Gaba, subunits and dependence

[dooble]

Dear everyone,

I hope there hasn't been any thread like this before and sorry if this is not ADD.

Anyway, opiates and benzodiazepines don't cause crossdependency right? And probably, say, different types of GABA-A agonists don't cause crosstolerance and crossdependence. But where does the dependence kick in, does it all depend on the subunit and overstressing the subunit?

I mean, different benzos work pretty much on the same benzodiazepine receptors and cause dependency all the same. And Z-drugs work on these receptors also, right? But what about etifoxine, which is supposed to work on β2 and β3 subunits of GABA-A. Will etifoxine be similar enough to benzos that it will cause crossdependancy? Or could I alternate with etifoxine and benzos and avoid dependency? (Not saying etifoxine is something worth of abuse though...)

I hope I made the problem clear enough, and I hope I do not insult anyone with my poor knowledge of Gaba receptors and all .

 

[ebola?]

different types of GABA-A agonists don't cause crosstolerance and crossdependence.

To some extent, they DO tend to, though the cross-tolerance is less complete than with ligands with more similar activity profiles.

And Z-drugs work on these receptors also, right?

These are slightly more selective among alpha-subunits (I don't know how off hand though).

ebola

 

[Hammilton]

The Z-drugs tend to be selective for GABA-A receptors which contain an alpha-1 subunit.

There are dozens, perhaps hundreds of different GABA-A receptors in your brain, composed of various alpha, gamma and beta subunits. The GABA-A receptor is not a homogenous thing- it's really best thought of as a family of receptors. The benzodiazepine receptor is composed of an alpha and a gamma subunit, formed between where the two meet. A drug that is said to be alpha-1 selective will bind only to GABA-A receptors which contain alpha-1 subunits. They may have other gamma and beta subunits, but they must have the alpha-1.

For whatever reason, GABA-A receptors containing an alpha-1 subunit seem to induce sedation more. That may be a result of their own particular activity or their location in the brain.

They're definitely able to suppress one another's withdrawal, but that's probably because they're spread out across the brain enough that enhancing the activity of one type of GABA-A receptor will be able to make up for the lack of another one. I can't say I've looked into this a lot, but I'd bet if there are any selective ligands that aren't able to block withdrawal from a ligand selective at another type of GABA-A receptor you'd find the difference to be in the areas they're expressed in.

 

[neur0net]

Anyway, opiates and benzodiazepines don't cause crossdependency right? And probably, say, different types of GABA-A agonists don't cause crosstolerance and crossdependence. But where does the dependence kick in, does it all depend on the subunit and overstressing the subunit?

In a word, no, opioids and and GABA-A drugs should not cause any cross tolerance because they're not active at the other's receptor site (unless we were talking about a drug that binds to both mu-opioid AND GABA-A; to my knowledge no such compound exists). Different types of GABA-A agonists will certainly cause cross-tolerance unless we're talking about an agonist which is highly selective for only one subtype. The family of benzos, for example, have a wide variety of binding affinities at different subunits (which would explain the subtle differences between them), so you'd expect them to be cross-tolerant (which they are). This is further complicated by the fact that we're still largely ignorant as to what each subunit actually does. Alpha-1 (the primary target of zolpidem) seems to be related to sedation, alpha-3 seems related to memory, but there is still much to be learned. Maybe inducing massive down-regulation of one specific subunit results in less severe withdrawal effects than others...who knows? I'd like to find out, but it may be a while before specific questions like these get answered.