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

Phencyclidine, ketamine, dizocilpine, and LSD all show higher affinity for the high-affinity state of the dopamine D2 receptor (D2High) than for the NMDA receptor. Phencyclidine had a Ki of 2.7 nM at D2High versus 313 nM at the NMDA receptor; ketamine had a Ki of 55 nM at D2High versus 3100 nM at NMDA sites; dizocilpine had a Ki of 0.3 nM at D2High versus a Kd of 1.8 nM at NMDA; LSD had a Ki of 2 nM at D2High. Because these psychotomimetics are more potent at D2High, their psychotomimetic action likely involves D2 agonism. In vivo, these drugs test a combined hyperdopamine and hypoglutamate theory of psychosis.

Study at a glance

Abstract

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, D2High, their dissociation constants (Ki) were obtained on [3H]domperidone binding to human cloned dopamine D2 receptors. Phencyclidine had a high affinity for D2High with a Ki of 2.7 nM, in contrast to its low affinity for the NMDA receptor, with a Ki of 313 nM, as labeled by [3H]dizocilpine on rat striatal tissue. Ketamine also had a high affinity for D2High with a Ki of 55 nM, an affinity higher than its 3100 nM Ki for the NMDA sites. Dizocilpine had a Ki of 0.3 nM at D2High, but a Kd of 1.8 nM at the NMDA receptor. LSD had a Ki of 2 nM at D2High. Because the psychotomimetics had higher potency at D2High 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.