Modulating chloride channels to avoid or reverse dependence on hypnotic and sedativ

[Neuroprotection]

I have read some articles claiming that a small molecule, acting as a synthetic chloride channel has been developed for the treatment of cystic fibrosis. Since gabaA receptors are gated chloride channels, and tolerance to depressant drugs such as benzodiazepines ethanol and barbiturates, results in confirmational changes and desensitisation of the chloride channel, I wonder if this discovery could be applied to avoid our solve addiction dependence and tolerance to see NS depressants. This is, if the newly discovered small molecule can be made to cross the blood brain barrier.
What are your opinions?
Could this molecule allow chloride ions to bypass the gabba receptor and produce a sedative and CNS depressant effect?

 

[serotonin2A]

Besides the issue of CNS penetration, there are several problems with that approach.

* A lot of the tolerance to GABAergic drugs is not caused by GABA-A desensitization but rather by compensatory changes in glutamate signaling. If you could get the synthetic Cl channel expressed in the brain then the same compensatory changes would still occur.

* GABA-A receptor signaling is complex. The receptors are not distributed uniformly but are enriched in certain places (the distribution differs by brain regions, cell types, and different parts of individual neurons). GABA-A channels with different subunit compositions have different properties, and those features are used to fine-tune signaling. Furthermore, most signaling is phasic, and the timing and rate of receptor activation plays an important part in signaling. These Cl channels lack any of that specificity. It is entirely possible that the overall effect would be to perturb brain function to a much greater extent then you normally see in sedative tolerance and dependence. In orther words, think of how muscimol is much more psychoactive than diazepam. These chloride channels would be even worse, because muscimol still increases Cl current using the existing framework of GABA-A signaling.

* Use of non-specific Cl channels could actually increase withdrawal and excitation. As an example, expressing the Cl channel in GABAergic interneurons would inhibit their firing, which would reduce GABAergic inhibition. That would be particularly bad for people using benzodiazepines because they are allosteric modulators and their effects depend on the presence of GABA. Although the Cl channels would also be expressed by downstream (excitatory) pyramidal neurons, GABAergic interneurons tend to have higher firing rates compared with pyramidal neurons and therefore are more susceptible to inhibition. Hence why local anesthetics tend to preferentially inhibit inhibitory neurons (this is why convulsions are a symptom of local anesthetic overdoses).

* Overdoses of those channels would probably cause fatal respiratory depression.

 

[Cotcha Yankinov]

Hey Serotonin, so it seems that kindling is quite the issue. Do you think that glutamate antagonists might be of use, maybe to help diminish some of the long term potentiation or something?

I think I heard about a glutamate antagonist (I forget which receptors) that was approved for epilepsy and was curious if it would be very effective as a sedative or mood stabilizer (maybe for mania?). I mean assume that if it is successful as an anti-epileptic that must mean that it is (overall) decreasing the excitability of the brain and unless there are some defiant brain regions whose activity increases you would expect sedation right?

 

[serotonin2A]

Hey Serotonin, so it seems that kindling is quite the issue. Do you think that glutamate antagonists might be of use, maybe to help diminish some of the long term potentiation or something?

I think I heard about a glutamate antagonist (I forget which receptors) that was approved for epilepsy and was curious if it would be very effective as a sedative or mood stabilizer (maybe for mania?). I mean assume that if it is successful as an anti-epileptic that must mean that it is (overall) decreasing the excitability of the brain and unless there are some defiant brain regions whose activity increases you would expect sedation right?

They may be effective at relieving some symptoms. The downside, however, is that Glu antagonists are usually intoxicating, which isn't surprising giving the importance of Glu signaling. Allosteric modulators might be a better way to go because their effects tend to be more subtle.

Regarding your second question, the drug is perampanel, which acts as an AMPA antagonist. It is a sedative but I have no idea if it would work as a mood stabilizer. It is now classified as schedule III in the USA. The DEA claims high doses produced eurphoria and effects similar to alprazolam and ketamine in studies looking at its abuse potential. I have no idea if that level of control is appropriate -- I haven't seen the actual studies. However, sometimes the DEA will cherry pick data that favors scheduling from abuse potential studies. For example, if you look at the studies the DEA used to support scheduling of lorcaserin, it doesn't seem like it really has abuse potential. It is undoubtedly psychoactive, but so is diphenhydramine. I think DEA and HHS now err on the side of caution and schedule all new drugs that have any hint of psychoactivity.