NMDA phencyclidine

Psychotomimetic Drugs. Figure 2 Chemical structures of the dissociative anesthetics phencyclidine (PCP) and ketamine. Both are arylcycloalkylamine derivatives that are open channel blockers of the NMDA channel. 

The NRl family is composed of one subunit with nine different alternatively spliced variants. Block by NMDA channel blockers such as ketamine, MK-801 and phencyclidine is affected by which splice variant of the NRl subunit is involved, probably because the NRl splice variant affects the kinetics of channel activation (the effectiveness of any channel blocker being dependent on how much the channel is open). The glycine binding site is on the NRl subunit and the glutamate binding site is on the NR2 and NR3 subunits. 

Based just on these results, PPI could simply be just another index of DA function but phencyclidine, an NMDA rather than DA receptor antagonist, which exacerbates... 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia. The hypothesis that hypofunction of a subpopulation of NMDA receptors contributes to the pathophysiology of schizophrenia has gained considerable support over the last decade (see Fig. 54-1). The dissociative anesthetics including phencyclidine (PCP) and ketamine when introduced clinically 40 years ago were noted to produce a syndrome that was difficult to distinguish from schizophrenia. These agents act as noncompetitive open-channel blockers of the NMDA receptor. 

Phencyclidine (PCP) psychosis faithfully masquerades as schizophrenia, though some say it resembles mania. PCP is discovered to block NMDA subtypes of glutamate receptors. Glycine and cycloserine, which stimulate NMDA receptors, are antipsychotic. 

The mechanisms of action of phencyclidine and ketamine are complex (Gorelick Balster, 1995). The drugs are non-competitive antagonists at NMDA receptors, and also bind to associated phencyclidine/sigma opioid receptors. They also have agonist actions at dopamine receptors, complex interactions with both nicotinic and muscarinic acetylcholine receptors and poorly understood interactions with noradrenergic and serotonergic systems. These multiple actions may combine to produce delirium and psychotic reactions. 

Glutamate systems have long been implicated in the pathophysiology of schizophrenia. Strong if circumstantial evidence comes from the psychosis associated with phencyclidine (PGP) administration PGP blocks of the ion channel the glutamate/NMDA receptor. Psychosis due to PGP and other noncompetitive NMDA antagonists includes the development of negative as well as positive symptoms and therefore is considered a better model of schizophre-... 

Animal research has revealed that antagonists, such as ketamine, phencyclidine, and dizocilpine [MK-801], at the NMDA receptor channel complex are clearly anxiolytic in animal models of anxiety. Because of the risk of abuse with phencyclidine-related drugs, which are thought to act at a site within the channel itself, antagonists at another site associated with the NMDA receptor channel complex—namely, those that act at the glycine-modulatory site on the NMDA receptor—are believed to have promise in the development of future anxiolytics [Hamon 1994]. 

The noncompetitive antagonists of glutamate include phencyclidine, ketamine, N-allylnormetazocine, dextromethorphan, and dyzolcipine. The action of these compounds depends on the previous opening situation of the channel. Unfortunately, some of these useful NMDA antagonists have a narrow therapeutic margin. This could explain the contradictory results of studies. 

FIGURE 13 — 11. Icon of phencyclidine (PCP). Phencyclidine is an antagonist of an ion channel site associated with the N-methyl- -aspartate (NMDA) subtype of glutamate receptor. 

FIGURE 13—12. Pharmacology of phencyclidine (PCP). Phenylcyclidine is an open-channel antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors at a site probably closely associated with the calcium ion channel there. This means that its site is probably inside the calcium channel, and it probably works best when the channel is open. 

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