Phencyclidine and Ketamine

Dissociative anesthetic is a term applied to phencyclidine and ketamine which induce a peculiar subjective state of dissociation from the environment, together with sedation, immobility, amnesia, analgesia, and ultimately coma. 

Taube, H.D. Montel, H. Hau, G. and Starke, K. Phencyclidine and ketamine Comparison with the effect of cocaine on the noradrenergic neurones of the rat brain cortex. Naunvn Schmi edeberas Pharmacol 294 47-54, 1975. 

Chait, L.D. Wenger, G.R. and McMillan, D.E. Effects of phencyclidine and ketamine on punished and unpunished responding in pigeons. Pharmacol Biochem Behav 15 145-148, 1981. 

Substance-Related Disorders CHAPTER 73 PHENCYCLIDINE AND KETAMINE... 

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. 

Other hallucinogenic drugs including substances related to LSD are mentioned under delirium. Phencyclidine and ketamine can also produce similar hallucinatory states without delirium including time distortion, distortion of body image, synaesthesia, visual hallucinations, depersonalisation, derealisation, paranoid ideation and a schizophreniform psychosis which includes the negative symptoms of schizophrenia (Gorelick Balster, 1995). 

Phencyclidine has been favoured as an illicit drug of abuse for some 20 years, but such a use appears to have declined recently owing to the availability of relatively inexpensive cocaine. The drug has the street names of "PCP", "angel dust and "crystal". The structures of phencyclidine and ketamine are shown in Figure 15.7. 

Both phencyclidine and ketamine bind with high affinity to a number of receptors in the brain, but it is now accepted that the primary target is the sigma-PCP receptor site located in the ion channel of the NMDA excitatory amino acid receptor complex. The precise function of this receptor in the brain is still the subject of debate. It is now known that there are two distinct sigma receptor sites in the mammalian brain (ctj and a2) which are not associated with the NMDA receptor complex. Haloperidol and the atypical neuroleptic remoxipride bind with high affinity to such sites, and it has been postulated that some typical and atypical neuroleptics may owe some of their pharmacological effects to their action on such receptors. 

Considerable attention is now being paid to the way in which phencyclidine and ketamine block the ion channel controlled by the NMDA receptor. This prevents the movement of calcium ions in particular into the cell which, in the case of the NMDA receptors situated in the hippocampus, inhibits long-term potentiation and thereby blocks memory... 

These molecules cause significant changes in the perceptual system, producing sensory illusions and inducing a distortion of reality, the sense of space and time, to the point of hallucination. Natural, synthetic or semisynthetic substances can cause hallucinogenic effects psilocin, psilocybin, mescaline, and LSD. Hallucinogenic effects are also created by phencyclidine and ketamine, but these molecules have a dissociative character. 

The glutamate hypofunction hypothesis relies on the fact that phencyclidine and ketamine, both potent noncompetitive N-methyl-D-aspartate (NMDA)-glutamate receptor antagonists, induce schizophrenia-like symptoms in healthy individuals and worsen some symptoms in schizophrenia patients... 

Dextrophan and to a lesser degree dextromethorphan bind to the PGP and ketamine binding site on the N-methyl-D-aspartate (NMDA) receptor, which probably accounts for their similar dissociative psychotropic actions (see Phencyclidine and Ketamine). 

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