Various Drugs that Affect the GABA A Receptor
Gamma Amino Butyric Acid aka GABA is the primary inhibitory neurotransmitter in the brain and it acts to oppose Glutamate, the primary excitatory neurotransmitter brain. As mentioned previously, there are two primary Gabanergic Receptors: the Ionotropic GABA A receptor, and the G-protein coupled GABA B receptor. No need to understand the difference for now, we will go in more detail in a future article.
Today we will focus on the GABA A receptor and explore all the different ways different drugs can bind to this receptor subtype and discuss the
Gamma Amino Butyric AcidVarious Drugs that Affect the GABA A Receptor
The GABA A receptor is a ligand-gated ion channel. What this means in simple terms is that the GABA A receptor acts as a channel that allows for chloride-ions to pass through when GABA (or any other other GABA A agonist compounds) binds to the receptor. GABA A drugs all impact this channel’s ability to allow through chloride ions through one way or another. Let’s walk through the major different possible interactions and some example drugs.
GABA A Agonism
This is the simplest and most straightforward way of interacting with the GABA A receptor and describes any interaction whereby a compound binds to the GABA A receptor and opens it, similar to what GABA itself would do. The compound tends to bind to the “orthosteric” i.e. primary site on the GABA A receptor.
Direct agonism of the GABA A receptor leads to anxiety relief, disinhibition, pro-social behavior, memory loss, euphoria, and other characteristic “drunk” effects.
Examples: GABA
GABA A Agonism with Structural Selectivity
Z-Drugs (such as zolpidem aka ambien) are a class of drugs also known as non-benzodiazepines. These drugs tend to have a very similar effect as benzodiazepines, but without belonging to the benzodiazepine class. In addition to action as GABA A Positive Allosteric Modulators (explained below) just like benzos, Z-Drugs tend to exhibit a certain amount of direct GABA A agonism. However, this agonism seems to be very selective for only certain subtypes of GABA A receptors that contain the a2 and a3 subunits. What this specifically means is complicated, but this is often credited for the weird dream-like hallucinatory effects Z-Drugs are famous for.
This effect is also hypothesized to contribute to some of the hallucinogenic effect of the atypical hallucinogen Amanita Muscaria mushroom.
Z-Drugs are named due to the fact that a large number of them have names starting with the letter Z such as Zolpidem or Zopiclone.
From the webcomic “Toothpaste for Dinner”: https://www.toothpastefordinner.com/index.php?search=Ambien+Walrus Examples: Zolpidem, Zopiclone, Zaleplon, Pagaclone, Muscimol, etc
https://pubmed.ncbi.nlm.nih.gov/2157817/
GABA A Positive Allosteric Modulation (Barbiturates site)
All forms of Allosteric Modulation refers to when a ligand binds to an alternative “allosteric” site on the receptor as opposed to binding to the primary “orthosteric” site. We have discovered numerous different allosteric sites on the GABA A receptor, with various classes of drugs binding to different ones amongst them.
Some of the first GABA A PAMs we discovered were drugs in the Barbiturates class, and they became widespread for their sedative, anxiolytic, and disinhibiting effects. Various barbiturates have been deemed the “truth” serum, while others have been used in anesthesia and even lethal injections.
Barbiturates work by binding to the barbiturate allosteric site on the GABA A receptor, which allows the GABA A ion channel to be open for longer. This essentially has a multiplicative effect on your body’s endogenous GABA. Some barbiturates also bind to the orthosteric site and act as GABA A agonists as well.
Barbiturates are easy to overdose due to the self-potentiating effect it has by being both a GABA A agonist and PAM. High dosages, especially in combination with alcohol could easily lead to dangerous levels of respiratory depression. It is because of these risks that the medical field has eventually migrated onwards to benzodiazepines, which are far safer.
Examples: Allobarbital, Amobarbital, Barbital, Phenobarbital, Secobarbital, Sodium Thiopental
https://pubmed.ncbi.nlm.nih.gov/8719918/
https://pubmed.ncbi.nlm.nih.gov/23205959/
GABA A Positive Allosteric Modulation (Benzodiazepine site)
Benzodiazepines, a common powerful anti anxiety medication, have mostly supplanted barbiturates in the treatment of anxiety. Benzodiazepines bind to the benzodiazepine allosteric site on the GABA A receptor and has the effect of allowing for more frequent activations of the ion channel. This essentially also has a multiplicative effect on your body’s endogenous GABA, similar to barbiturates. However, more frequent activations inherently leads to less total ion passage than barbituates’ effect, leading benzos to be deemed as safer than the older barbiturates.
Due to benzodiazepines having a somewhat safer form of positive allosteric modulation and the fact that they do not simultaneously act as PAMs and agonists, they are far safer in an overdose compared to barbiturates. It is very difficult to reach fatal levels of respiratory depression from a benzo alone, but care should be taken to avoid this anyway as benzo overdoses have potentially heavy social consequences* even without physical harm. (*the level of disinhibition and memory impairment characteristic of a high dose benzo experience tends to lead one to commit very inappropriate acts or crimes that can have dire consequences. In other words, don’t be a bartard).
Note about Z-Drugs: In addition to the hallucinogenic direct agonism described earlier, Z-drugs also act as positive allosteric modulators. They bind to a site that overlaps with the Benzo site
Examples: Alprazolam, Lorazepam, Clonazepam, Etizolam, Clonazelam, Midazolam, Bromazolam, etc
https://pubmed.ncbi.nlm.nih.gov/17979718/
GABA A Positive Allosteric Modulation (Ethanol site - Disputed)
Although we are unclear how exactly Ethanol impacts its effects, the consensus is that Ethanol seems to act as a positive allosteric modulator of GABA A (among myriad other effects) in a manner very similar to benzos. How it exactly achieves this, and which exact site it binds to is both unclear Some have proposed that Ethanol binds to a separate “Ethanol” allosteric site. This hypothesis is often disputed and no universal agreement exists yet on the exact binding site of ethanol or other alcohols.
Examples: Ethanol (Drinking Alcohol), 2m2b
GABA A Positive Allosteric Modulation (Carisoprodol site)
Carisoprodol, brand name Soma, is a unique muscle relaxer that doesn’t seem to bind to either the benzodiazepine nor the barbiturate allosteric sites. Instead, carisoprodol seems to bind to a third lesser known allosteric site and acts as a PAM there instead.
Carisoprodol is one of the strongest muscle relaxers in this class and high dosages can lead to severe non-harmful myoclonus (muscle twitches / jerks) due to excess muscle relaxation.
Examples: Carisoprodol
GABA A Competitive / Orthosteric Antagonism
Similar to a direct GABA A agonist, some drugs can act as GABA A competitive antagonists. These compounds bind to the same orthosteric site that GABA itself binds to, but either has a weaker effect than GABA itself or has no effect whatsoever. These molecules compete with GABA for spot in GABA A receptor orthosteric sites, but don’t open the ion channel afterwards. This has an overall impact of decreasing the effects of your endogenous GABA (or any other GABAnergic substances you may have consumed)
Examples: Bicuculline
GABA A Negative Allosteric Modulation
Similar to positive allosteric modulators, Negative Allosteric Modulators are compounds that bind to some allosteric site and has the effect of weakening the action of the receptor itself. This is unlike, competitive antagonists, above, which works by binding to the orthosteric site. Instead NAMs bind to an allosteric site (similar to PAMs), but simply act negatively instead of positively after binding to the allosteric site.
These drugs are likely to be convulsant, stimulating, and induces neuroplasticity; due to the excitotoxicity and seizure risks, GABA A NAMs are potentially a bit risky to use.
Flumazenil is an example of a drug in this class and can be used to treat a benzo / barbiturate overdose.
Examples: Flumazenil
GABA A Noncompetitive / Allosteric Antagonism
Let’s imagine a Negative Allosteric Modulator that not only inhibits the action of the GABA A receptor, but rather completely disables the receptor as a whole. This category of “complete NAMs” are known as Noncompetitive Antagonists. Compare Noncompetitive Antagonists with Competitive Antagonists: whereas competitive antagonists competes with GABA for a spot at the orthosteric site, Noncompetitive Antagonists bind to a separate allosteric site and completely disables the receptor. This means that no matter how much excess GABA molecules are around, they would never be able to “win the game of musical chairs”, since they are not even competing for the same spot.
A large enough GABAnergic overdose would be able to overwhelm a competitive antagonist’s ability to antagonize GABA A due to it having to win the game of musical chairs first. A large enough GABAnergic overdose would NOT be able to overwhelm a noncompetitive antagonist’s effect since the noncompetitive / allosteric antagonist would completely disable the receptor as a whole until your neuron makes new ones.
Pentylenetetrazol is a drug that exhibits this effect by binding to a 4th allosteric site on the GABA A receptor that’s separate from the 3 mentioned above (benzo, barb, carisoprodol binding sites). This is the same allosteric site that the poisonous plant molecule Picrotoxin binds to. As expected, both Pentylenetetrazol and Picrotoxin have convulsant and stimulant effects.
Examples: Pentylenetetrazol, Picrotoxin
