What is the mechanism of action?
Gaboxadol's mechanism of action is actually fascinating.
It's a ligand for GABA-A receptors just like benzodiazepines, z-drugs, & barbiturates. However, it works on an entirely different subset of these receptors. So, it has a very different effects profile.
Basically, Gaboxadol only interacts with GABA receptors that contain a δ-subunit (in place of the more common γ-subunit). Benzodiazepines do not bind to these types of receptors at all. They only bind to a specific allosteric site on the GABA receptor that occurs at the interface of α- & γ- subunits. So, GABA receptors lacking a γ-subunit (and that have a δ-subunit instead) are benzodiazepine-insensitive (that's how they're officially referred to).
The reason why this makes such a difference is because δ-containing GABA receptors are located primarily extrasynaptically and mediate "tonic inhibition" (as opposed to the "phasic inhibition" that Benzos mediate).
Phasic inhibition is the traditional way we think of how neurotransmitters work: GABA is released in discreet packets (i.e. via presynaptic vesicles) into the synaptic cleft and bind to GABA receptors on the postsynaptic neuron. That's phasic inhibition.
However, when this happens, small amounts of these neurotransmitters "leak out" or spill over into the extrasynaptic space (especially during periods of heavy or high frequency stimulation) and bind to receptors located extrasynaptically (elsewhere on the neuron, not in or near the synapse). This is called tonic inhibition. And these extrasynaptic receptors sort of set the “tone” for the overall excitability of the neuron. They’re sort of like little gain controls that neurons use to gauge their own activity as well as the activity of neighboring neurons. They're also sometimes referred to as "ambient sensors".
A drug that primarily mediates tonic inhibition (like Gaboxadol) would have very different therapeutic applications than those that primarily mediate phasic inhibition (such as Benzodiazepines). For example:
- Phasic inhibition is extremely effective for sleep initiation/onset. But tonic inhibition would potentially be much more effective for sleep maintenance & sleep quality.
- Phasic inhibition = great for resolving acute epileptic events. Whereas conditions characterized by chronic, low grade excitation (such as essential tremor) might benefit more from tonic inhibition.
- Acute panic attacks --> phasic inhibition. Generalized anxiety --> tonic inhibition.
- ...etc.
(Note: There's also the fact that δ-GABA receptors are expressed very differently throughout the brain compared to the more widespread γ-containing GABA receptors. They're much more highly enriched in the cerebellum (specifically cerebellar granule cells), thalamic relay nuclei, dentate gyrus of the hippocampus, etc.)
γ = gamma
δ = delta
α = alpha
Edited by Furniture, Today, 08:02 PM.
