Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics.
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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Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada. philip.seeman@utoronto.ca
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D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004294:Domperidone / Q000493:pharmacokinetics; D004298:Dopamine / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D007700:Kinetics; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000502:physiology*; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology
D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D004294:Domperidone; D007649:Ketamine; D016291:Dizocilpine Maleate; D008238:Lysergic Acid Diethylamide; D010622:Phencyclidine; D004298:Dopamine