Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

Although phencyclidine and ketamine are used to model a hypoglutamate theory of schizophrenia, their selectivity for NMDA receptors has been questioned. To determine the affinities of phencyclidine, ketamine, dizocilpine and LSD for the functional high-affinity state of the dopamine D2 receptor, D2(High), their dissociation constants (K-i) were obtained on [H-3]domperidone binding to human cloned dopamine D2 receptors. Phencyclidine had a high affinity for D2(High) with a K-i of 2.7 nM, in contrast to its low affinity for the NMDA receptor, with a K-i of 313 nM, as labeled by [H-3]dizocilpine on rat striatal tissue. Ketamine also had a high affinity for D2(High) with a K-i of 55 nM, an affinity higher than its 3100 nM K-i for the NMDA sites. Dizocilpine had a K-i of 0.3 nM at D2(High), but a K-d of 1.8 nM at the NMDA receptor. LSD had a K-i of 2nM at D2(High). Because the psychotomimetics had higher potency at D2(High) than at the NMDA site, the psychotomimetic action of these drugs must have a major contribution from D2 agonism. Because these drugs have a combined action on both dopamine receptors and NMDA receptors, these drugs, when given in vivo, test a combined hyperdopamine and hypoglutamate theory of psychosis.