Daily use of NMDA antagonists and Long-Term Potentiation (LTP)

[Burn it up]

I was browsing through the Big and Dandy 3-MeO-PCP thread and found some cases of users that were taking low doses of the drug up to three times daily for extended periods of time (sometimes even years). So basically we are talking here of a chronic regime in which the user is almost all of the time under the effects of this arylcyclohexylamine.

As NMDA antagonists interfere with Long-Term Potentiation, I would expect these users to report some sort of cognitive impairment or learning and memory difficulties. However, users did not report any of these kind of problems throughout that use, neither did they need to substantially increase their dosage with time to reach the desired effects.

My question is, what could theoretically happen to a brain in which the LTP is chronically hindered? Should it not produce very discernible visible symptoms? Is maybe 3-MeO-PCP not blocking the LTP for some reason?

Thanks.

 

[aced126]

The repercussions are dose dependent. Here is a brain imaging study of people on heavy ketamine regimens. It is clear that many users, especially the heavier ones, have suffered atrophies in different parts of the brain.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713393/

I don't think this has anything to do with LTP, but rather simply neurotoxic insults to certain neurons from excessive glutamatergic stimulation.

 

[Cotcha Yankinov]

I think one of the main findings with chronic ketamine users was increased delusional thinking in ex-users.

I should mention that NMDA dependent LTP is not the only form of LTP, but NMDA antagonist abuse may result in genetic changes to GABA interneurons as well, and these particular changes like reduction of GAD67/parvalbumin expression are seen in schizophrenics, perhaps hence some of the delusional thinking.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724170/

"NMDARs are critical to both the development and adult function of GABAergic interneurons. In cultured cortical neurons, NMDAR antagonism with ketamine reduces expression of GAD67, a GABA synthesizing enzyme that defines a major population of inhibitory interneurons (Kinney et al., 2006). This same manipulation in PFC slices reduces inhibitory synaptic transmission (Zhang et al., 2008).

NMDARs also regulate expression of parvalbumin (PV) (Kinney et al., 2006), a Ca²⁺ binding protein that defines a subpopulation of interneurons and modulates its firing properties (shown in thalamic reticular nucleus [TRN]; Albéri et al., 2013) and plasticity (shown in cerebellum; Caillard et al., 2000). The causal link between PV and GAD67 levels and behavior is reinforced by bidirectional manipulation of PV and GAD67 protein levels in the hippocampus of the awake mouse; learning is improved by pharmacogenetic enhancement of PV expression, and diminished by its pharmacogenetic reduction (Donato et al., 2013).

Genetic ablation of NMDARs reduces GAD67 and PV in the intact mouse cortex and hippocampus, a deficit that is associated with schizophrenia-like behaviors such as novelty-induced hyperlocomotion and impaired prepulse inhibition (Belforte et al., 2010). These studies show that NMDAR signaling is required for GABAergic cell development and behavior, suggesting that NMDAR hypofunction contributes to abnormalities in GABAergic markers seen in schizophrenia."


I think there is some concern with the use of ketamine as an anesthetic in infants because of effects on GABA interneurons in developing stages.