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

Mol Psychiatry. 2005 Sep;10(9):877-83. doi: 10.1038/


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.

MeSH terms

  • Animals
  • CHO Cells
  • Cloning, Molecular
  • Corpus Striatum / metabolism
  • Cricetinae
  • Dizocilpine Maleate / pharmacology
  • Domperidone / pharmacokinetics
  • Dopamine / pharmacology
  • Dopamine Plasma Membrane Transport Proteins
  • Excitatory Amino Acid Antagonists / pharmacology
  • Ketamine / pharmacology
  • Kinetics
  • Lysergic Acid Diethylamide / pharmacology*
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / physiology*
  • Membrane Transport Proteins / drug effects
  • Membrane Transport Proteins / physiology*
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / physiology*
  • Phencyclidine / pharmacology*
  • Rats
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / physiology


  • Dopamine Plasma Membrane Transport Proteins
  • Excitatory Amino Acid Antagonists
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Receptors, Dopamine D2
  • Domperidone
  • Ketamine
  • Dizocilpine Maleate
  • Lysergic Acid Diethylamide
  • Phencyclidine
  • Dopamine