).345
3. Neurotransmitters in ADHD
In ADHD, the transmission of information in the brain is impaired, primarily in relation to the neurotransmitters dopamine and norepinephrine.
Dopamine and norepinephrine are also involved in stress responses.
Acute stress increases dopamine and norepinephrine levels in the PFC.6 However, the decisive factor is what type of stress is involved.7 Chronic stress can be accompanied by a reduction in dopamine and norepinephrine levels.
In light of the fact that dopamine and other neurotransmitters are not globally elevated or depressed throughout the brain in ADHD and stress, the research approaches still discussed today,8 measuring total dopamine levels in urine, no longer seem necessarily purposeful.
Stimulants and atomoxetine increase dopamine levels in the PFC and striatum. Overdosing can result in dopamine levels being as far from optimal as before. Therefore, a very slow up-dosing is advisable.
We explain in detail the interplay between neurotransmitters and stress and the effects of optimal, excessive, and decreased neurotransmitter levels in ⇒ Neurotransmitters in stress.
For the individual neurotransmitters, see the following subsections:
Böhm (2020): Neurotransmission und Neuromodulation, S. 113, 114 in “Mediatoren und Transmitter”, in Freissmuth, Offermans, Böhm (2020): Pharmakologie und Toxikologie – Von den molekularen Grundlagen zur Pharmakotherapie, 3. Aufl. ↥
Cools, D’Esposito (2011): Inverted-U shaped dopamine actions on human working memory and cognitive control; Biol Psychiatry. 2011 Jun 15; 69(12): e113–e125. doi: 10.1016/j.biopsych.2011.03.028; PMCID: PMC3111448; NIHMSID: NIHMS286132; ↥
Weber, Conlon, Stutt, Wendt, Ten Eyck, Narayanan (2022): Quantifying the inverted U: A meta-analysis of prefrontal dopamine, D1 receptors, and working memory. Behav Neurosci. 2022 Apr 7. doi: 10.1037/bne0000512. Epub ahead of print. PMID: 35389678. ↥