Neurotransmitters and an introduction to neuropharmacology

General communication of neurons

Although neuron communication has been covered here is a quick recap: Neurons communicate through synapses, the point of contact between an axon terminal and the post synaptic neuron. It is at the synapse that the presynaptic neuron releases neurotransmitters which will in hyperpolarise or depolarise the post synaptic neuron. Enough local depolarisations can lead to an action potential but this can be blocked by hyperpolarisation. Different neurotransmitters lead to different effects.

Defining Neurotransmitters

The definition of a neurotransmitter is a chemical which acts to carry the change from presynaptic neuron to postsynaptic neuron. It must be released from synaptic depolarisation and artificial application of the chemical to the postsynaptic neuron must trigger the same effect.

The most common neurotransmitters are

• Glutamate (Present in 90% of excitatory synapes)
• GABA (30% of inhibitory synapses)
• Acetylcholine (present in 5% of neurons)
• Dopamine, serotonin, noradrenaline (less common but still essential)

Defining types of neurotransmission

You can have excitatory and inhibitory neurotransmission. Excitatory neurotransmission is where the action potential in the presynaptic neuron leads to release of an excitatory neurotransmitter being released in the synapse (usually glutamate). Inhibitory neurotransmission is the release of an inhibitory neurotransmitter after AP (often GABA).

Dale's principle

Historically the idea of what neurotransmitters got released was that every neuron has a flavour of neurotransmitter they release, one neuron, one neurotransmitter. This has now been revised heavily and often a mix of neurotransmitters are released on AP. However, it is still safe to think about neurons as being excitatory or inhibitory, with glutamate and GABA being major actors.

Components of excitatory neurotransmission

This is where the neurotransmitter leads to depolarisation. Glutamate activates AMPA and NMDA receptors leading to depolarisation. These are the main mentioned receptors in excitatory neurotransmission.

What is AMPA?

This is a ligand gated ion channel that will let sodium ions in as glutamate binds to it. It’s properties can also be altered by other molecules.

What is NMDA?

This is an ion channel which lets Ca²⁺ and Na⁺ into the cell. It has a mechanism of opening which makes it slower to activate: in its closed form it has an Mg²⁺ stuck in it, which is held there by the electrochemical gradient. This stops anything from flowing into the cell. On depolarisation the electrochemical gradient subsides, letting the Mg²⁺ go free and letting Na⁺ and Ca²⁺ into the cell.

NMDA provides a longer depolarisation, but with a lower peak.

Excitatory Neurotransmission and Long term potentiation

Long term potentiation is a process which allows neurons to fire with a lower stimulus threshold. Essentially a stronger connection and better connection. This is the synaptic plasticity and is the primary cellular mechanism for learning and memory.

We think this because NMDA antagonists can cause amnesia and are often used as aesthetic agents.

Tetanus is a very strong potentiate for LTP. NMDA is long term depolariser and can easily lead to tetanus so it is a larger actor, but both AMPA and NMDA are implicated.

The mechanism for LTP is the calcium ions from the NMDA leads to more AMPA receptors released to the synaptic gap, leading to easier reaching of threshold.

Components of inhibitory neurotransmission

This is where the neurotransmitter released leads to hyperpolarisation in the postsynaptic neuron.

In the case of GABA it occurs via directly opening GABA_a Cl- channels leading to chloride ion influx and a hyperpolarisation of the cell.

It also activates GABA_b channels which are GPCRs which lead to slower but longer inhibition. (functionally analogous to NMDAs)

Introduction to Neuropharmacology

The idea of treating psychiatric disorders and diseases originates with the idea that they are propagated from imbalances of neurotransmitters in the brain. Some examples being:

• Epilepsy: Too much excitation from glutamate
• Anxiety: High levels of noradrenaline
• Parkinsons: dopamine producing neurons die
• Depression: Low levels of several neurotransmitters
• Schizophrenia: too much dopamine in certain areas
• ADHD: Low levels of dopamine

Neuropharmacology attempts to address these via prescribing drugs that try to return the NT levels to baseline.

The general classes of neuropharmacological drugs are:

• Neuroreceptor agonists All endogenous neurotransmitter fit into this role, these are things that activate the receptors (ion channels for example)
• Neuroreceptor antagonists
• Neurotransmitter reuptake inhibitors
• Releasing agents
• Enzyme inhibitors
• Positive allosteric modulators

(Neuroreceptor) Antagonists

Antagonists make receptors work less well. Some completely stop them from working some cause a smaller inhibitory effect.

Ketamine as an NMDA antagonist:

An example is ketamine. It causes amnesia at very high doses inhibiting the excitatory activity of glutamate. In moderate doses it works as a antidepressant. A current theory for the mechanism for this is disinhibition.

Disinhibition is where there is inhibition of the inhibitory neurons leading to net excitation increasing long term potentiation and BDNF (Brain Derived Neurotrophic Factor) production.

In moderate doses ketamine also can cause analgesia.

Reuptake inhibitors

Reuptake inhibitors inhibit the transporters that clear neurotransmitters from the cleft back into the axon terminal. When cleared the NTs can no longer act on the receptors (NTs are metabolically expensive so the body will try to recycle).

Reuptake inhibitors are good as they boost existing connections and AP.

It is very ill advised to coprescribe enzyme inhibitors and reuptake inhibitors as there is nothing to clear NTs leading to uncontrolled tetanus.

Examples of reuptake inhibitors

• SSRIs selectively inhibits the clearing of serotonin. Used for treating depression (e.g. Escitalopram)
• SNRIs act on serotonin and norepinphrine (e.g. Venlafaxine)
• NDRIs act on norepinephrine and dopamine. Used for ADHD (e.g. Ritalin aka methylphenidate)

Releasing agents

Releasing agents work by binding to reuptake transporters and vesicle storage proteins. This leads to neurotransmitters building up in the cytoplasm and the transporters will reverse (unexplained in lecture). This all leads to higher levels of neurotransmitters in synapse and increased signalling.

Amphetamines are the most common type of releasing agents.

Enzyme inhibitors

Enzyme inhibitor have a pretty self explanatory name. The enzymes which modify free neurotransmitter in the synaptic cleft are targeted. This means the time of neurotransmitter in the cleft is increased and leads to more signalling.

It is very ill advised to coprescribe enzyme inhibitors and reuptake inhibitors as there is nothing to clear NTs leading to uncontrolled tetanus.

As they inhibit enzymes often they also effect other processes and enzymes for example in the liver.

Positive allosteric modulators

PAMs work by boosting the effects of the receptor if it binds at the same time as a neurotransmitter. This is an advantageous mechanism, as it boosts with the natural activity.

Some examples of PAMs are benzodiazepines and alcohol.

Propofol as a PAM for GABA_A

Propofol is a PAM that targets GABA_A receptors. this leads to general decrease in neurotransmission and is commonly used to induce anaesthesia