Neuroscience Ketamine maybe increasing learning speed through modifying LTP?

[someguyontheinternet]

So I've been doing some reading on ketamine recently and came across some interesting info. It sounds like ketamime use may cause some changes in the regulation of AMPA receptors, these changes seem to include upregulation and a change in subtypes leading to greater calcium permeability in some circuits.

Not only is sufficient AMPA activation needed to unblock the NMDA pore, which leads to LTP, but there are also calcium induced LTP pathways through CaMKII (iirc)

Might ketamine use leading to increased rates of LTP at some synapses possibly leading to improved learning in some areas? Food for thought

Maybe I'm just trying to make myself feel better about all the ketamine I've been railing recently

https://www.sciencedirect.com/science/article/abs/pii/S0028390818306841

Ketamine induces opposite changes in AMPA receptor calcium permeability in the ventral tegmental area and nucleus accumbens - Translational Psychiatry

Ketamine elicits rapid and durable antidepressant actions in treatment-resistant patients with mood disorders such as major depressive disorder and bipolar depression. The mechanisms might involve the induction of metaplasticity in brain regions associated with reward-related behaviors, mood...

www.nature.com

 

[ecstacylover]

Acute ketamine impairs working memory and episodic memory encoding, so it's going to be counterproductive. There's also some evidence that ketamine impairs semantic memory, although at times when I was taking far too many NMDA receptor antagonists, I never noticed many issues with semantic memory. This just goes back to the fact that not all types of synaptic potentiation rely on NMDAr signaling, and that ketamine can potentiate certain synapses (like in the study you linked). But the working memory issues in particular are going to make learning anything difficult, as it will impair efficient manipulation of recent information (think when you read a book and you can rapidly remember how you got to the current line, without re-reading the previous few lines again—that relies on working memory).

And the working memory issues will probably persist with any compound that blocks GluN2B-containing NMDA receptors, as these are necessary for persistent firing of PFC "delay cells" during working memory tasks. Similarly any compound that blocks calcium influx through NMDA receptors (basically any NMDAr antagonist) will prevent CaMKII activation/LTP induction, and this probably underlies the impairment in episodic encoding.

Post-acutely, it probably depends on the duration of use. Acute use probably leads to BDNF-dependent synaptic upscaling in the hippocampus (basically a potentiation of unitary AMPAr amplitudes that preserves relative synaptic strength) and this might lead to more efficient encoding, as well as underlying the antidepressant effects. Psilocybin and LSD have been shown to increase "openness" (definition: openness is considered to be one of the major dimensions of personality and is linked to imagination, aesthetic appreciation, novelty-seeking, non-conformity, and creativity) and may also affect BDNF signaling. No studies have examined the effect of ketamine on openness afaik, but ketamine always significantly increased curiosity for me (which also seems to fall under that umbrella).

Chronic ketamine use otoh might possibly lead to BDNF-dependent downscaling in the hippocampus, which is what underlies the antimanic effects of lithium. Moral of the story, acute and chronic BDNF have wildly different synaptic effects. The Monteggia lab has a very helpful review.

Completely anecdotal, but in my days of dissociative abuse there were oftentimes when I had a post-acute hypomania, but with longer binges this seemed to shift towards an antimanic effect (e.g. anhedonia, emotional blunting and alogia). So I wonder if synaptic upscaling in acute use underlies the hypomanic effects people often report from dissociatives. Would be interesting to see what effect chronic application of ketamine does to hippocampal synapses, as it seems a downscaling might explain the antimanic effects I experienced.

 

[Skorpio]

I currently hold the hypothesis that the psychological benefit of ketamine action is downstream of BDNF signaling. I am unsure if the mechanism of TrkB activation is due to increased BDNF release or some direct mechanism such as direct binding of the drug at bdnf receptors (there have been papers which support both hypotheses, though I feel like the direct binding hypothesis is less common, as well as differences in results where psychadelics are given to 5ht2a knockout mice/with a 5ht2a antagonist).

I just came across this recent paper which shows that ketamine and serotonergics share some regions of overlap with this high frequency oscillation pattern of neuron elf tricks potential (such as the ventral striatum). To be frank, this paper is beyond me, but the discussion suggests that it contradicts models where the firing rate of mPFC neurons is directly liked to their ability to gate signals. They suggest rather than simple firing rates, the function of the circuits is more closely linked to the ability of these periodic oscillatory states to form. I'd love some other takes on this, especially you @someguyontheinternet as you apparently partake in the dark arts (aka electrophysiology).

I think it would be interesting to see what effects ketamine and 5ht2a psychs have on synaptogenesis in bdnf/Trkb knockout mice, as I bet there are nuances beyond the shared mechanism.

 

[someguyontheinternet]

I haven't had enough time to go over the synchronous states paper and learn what I feel I need to in order to address it but the pattern of neuronal firing and neurons acting as oscillators or integrators is, I think, quite an important part of neuronal computation but as it stands the theory is still over my head as well. I'm still working on learning more about the underlying systems before I feel I'm ready to attack the issue from a larger systems perspective.

When it comes to the BDNF paper it is possible that the pathway could be linked to an increase in plasticity and it may be involved in the antidepressant action of ketamine as well. The line of research that I've personally had interest in when it comes to the impact of ketamine on affective states is from an opioid signaling perspective. This paper is one that shows that the antidepressant effect of ketamine is likely directly linked to it's action on opioid signaling. There may be reinforcing effects of increased plasticity on the duration and robustness of antidepressant effect through increased plasticity and that may be an interesting avenue of research.

 

[ecstacylover]

This paper is one that shows that the antidepressant effect of ketamine is likely directly linked to it's action on opioid signaling. There may be reinforcing effects of increased plasticity on the duration and robustness of antidepressant effect through increased plasticity and that may be an interesting avenue of research.

The problem with that paper is that a 50mg dose of naltrexone could have substantial off-target effects, also blocking KOR, and interacting with actin binding proteins like filamin A, which could conceivably interfere with structural aspects of synaptic plasticity. Although see also the result that ketamine increases b-endorphin in PFC and that b-endorphin antibody can block its AD response in rat.

Similar to ketamine, scopolamine may also exert rapid AD effects through synaptic plasticity, and 0.15mg scopolamine 2x/day+1mg naltrexone 2x/day for 4 weeks reduces symptoms of MDD. This dose of naltrexone would still be expected to occupy ~50% of MOR, so these results support a lack of MOR involvement in psychoplastogen AD response.

Ofc there could be differences between ketamine and scopolamine's MOR-dependence, as they activate plasticity machinery through different upstream mechanisms. And conceivably ketamine could increase opioid neuropeptide release via GABAergic disinhibition analogous to how it increases release of glutamate, dopamine, etc. Or perhaps a baseline level of opioidergic tone is necessary for activation of plasticity machinery. But it would be more accurate then to say MOR plays a permissive role in the AD effects, rather than driving them.

This paper also claims the lack of other NMDAr antagonist in clinical trials, but the problem is those other drugs had different pharmacology. Memantine is an open channel blocker, but unlike ketamine it doesn't block spontaneous NMDAr signaling, which is why it fails to induce plasticity. CERC-301 is a GluN2B specific antagonist, so if the NMDAr mediating plasticity generally don't incorporate GluN2B subunits, then it would be expected to lack efficacy. D-cycloserine is an NMDAr glycine site partial agonist and NMDAr antagonist at higher doses, which complicates interpretation. Similar to ketamine, I expect quite a few arylcyclohexylamines would show lasting and rapid AD efficacy in clinical trials.

 

[SpiralusSancti]

Maybe I'm just trying to make myself feel better about all the ketamine I've been railing recently

Thought that the moment I saw, ya know, that thing up there, the name of the thread...I'm a bit forgetful these days cuz of nmda antagonists or whatever lol Just kidding, kind of xD

Similar to ketamine, scopolamine may also exert rapid AD effects through synaptic plasticity, and 0.15mg scopolamine 2x/day+1mg naltrexone 2x/day for 4 weeks reduces symptoms of MDD. This dose of naltrexone would still be expected to occupy ~50% of MOR, so these results support a lack of MOR involvement in psychoplastogen AD response.

You may remove may! It is almost just as strong AD as K just nowhere near lasting, in fact seems more to last for the duration of main effects and that’s it. I tried it in form of plants with various tropane alkaloids but when I was, really depressed I realized why it’s tested to be used in a similar way as K spray, from what I read before. I imagine when I try it extracted nasally it’ll work even better.

What are your thought on safety of scopolamine use? Personally I can’t see it getting dangerously addictive as K but also isn’t “life changing” in a way K can be so they are two separate worlds and probably each suited for certain person.

 

[someguyontheinternet]

Something that's been getting some research is the antidepressant effects of kappa opioid antagonists, so that may actually explain the effects of naltrexone. I don't know where research currently stands on ketamine's action at kappa but I wonder if it may be an antagonist

Kappa-opioid antagonists for psychiatric disorders: from bench to clinical trials

Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which ...

www.ncbi.nlm.nih.gov

https://www.sciencedirect.com/science/article/abs/pii/S0223523422006870?via%3Dihub

 

[ecstacylover]

What are your thought on safety of scopolamine use? Personally I can’t see it getting dangerously addictive as K but also isn’t “life changing” in a way K can be so they are two separate worlds and probably each suited for certain person.

Haven't tried it myself and idk about it's safety. Dissociatives have always been super addictive for me (despite not finding any other drug classes very addictive), and in general they seem fairly addictive for people with a steady supply. I doubt scopolamine would be as dangerous in that regard, especially as it doesn't sound very recreational.

 

[SpiralusSancti]

Haven't tried it myself and idk about it's safety. Dissociatives have always been super addictive for me (despite not finding any other drug classes very addictive), and in general they seem fairly addictive for people with a steady supply. I doubt scopolamine would be as dangerous in that regard, especially as it doesn't sound very recreational.

Yeah my thoughts exactly. When I was in WDs and very depressed on the verge suicidal I would chew up just a bit (enough to feel some effects) of scopolamine containing plant and depression was gone very fast and it also worked great for sleep. So I imagine having scopolamine spray would work perfect, both for ROI and lack of atropine and other alkaloids. At least in a mixture with other alkaloids I wouldn’t say it’s low addictive potential is really about lack of recreational value but more cuz of side-effects and inherently being less addictive than K. I also find disassociates very addictive but again I don’t think so much cuz they are inherently addictive but cuz I love the effects so much. Also on few occasions I did K for like a month of pretty much daily use stopping it wasn’t any problem. But as with K, nitrous, ether it’s more or less once you pop you can’t stop. On the other hand I didn’t find DXM (maybe cuz I tried it in a nasty syrup form only) and 3-meo-PCP (maybe cuz I pushed dose really high so getting back to that mind-state right away wasn’t appealing) addictive.