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

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.

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Acknowledgements

We thank Dr H-C Guan for excellent technical assistance. Françoise Ko was supported by the University of Toronto Adel Sedra Scholarship and an Ontario Graduate Studentship. This research was supported by the Ontario Mental Health Foundation (Regular and Special Initiatives grants), NARSAD (the National Alliance for Research on Schizophrenia and Depression, to PS and FL), the CIHR (Canadian Institutes of Health Research, to FL and PS), the CPRF (Canadian Psychiatric Research Foundation, to FL and PS), NIDA (the National Institute on Drug Abuse), the SMRI (Stanley Medical Research Institute, to PS) and by donations from Dr Karolina Jus and the Medland and O'Rorke families.

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Seeman, P., Ko, F. & Tallerico, T. Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. Mol Psychiatry 10, 877–883 (2005). https://doi.org/10.1038/sj.mp.4001682

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Keywords

  • dopamine receptor
  • phencyclidine
  • domperidone
  • ketamine
  • NMDA receptors
  • psychotomimetics

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