Theorising about synaptic plasticity

Firstly, this thread is about theory, not practice. DO NOT UNDER ANY CIRCUMSTANCE assume anything said on this thread is valid and attempt to put any of it into practice because it may (in fact, its likely to) result in brain damage and/or death. Definitely don't put any faith in MY theories, I'm only a chemistry student with a passion for pharmacology. I know nobody on this forum would actually be silly enough to endanger themselves like that, I just feel like its best to add a disclaimer like that because you never know who might come across the thread.

Alright so I'm interesting in the concept of directing synaptic plasticity for many reasons. One of the reasons is I see that lots of people suffer greatly trying to get off psychiatric drugs due to the neurological changes that long term use of these drugs have produced. A well known example is benzodiazepine withdrawal syndrome. After the acute phase which usually lasts a few weeks, they have a variety of long lasting symptoms, many of which are certainly not mild symptoms, and this can go on for years depending on how long the person was using the benzodiazepine. Some unfortunate people can even develop some of these long lasting symptoms after relatively short term use (i.e. a couple of months) of low doses (i.e. 0.5mg of alprazolam daily). Even the drugs which doctors and psychiatrists today often claim are non addictive and do not cause withdrawals, do in fact cause serious withdrawal syndromes in people who use them long term (i.e. for a year or longer). Two examples are gabapentin and trazodone.

I believe that gaining an understanding of how various classes of drugs cause these brain changes will eventually enable us to intentionally direct these synaptic plasticity processes, which will of course open up a whole new paradigm in psychiatry. So heres some theories of mine, based on my very limited understanding, please feel free to add to them and point out errors in my thinking etc. Also can you share any knowledge and theories you have about this subject in general.

So it appears that glutamergic receptors are strongly connected to the changes produced by long term use of drugs. NMDA antagonists have been shown to prevent tolerance to various classes of drugs including benzodiazepines, opioids and amphetamines:
http://www.pnas.org/content/90/14/6889.full.pdf
Positive allosteric modulators of the AMPA receptor (known as ampakines) have been shown to enhance learning and memory:
http://www.jneurosci.org/content/18/7/2740.full.pdf
So it appears glutamate receptors play a significant role in synaptic plasticity. I'm theorising that if one were to co-administer an NMDA agonist along with a benzodiazepine, tolerance to the benzo would develop faster, and conversely if one administered glutamate agonists/enhancers with a BZ antagonist like flumazenil, then these long term changes produced by benzos would be reversed at a faster rate than usual. An obvious big problem with this is glutamate excitotoxicity. Reducing GABA activity and increasing glutamate activity, will vastly increase the excitotoxicity that occurs, so what is needed is a method of preventing the excitotoxicity far enough down the cascade that it doesn't interfere with the glutamatergic neuroplasticity properties. Starting with the NMDA receptor, binding of glutamate to this receptor opens up a cation channel, and from what I've read Ca2+ influx is what triggers the excitotoxicity.

I have very little knowledge of what occurs after this calcium influx, but I know that at some point, it results in the synthesis of nitric oxide and that this nitric oxide may kill neurons. I read a highly informative article about this, but I can't find it. There are various articles covering nitric oxides role in glutamate excitotoxicity:
https://www.sciencedirect.com/science/article/pii/030439409290442A
In the article I read, they talked about an experiment where they studied aspartate neurotoxicity in neural cells in vitro. They observed that co-administering methyl arginine (a nitric oxide synthase inhibitor) prevented this neurotoxicity. They also attenuated it with calmodulin inhibitors and superoxide dismutase. Superoxide dismutase interests me because it would appear that a significant cause of nitric oxides neurotoxicity is when it reacts with superoxide to form the neurotoxic metabolite, peroxynitrate. I'll expand more on all this later when I have the time, but thats the core of my theory so far, the idea of administering glutamate agonists to enhance synpatic plasticity, co-administering a particular drug to direct that synpatic plasticity, and co-administering substances to prevent glutamate excitotoxicity.

Heres an article I just found which talks about the role of tissue plasmogen activator in excitotoxicity:
http://jcs.biologists.org/content/119/2/339.full.pdf

birchswing said:

As such, I didn't understand a lot of what you wrote, but having participated in the benzo recovery communities, I've heard of people having success using small amounts of flumazenil for protracted benzodiazepine withdrawal (used after they've finished getting off the drug), the explanation being that it helps resensitize benzodiazepine receptors.

Click to expand...

Sorry, I was rushing a bit when I started the thread so I didn't word it too well. Yeah, thats what I'm talking about, reversing the protracted withdrawal symptoms after they've past the acute phase of the withdrawal. Flumazenil should theoretically accelerate the recovery process by doing the opposite of the benzo did, and combining it with glutamatergic drugs (i.e. ampakines, piracetam, NMDA, kainic acid etc.) should vastly accelerate the process. Desensitisation of the benzodiazepine site is just one of the possible mechanisms behind these long lasting withdrawals, another one is uncoupling of the receptor which means that drugs binding to the BZ site no longer modulate the GABA_A receptor as effectively. Then theres downregulation of the GABA_A receptor itself. And another mechanism which is known to contribute to these long lasting withdrawals is changes in the glutamergic system (i.e. upregulation of NMDA receptors). The reversal of all these processes may take years (or may never happen at all) under ordinary conditions, but may take place relatively rapidly (i.e. in a matter of weeks) by using the flumazenil in conjunction with glutamatergic drugs to direct synaptic plasticity. With this approach you don't need to know the exact mechanism behind the withdrawal, instead you can blindly direct the synaptic plasticity by doing the opposite of what caused the changes in the beginning. However its always best to know the exact mechanism behind things. According to this article:
http://www.hindawi.com/journals/aps/2012/416864/

Already in 1984, an electrophysiological study indicated that allosteric coupling may play a role by showing a 50% decrease in the GABA enhancement of benzodiazepine-binding without significant changes in benzodiazepine-binding site density or affinity.

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If I interpreted that correctly, that would indicate that desensitisation and downregulation of the BZ site, aren't involved in benzodiazepine withdrawals. That narrows it down a bit.

As for co-administering flumazenil during benzodiazepine treatment, I never thought of that. I see no reason why that wouldn't work. The patient could administer flumazenil every couple of weeks or so to prevent themselves from building up dependance. Another method would be to administer a nitric oxide inhibitor such as methylene blue which have been shown to prevent tolerance to various drugs, in the same way NMDA antagonists do. The problem with the latter though is that tolerance to NMDA antagonists develops pretty rapidly too. In my experience, its as easy to have a conversation about psychopharmacology with a plumber as it is with the average GP. I've only talked to 3 of them though. I'd like to talk to a psychiatrist about things like this.