Gaba-B agonists, dopamine feed back loop, NMDARs, BDNF... Help me connect the dots

I was just talking about Phenibut/Baclofen and GABA on another thread. I think our understanding of the exact receptor affinities, and their interactions with one another is lacking. You can see mine and /u/DeltruS's discussion here.

Phenibut seems to have a higher affinity for the α2δ voltage-dependent calcium channels than the GABA(B) receptors. It also positively modulates dopamine receptors, along with antagonizing β-phenethylamine. The β-phenethylamine antagonism would explain the extra anti-anxiety effect that Phenibut has, and the quick tolerance buildup. Baclofen has a higher affinity for GABA(B), but would be lacking in the β-phenethylamine antagonism, and probably the dopamine modulation. This would explain the slower tolerance buildup it shows, but could also explain the more potent effects on an amphetamine comedown. The GABA(B) receptors control membrane excitability of the calcium and potassium channels, which would be experiencing larger influxes after amphetamine use.

Essentially AMPA receptor activation can cause depolarization of the neuron, which makes it possible for the NMDA channel to clear the calcium blockage, and allow NMDA activation to instigate calcium influx into the cell; which is what sends cascading electrical signals between neurons. So that is the relationship between the AMPA and NMDA receptors. GABA(B) agonism lowers membrane excitability, which lowers AMPA/NMDA excitability, and lowers calcium influx into the cell. Amphetamine increases glutamate, which is doing the opposite, and increasing calcium influx into the cell.

As to OP's thinking that he/she has NMDA hypofunction, it's an interesting hypothesis. It very well could be that OP's receptor balance is off, and that the increased glutamate release from amphetamine, followed by antagonism of GABA(B), might be bringing that back to a more balanced state. It could also be that the dopamine release from the amphetamine was still going, and that the addition of a GABA(B) antagonist reduced the anxious side effects, and made him feel fucking awesome. Amphetamine and GABA agonism at the same time does feel pretty damn awesome for most people. There are too many variables at play to say for sure, though.

I will say that your first time on Phenibut you are getting a direct dopamine activation, a GABA(B)/VDCC agonism, and β-phenethylamine antagonism. That is what leads to the initial awesome feeling. It's the anxiety inhibition/antidepressant effects of the GABA and β-phenethylamine antagonism, with the rush feeling of dopamine activation. On the tail end of amphetamine you would also be getting the dopamine activation, which paired with GABA(B) agonism, would feel very similar to the first time on Phenibut. It's just that the dopamine and β-phenethylamine antagonism effects seem to be very quick to build tolerance. So that first time feeling is very hard to get back to with Phenibut.