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, 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. Keywords: dopamine receptor; phencyclidine; domperidone; ketamine; NMDA receptors; psychotomimetics While the clinical anti-dopaminergic actions of antipsychotic drugs are compatible with the hyperdopamine hypothesis of psychosis and schizophrenia, 1,2 the psychoses caused by glutamate antagonists such as phencyclidine or ketamine suggest a hypo-glutamate component in psychosis. [3][4][5] However, phencyclidine also lowers plasma prolactin 6 and elicits rotation, 7 suggesting a direct or indirect dopaminemimetic action of phencyclidine.Although phencyclidine and ketamine are not selective for glutamate NMDA receptors, 8 the precise affinities of these drugs for dopamine D2 receptors need to be clarified in order to determine their dopaminergic and non-dopaminergic components of action. More specifically, although phencyclidine had a dissociation constant of 37 000 nM at the D2 receptor in rat striatal homogenate, 8 phencyclidine had a dissociation constant of 1.3 nM for the functional high-affinity site of the cloned D2 receptor, or the D2 High receptor. 9 This apparent discrepancy may be resolved by the recent finding that dopamine itself has a dissociation constant of 3000 nM when competing vs [ 3 H]raclopride at striatal D2 receptors, but has a dissociation constant of 1.5 nM at the D2 High receptor when the link between dopamine D1 and D2 receptors is blocked by the D1 antagonist SCH23390. 10 The link between D1 and D2 receptors arises from several sources, including the colocalization of dopamine D1 and D2 receptors in at least 50% of the medium spiny neurons in the striatum, the cooperation and mutual potentiation of D1 and D2 agonists on various behaviors, and the biochemical conversion of D2 receptors from their functional high-affinity state, D2 High , into their low-affinity state, D2 Lo...

Dopaminergic Control of Sleep–Wake States

“…Importantly, this is consistent with neurotransmitters levels observed during REM sleep (Trulson and Jacobs, 1979;Park et al, 1999;Lena et al, 2005), and during the waking period of DAT-KO mice immediately after exposure to novelty (Gainetdinov et al, 1999(Gainetdinov et al, , 2001). This also predicts that psychosis may be generated by pharmacological agents that activate the D 2 dopamine receptor while altering specific aspects of glutamatergic or serotonergic transmission (Kapur and Seeman, 2002;Seeman et al, 2005). …”

“…Furthermore, drugs that increase endogenous dopamine release (e.g., amphetamines) were found to induce psychosis in healthy individuals and exacerbate psychotic symptoms in schizophrenic patients (Snyder, 1972). Recent evidence also suggests that other pharmacological agents that induce psychosis in healthy individuals (e.g., PCP) demonstrate significant potency for the D 2 dopamine receptor (Kapur and Seeman, 2002;Seeman et al, 2005).…”

Behavioral genetic contributions to the study of addiction-related amphetamine effects

“…Another study used 26 of the BXD RI strains and found no evidence for a genetic correlation between the locomotor stimulant responses to phencyclidine and methamphetamine (Alexander et al, 1996). Therefore, although both drugs can produce psychotic states in humans, and they share the involvement of dopamine in their behavioral effects (Del Arco et al, 2007;Seeman et al, 2005;Zhang et al, 2001), the genetic mechanisms that determine sensitivity to these drugs may be disparate. Janowsky et al (2001) made use of a large database of BXD RI strain means for multiple drug-related traits to identify genetic correlations with DAT density.…”

A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

“…Besides its well-established NMDAR antagonism, PCP also acts as a D2 receptor (D2R)-like agonist. [46][47][48] We performed a battery of molecular and behavioral tests that revealed a preserved D2R neurotransmission in Ddo − / − mice, thus corroborating a glutamatergic origin for the different responsivity to PCP observed in Ddo − / − mice (see Supplementary Information and Supplementary Figure S2). fMRI response induced by PCP in Ddo − / − mice Because D-Asp can modulate NMDAR-related functions, [18][19][20][21]38 we used Ddo − / − mice to assess whether genetically driven D-Asp elevation can modulate the aberrant neurofunctional cascade underlying the psychotomimetic effect of PCP.…”