Dopamine receptor contribution to the action
of PCP, LSD and ketamine psychotomimetics
Seeman P, Ko F, Tallerico T.
 1Department of Pharmacology,
University of Toronto, Toronto, Ontario, Canada
 2Department of Psychiatry,
University of Toronto,
Toronto, Ontario, Canada.
Mol Psychiatry. 2005 Apr 26
ABSTRACTAlthough 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.LSD
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