Comment · Tue, January 19, 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
Why do people keep calling faso a gaba b antagonist? More likely it causes an influx of excitation and the body responds with long lasting epigenetic homeostatic responses. I think gaba b causes downstream effects and faso also causes SOME of these downstream effects. I still have that "feeling" from faso and the feeling isn't the same as baclofen, there is no motivational effect. It feels less smooth.
Everything needs more research but please stop calling faso a gaba b antagonist and stop calling phenibut primarily a gaba b agonist.
u/MisterYouAreSoDumb · Ceretropic & Nootropics Depot
Biochemical data showed that repeated administration of NS-105 increased the number of GABAB receptors in rat cerebral cortex without affecting the binding properties of β-adrenoceptors and 5-HT2 receptors.
NS-105 also reversed memory disruption induced by baclofen, a potent GABA(B) receptor agonist, but all of reference drugs did not. These results suggest that antiamnestic action of NS-105 is due to the facilitation of cholinergic neuronal activity and the suppression of GABA(B) receptor-mediated responses.
So while calling it a GABA(B) antagonist is not completely proven yet, it does seem to up-regulate the GABA(B) receptors. That could be through allosteric mechanisms, or it could be through direct antagonism. However, the key takeaway is that it does up-regulate the GABA(B) receptors, and does reverse the memory deficits from GABA(B) agonists. Could that be through increased excitation alone, causing downstream effects? It's definitely possible.
As to your comment on Phenibut not being a GABA(B) agonist, I am not sure why you take that position, as it is pretty well established that is its main mechanism. Sure, it does have other dopaminergic actions, due to the phenyl group. However, the primary effects are GABA(B) mediated.
Comparative pharmacological activity of optical isomers of phenibut
An GABAB receptor-selective antagonist (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP35348) inhibited the antidepressant and antinociceptive effects of R-phenibut, as well as locomotor depressing activity of R-phenibut in open field test in vivo. The radioligand binding experiments using a selective GABAB receptor antagonist [3H]CGP54626 revealed that affinity constants for racemic phenibut, R-phenibut and reference GABA-mimetic baclofen were 177 ± 2, 92 ± 3, 6.0 ± 1 μM, respectively. We conclude that the pharmacological activity of racemic phenibut relies on R-phenibut and this correlates to the binding affinity of enantiomers of phenibut to the GABAB receptor.
Phenibut \(β-Phenyl-GABA\): A Tranquilizer and Nootropic Drug
Phenibut (β-phenyl-γ-aminobutyric acid HCl) is a neuropsychotropic drug that was discovered and introduced into clinical practice in Russia in the 1960s. It has anxiolytic and nootropic (cognition enhancing) effects. It acts as a GABA-mimetic, primarily at GABAB and, to some extent, at GABAA receptors. It also stimulates dopamine receptors and antagonizes β-phenethylamine (PEA), a putative endogenous anxiogenic. The psychopharmacological activity of phenibut is similar to that of baclofen, a p-Cl-derivative of phenibut.
So I am a bit confused as to why you want people to stop mentioning the established effects of Phenibut. Sure, the reduction in Phenibut tolerance by Fasoracetam is still speculation. However, the mechanisms do make sense, and they do have studies behind their reasoning. Fasoracetam is never going to feel the same as Baclofen, as they are causing opposite effects. In fact, Fasoracetam has been shown to counteract Baclofen when taken as the same time.