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

Seeman P, Ko F, Tallerico T.
[1] 1Department of Pharmacology,
University of Toronto, Toronto, Ontario, Canada
[2] 2Department of Psychiatry,
University of Toronto,
Toronto, Ontario, Canada.
Mol Psychiatry. 2005 Apr 26


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 [(3)H]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 [(3)H]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.
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