Acetylcholine

Acetylcholine (ACh, 2-acetoxyethyl)trimethylammonium, 2-(trimethylammonium)ethyl)acetate, C7H16NO2) is a biogenic amine and neurotransmitter.
It is found in the central and peripheral nervous system (CNS, PNS).
Acetylcholine is involved in

• the mediation of voluntary contraction of skeletal muscles
• Signal transmission in preganglionic sympathetic and in all parasympathetic neurons

Acetylcholine is very similar in structure to nicotine and binds to the same receptors. The high comorbidity of ADHD and smoking indicates a connection.¹

• 1. Control ranges of acetylcholine
• 2. Synthesis of acetylcholine
• 3. Release of acetylcholine
• 4. Binding of acetylcholine
• 5. Breakdown of acetylcholine
• 6. Acetylcholine and dopamine
  • 6.1. β2-Nicotinic receptor agonists reduce tonic and increase phasic dopamine in the striatum
    • 6.1.1. Acetylcholine
    • 6.1.2. Nicotine
  • 6.2. β2-Nicotinic receptor antagonists reduce phasic dopamine in the striatum
  • 6.3. Acetylcholine activates dopaminergic neurons in VTA
  • 6.4. Acetylcholine causes phasic dopamine release in the striatum
  • 6.5. Ovarian hormones influence dopamine release via cholinergic interneurons
• 7. Acetylcholine and ADHD
  • 7.1. Noradrenaline reuptake inhibitors increased extracellular ACh (only) in the cortex and hippocampus
  • 7.2. Imbalance between ACH and DA?
• 7.3. ACh receptors and spatial memory

1. Control ranges of acetylcholine¶

• Memory formation²

• neuromuscular transmission of excitation
• Control of the autonomic nervous system
• Reward

2. Synthesis of acetylcholine¶

Synthesis in acetylcholinergic terminals from choline and acetyl-CoA by the enzyme choline acetyltransferase. Choline is a precursor of acetylcholine as well as phosphatidyl-choline and sphingomyelin.
Most choline in the body is found in phospholipids. Choline-containing phospholipids (especially phosphatidylcholine and sphingomyelin) are structural components of cell membranes and precursors for intracellular messengers. Phosphatidylcholine is a necessary component of VLDL (Very Low Density Lipoprotein), which is required for the transport of cholesterol and fat from the liver to other parts of the body.³
Uptake by antiporters in salivary vesicles. In this way, 5,000 to 10,000 acetylcholine molecules are stored in the cytoplasm of nerve cells.

3. Release of acetylcholine¶

Release in response to an incoming action potential via exocytosis into the synaptic cleft.
Binding to cholinoceptors on the postsynaptic membrane leads to a change in ion permeability (Ca2+, Na+, K+), which can cause either excitation (depolarization) or inhibition (hyperpolarization) of the target cell.

4. Binding of acetylcholine¶

Cholinoceptors

• nicotinic acetylcholine receptors (nicotine receptor)
  • ligand-controlled ion channel
  • Binding of acetylcholine opens it and makes it permeable to sodium, potassium and calcium ions
• muscarinic acetylcholine receptors (muscarinic receptor)
  • G protein-coupled receptor
  • Binding of acetylcholine triggers effect via second messenger

5. Breakdown of acetylcholine¶

Acetylcholine is cleaved into choline and acetic acid in the synaptic cleft by acetylcholinesterase. The choline can be reused by the nerve cell by being taken up from the synaptic cleft by the sodium- and chloride-dependent choline transporter (ChT).

Keywords: 3D molecule, neurotransmitter

6. Acetylcholine and dopamine¶

6.1. β2-Nicotinic receptor agonists reduce tonic and increase phasic dopamine in the striatum¶

6.1.1. Acetylcholine¶

Acetylcholine is a β2 nicotinic receptor agonist and influences the release of dopamine in the striatum.⁴

The earlier assumption that deanol is a precursor of choline and would also increase acetylcholine is in doubt. Only at extremely high doses was an increase in acetylcholine found in rats, and only in the striatum. More on this under Deanol for ADHD

6.1.2. Nicotine¶

Nicotine is a β2 nicotinic receptor agonist. Nicotine reduces tonic and increases phasic dopamine release in the nucleus accumbens (striatum).⁵

6.2. β2-Nicotinic receptor antagonists reduce phasic dopamine in the striatum¶

Dihydro-β-erythroidine (DHβE) is a plant-derived competitive antagonist of nicotinic receptors. It is an inhibitor of nicotinic acetylcholine receptors containing β2 units (β2* NAChRs; β2 nicotinic receptors). DHβE reduces the phasic release of dopamine in the dorsolateral striatum⁵
Consequences are that reward anticipation, which is controlled by phasic dopamine in the striatum and even more so in the nucleus accumbens, is also increased by β2-nicotinic receptor agonists - such as nicotine - .

6.3. Acetylcholine activates dopaminergic neurons in VTA¶

Acetylcholine activates dopaminergic neurons of the VTA.⁶
Cholinergic brainstem neurons activate nicotinic and muscarinic M5 receptors. This has the following effects:

• increased dopamine bursts in VTA
• Influencing reward processes/addiction

However, whether the cell nuclei of the dopaminergic nerve cells are actually activated is questionable in view of the following two sections.

6.4. Acetylcholine causes phasic dopamine release in the striatum¶

Acetylcholine neurons in the striatum can trigger an action potential in the dopaminergic axons by activating acetylcholine receptors on dopamine axons, which in turn triggers a phasic release of dopamine at the dopaminergic terminals. This does not require a signal from the dopaminergic nucleus.⁷
In the striatum, 1 % to 3 % of neurons are tonically active interneurons that release acetylcholine (ACh). The axons of ACh neurons are intertwined with the axons of dopamine neurons in many places where dopamine axons have high concentrations of nicotinic ACh receptors (nAChRs). Synchronous activation of these ACh receptors in the distal dopaminergic axons by action potentials from the ACh neurons can directly control dopamine release, i.e. independently of the action potentials from the dopaminergic somata in the midbrain.
This mechanism could be the same as described in the following section.

A study showing that administration of deanol, a precursor of choline, which in turn is metabolized to acetylcholine, increased acetylcholine levels in the striatum of rats suggests that acetylcholine levels may be limited by the amount of the precursor deanol.⁸

6.5. Ovarian hormones influence dopamine release via cholinergic interneurons¶

Dopamine release from axon terminals in the NAc is rapidly modulated by local regulatory microcircuits independent of somatic activity in the VTA. Tonic (slow and regular) and phasic (short, burst/spike) dopamine release in the NAc is subject to strong modulation by cholinergic (ChAT) interneurons. The ChAT signal via α4β2*-containing nicotinic acetylcholine receptors (nAChRs), which are located directly at dopamine terminals.⁹
ChAT regulation of dopamine release by nAChRs is fundamentally different in males and females. This suggests that sex-specific differences in ChAT regulation of dopamine neurotransmission underlie sex-dependent differentiation in reward learning.⁹

• In female mice, ChAT regulation of dopamine release by α4β2*-nAChRs is mostly absent. Impaired nAChR modulation of dopamine release was not affected by the estrus cycle in intact (non-ovariectomized) females. However, impaired nAChR modulation of dopamine release was restored in ovariectomized females. 17β-Estradiol (E2) acutely increased dopamine release, which was blocked by α4β2*-NAChRs antagonists. Females showed a lesser effect of nAChR agonists on dopamine release, which would be expected with desensitized receptors.
• In behavioral studies, male mice learned faster than intact females when ChAT interneurons were activated.
• Independent of the hormonal cycle, circulating ovarian hormones influence the ability of α4β2*-nAChRs on dopamine terminals to modulate dopamine release in the NAc.

This mechanism could be the same as described in the previous section.

7. Acetylcholine and ADHD¶

The significance of acetylcholine in relation to ADHD has so far been largely unexplored.

A meta-analysis study reported increased choline levels in the blood of people with ADHD¹⁰

• PFC
• Striatum
• Anterior cingulate cortex.

The fairly recent discovery of direct control of dopamine release in the striatum by acetylcholine neurons⁷ requires a reassessment of the role of acetylcholine in relation to dopamine and ADHD. Our subsequent collection will need to be weighted in terms of the importance of each point.

7.1. Noradrenaline reuptake inhibitors increased extracellular ACh (only) in the cortex and hippocampus¶

Noradrenaline reuptake inhibitors increased extracellular ACh levels in the cortex and hippocampus, but not in subcortical brain regions of rats in vivo:¹¹
- Methylphenidate
- MPH (1.25 and 2.5 mg/kg) increased acetylcholine release in the cortex of rats by 173% and 212%, respectively¹²
- nAChRs do not appear to regulate methylphenidate-induced behavioral sensitization; however, inhibition of high-affinity nAChRs-beta2 reduced the induction of behavioral sensitization to high doses of MPH¹³
- Atomoxetine
- Reboxetine
- the cortical ACh increase (by ATX) was mediated by noradrenergic activation of the alpha-1 and/or the D1 dopamine receptor

Depression-related apathy can be treated well with noradrenergic antidepressants, but less so with SSRIs (which may even make it worse):¹⁴

• Dopamine agonists also appear to be effective in apathy
• Acetylcholinesterase inhibitors (which inhibit the breakdown of acetylcholine) are also effective, as are methylphenidate, atypical antipsychotics, nicergoline and cilostazol.
• We see this as a possible indication of a dopaminergic effect of acetylcholine, which is raised by noradrenaline reuptake inhibitors

7.2. Imbalance between ACH and DA?¶

It has been discussed whether ADHD could arise from an imbalance of the acetylcholinergic and dopaminergic neurotransmitter systems¹⁵

• in ADHD, the binding capacity (Bmax) of muscarinic acetylcholine receptors in fibroblasts appears to be reduced¹⁵

7.3. ACh receptors and spatial memory¶

The nicotinic acetylcholine receptor (nAChR) agonist ABT-418 improves spatial memory in SHR as well as methylphenidate.¹⁶ In another study, BT-418 improved cognitive processes but not impaired attentional performance resulting from loss of cortical cholinergic inputs.¹⁷