Understanding Neurotransmitters in the CNS

Now we're onto our third and final topic for PHAR3303: the CNS (Central Nervous System)! Personally I found this lecture to be a little bit complicated, but let's see how we go!

Types of Neurotransmission

There are many different types of neurotransmission. These include axo-dendritic (i.e. from axons to dendrites), axo-somatic, axo-axonic, dendro-dendritic and dendro-axonic. There are also other factors to be aware of, like co-transmission and volume transmission. Let's break things down a bit.

Axo-dendritic synapses

Axo-dendritic synapses (and axo-somatic synapses) are considered to be the "classical" synapses. A neurotransmitter is synthesised in the pre-synaptic neuron and is packaged into vesicles. When an action potential reaches the terminal, vesicles are released, depending on how much Ca²⁺ is around. Hence, neurotransmitter release can be regulated even though action potentials are all-or-nothing. The neurotransmitter can then cross the synapse and stimulate or inhibit receptors on the post-synaptic neuron. When the neurotransmitter is done doing its job, it may be degraded or transported back into the presynaptic neuron.

Axo-axonic synapses

Axo-axonic synapses occur when the axon of one neuron synapses with the axon of another. Axo-axonic synapses allow NA (noradrenaline) to inhibit ACh (acetylcholine) release and vice versa. This phenomenon, where one neurotransmitter inhibits the release of another, is called heterotropic inhibition, and the receptors involved are called presynaptic heteroreceptors.

In case you were wondering, homotropic inhibition (and facilitation) is a thing too. In homotropic inhibition or facilitation, a neurotransmitter acts on the neuron that it was released from. The receptors involved here are called presynaptic autoreceptors. Examples include α₂-adrenergic receptors, which allow NA to inhibit its own release, and β₂-adrenergic receptors, which allow NA to facilitate its own release.

Co-transmission

Most neurons have more than one neurotransmitter. Multiple neurotransmitters can be released together. Usually, at low stimulation frequencies, there will only be a localised increase in calcium concentration and release of only small neurotransmitters. At higher frequencies, calcium increases over a wider area, allowing more neurotransmitters to be released. Co-transmission may allow two somewhat opposing neurotransmitters to modulate each other, such as dopamine and cholecystokinin (CCK). Another advantage is that several neurotransmitters with different rates of action can be released at once, so one neurotransmitter can start off the response, followed by the second and then the third.

Volume transmission

Volume transmission is the phenomenon in which a neurotransmitter can be released from a non-synaptic site, or diffuse across to a different synapse and act there instead.

Types of Neurotransmitters

Neurotransmitters come in many different shapes and sizes. Smaller neurotransmitters include amino acid transmitters, neurotransmitters based off amino acids (e.g. dopamine, noradrenaline, adrenaline and so on, as I'll discuss later), purines (e.g. ATP and adenosine), acetylcholine, NO and something called anandamide, which inexplicitly got two slides all to itself. (I even checked the lecturer's list of publications and it doesn't appear to be a main focus of his.) Anandamide is an endogenous cannabinoid ligand (i.e. it reacts with cannabinoid receptors, specifically the CB1 receptor). It acts in a retrograde fashion (i.e. on the previous neuron). Anyway, back on topic: larger neurotransmitters include peptides, which are usually 3-30 amino acids long. Smaller neurotransmitters are often stored in small, clear vesicles, whereas larger neurotransmitters are found in dense vesicles.

Now for a bit more detail on what some of the neurotransmitters do!

• Acetylcholine- Synthesised from acetyl CoA and choline. Involved in arousal, motor control and memory.
• Glutamate- Primary excitatory neurotransmitter in the CNS. Involved in most things, but is particularly important in cell death and epilepsy.
• GABA- The main inhibitory neurotransmitter in the CNS.
• Glycine- The main inhibitory neurotransmitter in the spinal cord.
• Dopamine- Important in schizophrenia and in motivation.
• Noradrenaline and seratonin- Important in affective disorders, impulsivity and attention. Adrenaline, which is related to noradrenaline (hence the similarity in names), is scarce in the brain.
• Adenosine: Still not entirely sure, but one thing that is interesting is that caffeine can block adenosine receptors.

Neurotransmitter Synthesis

There are many different synthesis pathways, so I'm only going to touch on a few. (Actually, I don't think we need to know any synthesis pathways, but oh well, the more knowledge the better, right?) Generally, smaller neurotransmitters are synthesised in the terminal, whereas larger neurotransmitters are synthesised in the cell bodies and transported down to the terminals via axonal transport.

Glutamate

Glutamate can be synthesised from glutamine via the action of glutaminase (as also mentioned in my previous post on amino acid metabolism). This glutamine, in turn, arises from glial cells: glial cells take up glutamate and turn it into glutamine via glutamine synthetase. It's like a circle of life or something.

Catecholamines: Dopamine, Noradrenaline and Adrenaline

The synthesis of dopamine, noradrenaline and adrenaline starts off with tyrosine. Tyrosine hydroxylase converts tyrosine into L-DOPA. DOPA decarboxylase, a.k.a. "aromatic L-amino acid decarboxylase" (yes, it got renamed to something longer, but that's because the new name is more comprehensive) converts L-DOPA into dopamine. Dopamine can then be converted into noradrenaline via the action of dopamine β-hydroxylase, and noradrenaline can be converted into adrenaline via the action of phenylethanolamine N-methyltransferase.

Imidazoleamines: Histamine

Histamine is pretty simple. It is derived from the amino acid histidine, which is converted into histamine via histidine decarboxylase. And... that's it!

Indolamines: Serotonin (5-HT)

Serotonin is derived from tryptophan. Tryptophan is converted into 5-hydroxytryptophan via tryptophan 5-hydroxylase, which is then converted into serotonin (5-hydroxytryptamine, or 5-HT) via aromatic L-amino acid decarboxylase/ DOPA decarboxylase. Also, fun fact: serotonin in Mandarin is 血清素 (xue4 qing1 su4), as Google very helpfully told me when I wanted to double check whether or not serotonin and 5-hydroxytryptamine were the same thing.