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Cognition Improving Benzos?

Personally I'd say bugger the benzos. Chlormethiazole is just SO far superior in every respect it beggars belief. And unlikeso much of the modern crap being pushed as as anxiolytic/sedative/hypnotics it is actually effective. Neither ataxic, terribly cognitively impairing, nor does it leave a hangover after use. Yes, it will kill in an overdose, just treat like a barbiturate without the AMPA antagonist effects
and either totally refrain from alcohol use or keep use low. A few beers seems alright, but it doesn't take much alcohol whilst on this drug to knock you out cold.
 
Benzodiazepines increase functional GABA output, and GABA is inhibitory. So taking benzodiazepines will slow your brain down in general. However as Solipsis has mentioned, different alpha subunits on the GABA a ionotropic receptor are associated with different physiological effects. a1 is associated with hypnotic effects, a2 with anxiolysis and a5 with cognitive deficit. Some of the benzodiazepines prescribed for long term anxiety management like clonazepam are believed to possess a higher affinity for a2 subunits, possibly explaining their relative lack of cognitive deficit.

There are many opiates which act as agonists and antagonists at different opiate receptors, so there is definitely scope for the same thing to be applied to benzodiazepines. As Solipsis mentioned, a benzodiazepine agonist at a2 but antagonist/inverse agonist at a5 could act as an anxiolytic nootropic.
 
Possibly if you take flumazenil or another benzo receptor antagonist that has affinity for alpha5 you feel sharper, you'll also feel like absolute third-degree dogshit... but considering the link between intelligence and depression that seems about right. ;)
 
Interesting - no cognitive / amnestic impairment but mild stimulatory effects (Rundfeldt et al.), also pretty much no tolerance reported even after repeated use... and indeed dependency is also thought to be a function of the GABAR alpha5 subtype so that bodes well for it.
 
The anxiolytic effects are apparently a lot weaker tho and dont compare with real BZDR ligands.

Also isnt the dependence a consequence of a1 agonism ?
 
Yes I stand corrected, dependency is associated (so linked only not yet fully proven) with a1 agonism by comparing different benzos with different affinities:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453238/

The dependency is considered to be a consequence of GABAergically inhibited sympathomimetic neurotransmitters (which is a benzo effect but not yet narrowed down) which upon discontinuation go into overdrive.

I thought it was alpha5 because of this:

http://www.bluelight.org/vb/threads/550567-The-GABA(A)-Receptor-Complex-and-Benzodiazepines

So alpha1 is associated with dependency and the highest chance of causing dependency as a result - sorry Z-drugs you are not helping here -, alpha2 and alpha3 with anxiolysis, and alpha5 with cognition/memory.

In short: We want alpha2 selective ligands that still facilitate the anxiolysis (hopefully) but no sedation, dependency, impact on cognition or memory?
 
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