What is the pathway of NDMA antagonist tolerance?

[MyDoorsAreOpen]

I just read a good deal of neuroscientist Rhawn Joseph, PhD's online book about the brain, in doing my study for the medical boards. (Yes, I know that Prof. Joseph has a reputation for being a bit of a crackpot Creationist, but when he talks nothing but neuroscience, he knows what he's talking about; frankly it comes as a breath of fresh air to me to read a neuroscientist who writes for the general public without peppering his work with subtle plugs for atheism. I digress.)

Anyway, Joseph claims that evidence suggests NDMA receptors really do not upregualte, that is, they do not proliferate in number to any significant degree, as a response to pharmacological blockade. How, then, is the rather substantial (and in many anecdotal reports, nigh on irreversible) tolerance to NDMA receptor antagonists mediated? I would have thought that the CNS responds simply by upregulating the genes that code for more NDMA receptors to be inserted into the plasma membrane, and that these linger on in large numbers indefinitely, requiring ever higher doses of the antagonist drug for substantial blockade. But from what Joseph writes, that seems unlikely.

I don't think it's a matter of increased efficiency of metabolism, because the enzymes that degrade known NDMA antagonists are just your garden variety all purpose liver enzymes, which don't stay elevated forever, even after heavy duty jobs.

Nor do I see it as a case of receptor DOWNregulation. Doesn't that happen only to receptors that are hyperagonized, not antagonized, generally speaking?

How, then, does NDMA antagonist tolerance work? Because whatever pathway it uses, it's damn efficient -- your brain does NOT like THAT button pressed. It's been many months since I've done ketamine. I never abused it, and have probably done a maximum of one gram in my entire life, with big spaces between uses. But two years ago, 200mg insufflated landed me in the deepest, profoundest K hole, and made my friends quite worried about me. Last week, 150mg insufflated produced only the mildest of effects, which was pretty disappointing. (Granted I'd done a high second plateau DXM trip two weeks prior.)

Is there any known way to mitigate or reduce NDMA antagonist tolerance? I ask because I mostly count on these drugs as occasional visionary substances, but mostly to mitigate the tolerance of other drugs. If they lose their effectiveness for me, 'twould be a pity.

Finally, a sort of related question. Memantine is a nootropic NDMA receptor antagonist, with little affinity for any other receptors, that has no recreational value, and is prescribed for Alzheimer's dementia with mixed results. Would someone who'd been using Memantine for some time (not I), be unable to ever feel the enjoyable effects of ketamine or DXM?

 

[vortex30]

Well, first of all, you don't have a Ketamine tolerance from that tiny amount of use. The new K you are getting is probably cut. AFAIK, Ketamine tolerance IS mediated in the liver. Your liver becomes damned good at converting the Ketamine to Norketamine, which still produces effects, just less interesting ones. It also resides in the mind, you become familiar with the dissociated mindscape, fighting it is easier as time goes on, etc. After abusing Ketamine for months I could do it in school, walk around, sit in class without tripping out too hard on fairly high doses, simply by fighting it when I had to. If I lay back, close my eyes and 'let go' I would start to slip into the hole.

I'm sure someone else can clear this up a bit more for us, but that's my knowledge on the subject I thought I'd share.

 

[Jamshyd]

^ I don't know how much I buy into the liver theory. Can you tell me more about the science behind it?

MDAO: Very good questions there. I wonder myself as well, although somehow I always assumed that tolerance was due to upregulation...etc of receptors for other transmitters (eg. Dopamine) that happen further down the cascade caused by NMDA antagonists, and this is why moderate use produces almost no perceptible tolerance at all.

 

[MyDoorsAreOpen]

vortex30, if what you're saying it's true, then taking a drug that denatured, bound irreversibly to, or competitively inhibited the liver enzymes that conjugate ketamine (or DXM) soon before taking the K / DXM, would temporarily drop tolerance through the floor. This doesn't sound too hard to accomplish at all, as long as I'm careful not to take any other drugs metabolized by those same enzymes until their function was back up to normal again!

I agree -- I think the K I got was either cut, low quality, or a short bag. Also, as you described, I'm become more comfortable and familiar with the dissociative headspace -- it's still valuable, but it no longer has that 'unfathomably weird' quality to it that it did when I was new to it.

What you say about walking around in public all K'd up sounds a lot like my experience of being a functional stoner. I still feel the marijuana I smoke. But it only hits me like a trainwreck and is noticeably incapacitating when I'm in an unfamiliar set and setting, or I CHOOSE to notice it and feel it strongly.

 

[inverse_agonist]

What is the evidence he cites for the lack of upregulation?

Short and long term changes in NMDA receptor binding in mouse brain following chronic phencyclidine treatment.
J Neural Transm. 2007;114(8):995-1001.

Phencyclidine (PCP) is an antagonist of the NMDA subtype of glutamate receptor. PCP treatment induces psychosis in normal humans, which provides a valuable model of schizophrenia. PCP administration also models some of the symptoms of schizophrenia in experimental animals. NMDA hypofunction has been hypothesized to explain these schizophrenia-like symptoms. Acute or chronic administration of the NMDA receptor antagonist PCP has been shown to induce several short or long-term effects in both humans and experimental animals. In an attempt to clarify the neurochemical substrates of these effects in the present study, we used quantitative autoradiography to examine the effects of chronic (14 days) PCP treatment on NMDA receptor binding in mouse brain following both a short- (1 and 24 h) and long-term (14 days) delay after the last PCP treatment. NMDA receptors were targeted using [(3)H]MK801. Chronic PCP treatment increased [(3)H]MK801 binding consistently in the hippocampus in the short-term (p < 0.01). Conversely in the long-term, there were widespread reductions in NMDA receptor binding and this effect was most evident in the hippocampus where a 35% reduction of binding was found (p < 0.001). These results suggest that the hippocampus has a strong involvement in both the short and long-term effects of PCP treatment and that reduced NMDA receptor function might be one of the neurochemical substrates of the long lasting actions of PCP or PCP-induced psychosis. Importantly, this study shows that the long-term delay following chronic PCP treatment more accurately represents a state of NMDA hypofunction than the short-term PCP model.

For the most part, downregulation happens as a result of agonists, not antagonists, but this is not universal. 5-HT2A receptors are a notable exception:

http://www.ncbi.nlm.nih.gov/pubmed/11750789

There is a TON of research that's been done on the changes that follow long-term treatment with PCP and other NMDA antagonists (receptor expression, neurotransmitter levels, changes in interneurons, and more). The reason is that chronic NMDA antagonist treatment is considered a very useful model of schizophrenia, so there's widespread interest in using NMDA antagonists for new leads in schizophrenia research. Searching for things like "chronic phencyclidine" or "PCP schizophrenia" might be useful in addition to looking directly for things about tolerance.

 

[I NUK3D U]

didn't read any responses, and most of your OP is well over my head. Just wanted to add that you probably didn't have very good ket the second time around. Could be the easy answer, dunno

 

[(zonk)]

I do K alot and I find that tolerance certainly developes, I'm at the point where sniffing any possible amount does nothing at all, not even a body high. There is no cross tolerance however with other NMDA antagonists such as DXM or PCP. However I know of a couple of K/PCP users who have what seems like a reverse tolerance in that small amount can sometimes send them into a blackout and make em act like they're short circuiting but they are also totally fried from heavy usage and it's rare even in heavy users for me to see people with that much of what seems like brain damage from it use. One individual(female) reported getting a CT scan and said they told her she was perfectly healthy.

 

[The Smoking Man]

For the most part, downregulation happens as a result of agonists, not antagonists, but this is not universal. 5-HT2A receptors are a notable exception:

Likely because the 5-HT2A receptor displays constitutive activity (meaning, the receptor is active even without an agonist, and agonists just amplify this activity, whereas antagonists only prevent other ligands from binding to the receptor and thus keeping it at baseline). 5-HT2A inverse agonists upregulate the receptor.

 

[P A]

5-HT2A inverse agonists upregulate the receptor.

It's not that simple, at least not for some of the other constitutive 5-HT subtypes, including the close relative 5-HT2C. It looks like more obtuse/indirect intracellular mechanisms are at work here (as opposed to the usual predictable receptor kinetics):

http://molpharm.aspetjournals.org/content/55/5/863.full

As for the ketamine issue, could it have anything to do with a chronic change in the conformational state of the local receptor site, like an ionophore sensitization/desensitization phenomenon rather than plain old up- or down-regulation (receptor internalization/externalization)? I'm out of my depth here, but if someone could enlighten me, I'd appreciate it; I'm just as curious as MDAO here, as NMDA kinetics might have some personal relevance.

 

[deckmunki]

Bump; interested as I've noticed a significant building of tolerance to the mild dissociative effects of methoxetamine through chronic MXE administration, which also seems to have had a profound negative effect on my ability to experience visuals - or pretty much anything apart from the basic loss of consciousness - when indulging in a little laughing gas.

As an aside, the OP's writing style and questions are very clear, since even an idiot such as myself can understand the thinking at work here (well, most of it...).

/dm