NMDA Antagonists - Physical Dependance?

[SerotonergicHaze]

I've wondered this for a while, would long term administration of high doses of substances like DXM, Ketamine, MXE, PCP etc... cause physical dependance similar to what Alcohol does. Alcohol blocks glutamate and thus causes NMDA receptors to be overly sensitive, and this oversensitivity causes seizures, agitation and the other nasty hyperexcitiablity symptoms of Delirium tremens. Wouldn't the same thing happen with the NMDA antagonists? Or is this purely a GABA thing

 

[SNR]

I believe that alcohol has worse physical withdrawal symptoms as the lowered GABA and NMDA oversensitivity combined is the real cause of those seizures. Interesting question though. Perhaps long term high dose use of NMDA antagonists could cause excitotoxicity during an abrupt withdrawal.

 

[sekio]

No, you should be able to withdraw off long-term ketamine or methoxetamine (those are the two I know of that are mostly NMDA antragonists... DXM is really more of a SNRI so its withdrawal is different) with very little difficulty.

To the best of my knowledge the seizures and shit is GABA-mediated.

 

[atara]

Delirium tremens, the 'seizure' condition in alcohol withdrawal, is generally associated with GABA-A PAMs, and you also occasionally see similar problems in people who withdraw too quickly from benzodiazepines and barbiturates. I've never heard of a seizure or anything like it from ketamine cessation, or any other dissociative for that matter.

 

[basement_shaman]

If alcohol causes oversensitivity of the NMDA receptors then you would expect the opposite thing from NMDA antagonists as there would be desensitization happening preventing seizures and whatnot from causing problems.

 

[SerotonergicHaze]

I see, GABA has antiexcitory effects, since EtOH asks as a GABA agonist, these receptors become desensitized to GABA and thus the antiexitotory effects cease and the person has hyper excitiablity

Would the opposite effect occur with antagonists. If the receptor gets blocked, then it will become overly sensitive to an endogenous agonist? I.e if NMDA receptors become overly sensitive to endogenous NMDA would hyperexcitablity occur? Or would antagonism of NMDA, cause desensitization and thus antiexcitablity. I suspect the former.

According to wiki page on N-Methyl-D-Aspartic acid (they didnt cite a source of this)

NMDA receptors are particularly important when they become overactive during withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures.

Sorry if I'm not making too much sense, I'm a bit of a noob when it comes to pharmcodynamics