NMDA antagonist's subjective effects - synaptic vs. extrasynaptic NMDAr's?

[Cotcha Yankinov]

Some NMDAr stimulation is important for neuron differentiation and survival, but then again stimulation of some NMDAr's (extrasynaptic ones especially) results in apoptosis. We might infer from this that NMDA antagonists that are selective for the extra-synaptic receptors (Memantine) will be less harmful, but my question is -

Do you have to push the dose of Memantine to the point where it is really antagonizing synaptic receptors (Rather than extrasynaptic receptors) in order to get psychedelic effects? In other words, do extrasynaptic receptors contribute to action potential generation the same as synaptic receptors?

 

[serotonin2A]

I'm not sure why you asked "do extrasynaptic receptors contribute to action potential generation the same as synaptic receptors?". Extrasynaptic NMDA receptors don't contribute to action potential generation -- that is one reason why they are interesting.

 

[Cotcha Yankinov]

What do you think is the physiological function/purpose of extrasynaptic NMDAr's?

I was hoping one could achieve psychedelic effects with blockade of extrasynaptic receptors with a substance such as memantine but it sounds like you will have to push the dose to the point where you get significant synaptic receptor blockade?

 

[nAON]

The only thing re: glutamate and extrasynaptic off the top of my head is this article, which claims that they're involved in synchronising neuronal action. Interesting considering that some theories of psychedelic action are based on idea of different parts of the brain losing connectivity and synchrony.

 

[serotonin2A]

The only thing re: glutamate and extrasynaptic off the top of my head is this article, which claims that they're involved in synchronising neuronal action. Interesting considering that some theories of psychedelic action are based on idea of different parts of the brain losing connectivity and synchrony.

If you think about neuronal synchronization only in the context of psychedelic effects then you are really missing the bigger implications of those findings. Network oscillations play a fundamental role in neural processing and communication.

The other thing to consider is that the type of syncronization assessed in fMRI studies (including the studies of psilocybin that you are referring, which look at whether activity in connected structures is correlated) is a bit different then the synchronization of activity in a single network of cells.

 

[Limpet_Chicken]

I hypothesize the NMDAr (at least in some of of its subtypes and binding sites) acts as as a sort of co-incidence detector, look at schizos impaired ability to detect causality relationships, their general NMDAr hypofunction and the dissociating effects of anti-NMDAr encephalitidites, suffered when the body directs autoantibodies at the NMDAR receptor complex

 

[nAON]

If you think about neuronal synchronization only in the context of psychedelic effects then you are really missing the bigger implications of those findings. Network oscillations play a fundamental role in neural processing and communication.

The other thing to consider is that the type of syncronization assessed in fMRI studies (including the studies of psilocybin that you are referring, which look at whether activity in connected structures is correlated) is a bit different then the synchronization of activity in a single network of cells.

^ in the context of OP asking about psychedelic effects though.. after all, one could argue that 'psychoactivity' is just another word for 'brain not functioning correctly', and that all of these implications lead to this

And with ketamine for example there has been a reasonable amount of evidence that it disrupts both local synchrony and global connectivity. And one could even argue that all the 5HT2A-ish psychedelics like psilocybin are just a roundabout way of fucking with glutamtergic transmission and organization.

 

[serotonin2A]

And with ketamine for example there has been a reasonable amount of evidence that it disrupts both local synchrony and global connectivity. And one could even argue that all the 5HT2A-ish psychedelics like psilocybin are just a roundabout way of fucking with glutamtergic transmission and organization.

The fact that the effects of ketamine have been linked to local synchrony (which is what this article relates to) is kind of my point -- why bring up global synchrony, which is very different?

 

[Cotcha Yankinov]

So disrupting synchrony through blockade of extrasynaptic NMDAr's might result in psychedelic effects? And I would assume that long term disruption of this synchrony would have consequences?

Are we talking about thalamacortical resonance and that sort of stuff?

Also, if extrasynaptic NMDAr's don't contribute to action potentials, how the heck do they regulate synchrony?

 

[serotonin2A]

So disrupting synchrony through blockade of extrasynaptic NMDAr's might result in psychedelic effects? And I would assume that long term disruption of this synchrony would have consequences?

Are we talking about thalamacortical resonance and that sort of stuff?

Also, if extrasynaptic NMDAr's don't contribute to action potentials, how the heck do they regulate synchrony?

Everything you do to the brain potentially has long-term consequences -- memory and learning are examples of that. But that isn't inherently bad...

Oscillations in activity are a fundamental aspect of how networks of neurons function. The oscillations in a network of cells are often generated intrinsically, although they can also have an extrinsic source, for example thalamocortical rhythms. At a very basic level, you can think of the oscillations kind of like how transistors in a computer need rhythmic clock pulses to function. Like transistors in a digital computer, in turns out that certain types of neural processing require the firing of cells in the network to be synchronized. Glutamatergic cortical neurons show alternating periods of hyperpolarization and depolarization (so-called DOWN and UP states), and are more likely to fire during the latter period, which means that their activity starts to be synchronized to the rhythm of the UP states. So extrasynaptic NMDAR could be contributing to that depolarization. The cells have to be getting that info from somewhere, and having it come from other neurons would potentially be less useful...

Another source of intrinsic cortical rhythms is the feedback inhibition between Glu pyramidal neurons and GABAergic neurons. Those interactions are thought to generate gamma activity (high frequency rhythms, around 30-40 Hz).

As an example of a function to which synchronization contributes, it is thought that rhythmic activity allows cortical neurons to "store" info in working memory.

 

[Cotcha Yankinov]

Very interesting, thank you

Sorry to make this a personal issue but you might find this interesting on an academic level as well - I'm a big insomniac and was hoping you might shed some light on how this all relates to slow wave sleep.

Abstinent MDMA users show increased excitability of the cortex on fMRI (lining up with how the animal studies showed the dorsal neocortex remaines de-innervated after MDMA), and MDMA users do have sleep issues as well, MDMA users even respond differently to sleep deprivation than controls (I can find the studies if you'd like) while I myself have (per polysomnograph) extremely fragmented sleep with little slow wave sleep, and mostly just consolidated REM sleep towards the very end of the night.

So naturally I'm looking for any way to boost my slow wave sleep without resorting to GABA drugs, but my question is this - if synchronization is important for transferring memory from working memory to long term memory, and the extrasynaptic NMDAr's are contributing to that synchronization, then won't extrasynaptic NMDA antagonists impair the memory consolidating function of sleep?

But I assume that even though the up and down states wouldn't be very synchronized, you would still have a fundamentally (overall) inhibiting slow wave oscillation, and could probably expect the same amount of growth hormone release and other things like that? Or is it necessary for the inhibitory function of the slow wave oscillation to achieve distinct up and down states (to not have neurons depolarizing during the down state because of miss-synchronization)?

What do you expect would happen to slow wave oscillations if there was increased excitability in the cortex?

 

[serotonin2A]

Just to clarify, I wasn't linking the oscillatory activity to consolidation -- the oscillations in cortex are required to hold the information "on line". Most of the time it is not consolidated.

NMDAR antagonists would impair consolidation, but that is primarily because they block LTP and other mechanisms underlying learning and memory.

The rhythmic oscillatory activity occurs across multiple frequency bands simultaneously. Many bands are independent, originating through different mechanisms, so you can't generalize from one band to another. The cortical UP and DOWN states occur at a higher frequency than slow-wave oscillations and are not linked to that type of activity, which happens during some sleep phases or after administration of anesthetics.

 

[Cotcha Yankinov]

Okay so hopefully you can clear this up, from Wiki - "The firing rate of neurons in the neocortex also has an effect on slow-wave sleep. When the neurons are at rest and are hyperpolarizing, a period of inhibition occurs during a slow oscillation, called the down state. When the neurons of the neocortex are in the excitatory depolarizing phase and are firing briefly at a high rate, a period of excitation occurs during a slow oscillation, called the up state.<sup>"

Are extrasynaptic NMDAr's possibly contributing to the generation of a slow wave oscillation (at least the depolarization phase)? Or are slow wave oscillations generated in a different way? I don't understand how a oscillation can be inhibitory anyways...</sup>

 

[serotonin2A]

Sorry if I made this confusing. All the oscillations are accompanied by up and down membrane states, which is why neural activity ends up being synchronized. But the low-frequency activity is more of a quiescent, default state. If you cut out a section of cortex and put it in a dish, that is the type of activity you would see. So it isn't necessarily relevant to understanding how the cortex processes information.

If you are having trouble sleeping then the problem isn't that you need to find a way to boost slow-wave activity -- that activity state invariably happens once you fall asleep. The problem you are having is you can't initiate sleep, which is an issue with subcortical regions.

 

[Cotcha Yankinov]

If I am understanding this correctly - the slow wave oscillation does not generate sleep but rather once sleep happens you will see slow wave oscillations?

I really appreciate anything and everything you have to say on the matter of sleep or if you know somewhere I can learn more - I haven't been able to find much of anything regarding the physiology of sleep. Can you please tell me more about the possible issues with these sub cortical regions?