Acetylcholine & ADHD

Welcome to the wonderfully complex world of neurotransmitters, where today we're looking into the life of the brain's very own multitasking neurotransmitter, Acetylcholine (ACh). While a lot of us might be familiar with the two neurotransmitters dopamine, and serotonin, there are two others that I feel do not get the attention they deserve, gamma-aminobutyric acid (GABA), and Acetylcholine.

The GABA blog will be a topic for a different time, so for now we will focus on acetylcholine, specifically the relationship between acetylcholine, choline status, and ADHD.

Before we check out the relationship between ACh and ADHD, I want to first explain what excitatory and inhibitory means in the context of neurotransmitters, and give you a few examples of what they do.

 

Excitatory Neurotransmitters

• Function: Excitatory neurotransmitters increase the likelihood that the neuron they act upon will fire an action potential (a nerve impulse).
• Mechanism: When an excitatory neurotransmitter binds to its receptor on a neuron, it typically causes positive ions (like sodium, Na+) to enter the neuron, making the inside of the cell more positive. This process is called depolarization. If the depolarization reaches a certain threshold, it triggers an action potential, leading to the transmission of a signal down the neuron.
• Example: Glutamate is the primary excitatory neurotransmitter in the brain, playing a crucial role in learning and memory.

 

Inhibitory Neurotransmitters

• Function: Inhibitory neurotransmitters decrease the likelihood that the neuron they act upon will fire an action potential.
• Mechanism: When an inhibitory neurotransmitter binds to its receptor on a neuron, it often causes negative ions (like chloride, Cl-) to enter the neuron or positive ions (like potassium, K+) to leave the neuron, making the inside of the cell more negative. This process is called hyperpolarization. Hyperpolarization moves the membrane potential further from the threshold needed to trigger an action potential, thus reducing the chance of the neuron firing.
• Example: GABA (Gamma-Aminobutyric Acid) is the main inhibitory neurotransmitter in the brain, helping to prevent over-excitation and maintain a balanced neural activity.

Balancing Excitatory and Inhibitory Signals

The brain relies on a balance between excitatory and inhibitory signals to function properly. Too much excitation can lead to conditions like seizures, while too much inhibition can result in sedation or loss of function. Excitatory neurotransmitters are like the "accelerator" in the brain, pushing neurons to send signals, while Inhibitory neurotransmitters are like the "brake," slowing down or preventing the transmission of signals. Here are a few examples of neurotransmitters and how they work in terms of whether they are inhibitory or excitatory, or both!

GABA (Gamma-Aminobutyric Acid)

Inhibitory: GABA is the primary inhibitory neurotransmitter in the brain, reducing neuronal activity and calming the nervous system.

Dopamine

Both: Dopamine can be excitatory or inhibitory depending on the receptor subtype (e.g., D1 receptors are excitatory, D2 receptors are inhibitory).

Serotonin (5-HT)

Both: Serotonin can have both excitatory and inhibitory effects depending on the receptor subtype it interacts with.

Glutamate

Excitatory: Glutamate is the primary excitatory neurotransmitter in the central nervous system, playing a key role in synaptic plasticity, learning, and memory.

Norepinephrine (Noradrenaline)

Both: Norepinephrine is primarily excitatory, enhancing arousal and alertness, but can have inhibitory effects in some areas of the brain depending on the receptor.

Histamine

Excitatory: Histamine is generally excitatory in the brain, promoting wakefulness, alertness, and the inflammatory response.

Endorphins

Inhibitory: Endorphins are inhibitory neurotransmitters that reduce pain perception and promote feelings of well-being and relaxation.

Acetylcholine (ACh)

Both: Acetylcholine can be excitatory at nicotinic receptors and inhibitory at some muscarinic receptors depending on the context and location.

 

So, this categorization reflects the primary roles of these neurotransmitters, though their effects can vary based on the specific receptors and neural circuits involved. Also, there are a LOT more neurotransmitters out there, these are just some of the most popular ones. Anyways, let's dive into ACh!

 

What Is Acetylcholine?

Acetylcholine isn't just any neurotransmitter; it's sort of the brain's Swiss Army Knife, equipped with tools for everything from muscle movement to memory. Imagine it as the caffeine of your neural network, but instead of just making you feel nice and focused, it also helps you remember when your mother’s birthday is. Can’t forget that!

The Dual Life of ACh

As we saw above, ACh is one of those neurotransmitters that does both excitation and inhibition! As it relates to its excitatory properties, ACh binds to nicotinic receptors making neurons fire up, muscles contract, and your brain buzz with activity. Think of it as the 'go' signal in your brain's traffic system. In terms of its inhibitory effects,  ACh decides to play it cool with muscarinic receptors, sort of like a bouncer at the club, telling your heart to slow down or your neurons to take a chill pill.

When we are talking about the connection between ADHD and ACh status, we are focused on its excitatory effects, but I just wanted to let you guys know that it does in fact do both.

 

The Connection Between Acetylcholine and ADHD

While ADHD is often about dopamine and norepinephrine, ACh status seems to be playing a role that is often overlooked. We typically medicate ADHD with amphetamines, which primarily affect dopamine and norepinephrine, and not ACh. ACh is crucial for attention and memory, which ADHD folks tend to struggle with. Imagine trying to focus with a neurotransmitter (or pathway) that's not quite doing its job, sort of like trying to write with a pen that keeps drying up and not dispensing ink. The issue isn’t necessarily the ink (in this case ACh), but rather the reservoir transporting the ink to paper. Let’s see why this might be.

The CHT Gene

This gene is like the supply chain manager for ACh. If it's not working right, your brain's factory will have noticeable supply chain issues. Not enough ACh means cognitive functions like learning and memory might be as scattered as a toddler's toys after a birthday party.

Now this gene has several variants, but when it comes to ADHD, it appears that individuals with ADHD tend to have the Val89 variant. Having the Val89 variant is like having a slightly less efficient supply chain manager. It might not get choline (the raw material for ACh) into neurons as well, leading to less ACh production. For those with ADHD, this could be the straw that breaks the camel's back, potentially making symptoms worse. It's like trying to solve a puzzle with missing pieces.

 

How Can I Improve My ACh Status?

Cholinergics like Alpha-GPC (alpha-glycerylphosphorylcholine) and CDP-Choline (cytidine diphosphate-choline) may offer significant benefits to individuals with the Val89 variant of the CHT gene. The Val89 variant we now know is associated with a reduced efficiency in choline uptake which can lead to lower levels of acetylcholine synthesis in the brain.

Alpha-GPC and CDP-Choline are both potent cholinergic compounds that increase the availability of choline in the brain, which can compensate for the reduced choline transport efficiency seen in individuals with the Val89 variant. By providing more choline, these supplements help ensure that acetylcholine levels remain sufficient for optimal cognitive function, despite the genetic limitation. Additionally, both Alpha-GPC and CDP-Choline have been shown to cross the blood-brain barrier effectively, making them particularly valuable in enhancing cholinergic activity in the central nervous system, which could mitigate some of the cognitive challenges associated with the Val89 CHT variant.

For whatever reason,acetylcholine (ACh) often takes a back seat to dopamine and norepinephrine in discussions about ADHD. However, its role in attention, memory, and overall cognitive function is undeniable. The link between the Val89 variant of the CHT gene and ADHD highlights the importance of maintaining adequate ACh levels for optimal brain function. Individuals with this genetic variant may experience reduced choline uptake, leading to lower ACh production, which can exacerbate ADHD symptoms. However, cholinergics like Alpha-GPC and CDP-Choline offer a promising solution by enhancing choline availability in the brain, thereby supporting ACh synthesis and potentially improving cognitive outcomes for those affected.