1. ¹Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
2. ²Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

Correspondence: Dr P Seeman, MD, PhD, Departments of Pharmacology and Psychiatry, Medical Science Building, Room 4344, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: philip.seeman@utoronto.ca

Received 23 November 2004; Revised 4 March 2005; Accepted 21 March 2005; Published online 26 April 2005.

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, D2^High, their dissociation constants (K_i) were obtained on [³H]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 [³H]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 2 nM 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.