Comment · Thu, January 21, 2016 · Ceretropic & Nootropics Depot
Long-lasting downregulation of GABAergic synapses after repeated administration of anxiogenic drugs - possible implication for Fasoracetam?
Original post in this thread
I_Strahd · 5 points
Hello there,
I've been experimenting with a bevy of noots over the past couple years - and over that time, have remained consistently interested in fasoracetam for it's apparent potential in up-regulating the gaba system.
However, the use of gaba antagonists, for which this compound is considered, is still - in general - a mystery to me in terms of their long-term effect on an otherwise healthy brain.
Then today I happened upon this old study, which seems to make the case that:
"a long-lasting down regulation of GABAergic synapses can be obtained after repeated administration of anxiogenic, proconvulsant and convulsant negative modulators of GABAergic transmission. The latter finding further suggests that GABAergic synapses undergo rapid and persistent plastic changes when the GABAergic transmission is persistently inhibited."
http://www.ncbi.nlm.nih.gov/pubmed/1981393
and I'm left wondering...if fasoracetam's primary method of action is to antagonize gaba(b) receptors, will this, in actuality, have a negative impact on the functioning of the gaba system?
Similarly, will this mechanism hold,. in general, for all gaba antagonists?
And lastly, what is to be made of this c…
What they were answering
DeltruS · 2 points
[NFC-1[fasoracetam], a first-in-class, non-stimulant metabotropic glutamate receptor (mGluR) neuromodulator entering Phase 2/3](http://globenewswire.com/news-release/2015/09/09/767050/10148706/en/Medgenics-Acquires-Phase-2-Ready-CNS-Program-NFC-1.html)
http://www.ncbi.nlm.nih.gov/pubmed/9134967
http://www.ncbi.nlm.nih.gov/pubmed/9272724
For me, fasoracetam doesn't counteract baclofen, I've taken both at the same time. If I remember correctly, it counteracted some of its effects, but it still had a motivational effect and an effect on planning / decision making. This is hardly scientific, just going off what I felt. If I felt nothing then I'd believe that it was purely a gaba b antagonist.
I believe that faso may trigger/inhibit some of the same pathways that gaba b triggers/inhibits but not exactly.
As for phenibut, recent research has shown that it is primarily a gabapentinoid:
Recently, phenibut (β-phenyl-GABA), a close analogue of pregabalin (β-isobutyl-GABA), has been found to similarly bind to and block α2δ-containing VDCCs, notably with an affinity exceeding that of its other actions, effectively making it a gabapentinoid.
Here's the actual study rather than wikipedia: https://www.ncbi.nlm.nih.gov/pubmed/26234470
u/MisterYouAreSoDumb · Ceretropic & Nootropics Depot
That new study is very interesting! I had not seen it. It's saying that R-Phenibut's affinity for the α2-δ subunit of the VDCC is 4 times higher than its affinity for the GABA(B) receptor. They were only measuring anti-nociceptive effects, though. So the painkilling effects might be α2-δ VDCC related, where the antidepressant effects might still be related to GABA(B), or its other mechanisms. I think some more studies need to be run looking at the antidepressant, motivational, and sedating effects of R-Phenibut. I have a feeling the motivational and antidepressant effects are more to do with the phenyl group, and its effects on dopamine receptors and β-phenethylamine antagonism. This would explain why some people get such fast tolerance buildup to both Phenylpiraceatam and Phenibut, while not getting it to other GABA(B) ligands, or gabapentinoids. If you lose the dopamine modulation and the β-phenethylamine antagonism, you are left with only part of the effects.