Role of GABA in HPPD. Some thoughts on different drugs and susceptibility
SWIM has been reading that for HPPD antipsychotics don’t seem as effective for treating symptoms as GABAergics such as benzodiazepines. SWIM does not have HPPD but finds the condition interesting. HT2a agonists (all phenethylamine and tryptamine based psychedelics) result in increases in GABAergic activity. Other HT drugs such as HT1a agonists (antidepressants/anxiolytics including buspirone) and HT1b agonists (migraine drugs such as sumatriptan) also cause an increase in GABAergic activity. This poises the question, does repeated agonistic activation of HT receptors, especially HT2a cause permanent changes in GABA receptors and potentially a decrease in GABA levels overall? If so, are decreased levels of GABA vital in the development of HPPD? SWIM did some research and from what they found online it seems that there is a definitive link between reduced GABA and HPPD. This lead swim to numerous other questions.
Are GABA antagonists such as Thujone known for causing visual distortions? SWIM is aware that GABA antagonists such as glutamate contribute to firing of action potentials and can result in seizures and convulsions in high concentrations. SWIM wonders if the aura seen by epileptics before seizures consists of visual distortions. Could recreational use of thujone containing substances such as Absinthe and Wormwood contribute to and possibly cause symptoms similar to HPPD?
Some additional thoughts that SWIM has are:
-Are people that naturally have lower levels of GABA/increased levels of Glutamate more prone to developing HPPD with use of psychedelics? Could epileptics be especially susceptible?
-What about Opiates? GABA inhibits Dopamine release and opiates inhibit GABA, causing a release of dopamine. Salvia has been linked with HPPD in some instances so maybe it alters the GABA receptors?
-Could NMDA antagonists alleviate HPPD? Dissociatives such as Dextromethorphan, Ketamine and PCP have been shown to reduce the amplitude of Excitatory Post-Synaptic Currents which are responsible for glutamatergic release. A reduction in EPSCs would suggest inhibition of glutamatergic release and thus lower levels of glutamate.
-SWIM also wonders about cannabinoids. Cannabis causes GABA antagonism. Additionally, research has shown that potent CB1 agonists such as WIN 55212-2 have reduced the amplitude of EPSCs (which might contribute to the dissociative effects of synthetic cannabinoids) so could the lower levels of glutamate have a canceling effect on the GABA antagonism? Does a reduction in EPSCs initiate GABA release or just reduced Glutamate with minimal to no effect on GABA levels? So what effect do cannabinoids have on HPPD?
SWIM apologizes for how long-winded and all over the place this is but it fascinates him to no end. Given the mystery and lack of research surrounding HPPD this is naturally just speculation at this stage but makes SWIM wonder. These questions are directed towards not only those interested in/familiar with neuropharmacology but also those with HPPD, epileptics and people who recreationally use GABA antagonists. SWIM will clean this post up later today as they are currently running on only an hour of sleep and are starting to nod off.
Currently compiling list of sources. Should have them posted soon.
Re: Role of GABA in HPPD. Some thoughts on different drugs and susceptibility
A very interesting hypothesis. I don't know enough about HPPD to determine the veracity of it, but my pet giraffe has HPPD-like visual snow. He believes an easy way to test this would be to expose himself to GABA agonists and antagonists and record the results.
Re: Role of GABA in HPPD. Some thoughts on different drugs and susceptibility
Something that may shed some light on this...
SWIM was reading about adenosine receptors the other day and stumbled across a few studies about the concept of heteromers, which are essentially receptor sites made up of multiple g coupled protein receptors. Activation of which appears to allow for multiple effects, depending on the receptors location in the brain and body.
Some combinations include obvious ones like d1/d2 (dopamine), or A1/A2a (adenosine), but there are more complicated ones like CB1/D2, CB1/A2a and even "heterotrimers" like CB1/D2/A2a. There are likely heteromers and heterotrimers which are still unidentified and help produce various substances effects in ways that we don't understand yet, as well as complex drug interactions; in theory an Adenosine antagonist like caffeine or theophyline could very well block some of the psychoactive and somatic effects of a CB1 Agonist via blockade of adenosine dependent A2a/CB1 receptors. This quote is from a study called Striatal Adenosine A2A and Cannabinoid CB1 Receptors Form Functional Heteromeric Complexes that Mediate the Motor Effects of Cannabinoids
Quote:
At a functional level, we also demonstrated that CB1
receptor function is dependent on A2A receptor activation
both in vitro and in vivo. Thus, activation of A2A receptors
was necessary for CB1 receptor signaling in a human
neuroblastoma cell line and blockade of A2A receptors
significantly decreased the motor depressant effects of the
central administration of the synthetic cannabinoid receptor
agonist WIN 55 212-2 into the rat striatum."
Furthermore, in reference to SWIY's question on Cannabinoids, it is SWIMs understanding that CB1 receptors are primarily found on GABA neurons, so a CB1 - GABA connection seems likely; although it is probably infinitely more complex than that.
The only solid meaning SWIM can really find from any of this is that everything we know about all of this is just the tip of the iceberg.
Re: Role of GABA in HPPD. Some thoughts on different drugs and susceptibility
Good questions. Maybe its not so much a reduction in GABA though as specific subunits. When I was reading your post, I couldnt help remember a few articles on altered GABA receptors and hallucinations associated with schizophrenia. Perhaps there is similar occurances with HPPD?
Also, while I was looking up some of the information posted, I came across the use of medications that act at the glycine transporter GLYT1 to treat HPPD. Not to lump psychosis together with HPPD, but there is a lot of research on D-cycloserine and a reduction of schizophrenic symptoms. I would be interested in research regarding non-strychine glycine receptor agonism and whether this is a useful therapeutic for the treatment of HPPD.
Great post by the way. Thought provoking and I do wanna do some more reading on your ideas later.
