Comparison of Chlorpromazine, Haloperidol and Pimozide in the Treatment of Phencyclidine Psychosis: Da-2 Receptor Specificity

Aj, Giannini; Nageotte, C; Rh, Loiselle; Da, Malone; Wa, Price

doi:10.3109/15563658408992586

Cited by 30 publications

(10 citation statements)

References 15 publications

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“…Nevertheless, the present in vitro data are at least consistent with the clinical data on this topic. That is, the clinical agonist actions of phencyclidine and LSD in eliciting psychotic symptoms are selectively treated in the hospital emergency room by haloperidol and other dopamine D2-selective antagonists, 28,29 supporting the idea that dopamine D2 receptors are the primary target for eliciting psychotic symptoms. Although it has been claimed that psychotic symptoms elicited by ketamine are not blocked by haloperidol, 3 Giannini et al 30 have found that 5 mg of intramuscular haloperidol caused significant reductions in psychotic symptoms.…”

Section: Discussionmentioning

confidence: 90%

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

2005

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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...

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Section: Discussionmentioning

confidence: 90%

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

2005

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“…39,40 More importantly, studies in patients with PCP-induced psychosis (the state that the animal models are presumably reflecting) show that typical antipsychotics such as haloperidol and pimozide (a selective D 2 / 3 blocker) are much more effective than placebo, and result in remission of all symptoms. [41][42][43] To our knowledge there are no data on the use of atypical antipsychotics in clinical PCPinduced psychosis.…”

Section: Discussionmentioning

confidence: 99%

NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors—implications for models of schizophrenia

2002

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“…However, it is known clinically that haloperidol (which has a high affinity for D2 but a low affinity for glutamate receptors) effectively alleviates the psychosis secondary to phencyclidine or ketamine. 32,33 Moreover, it appears that glutamate receptor agonists such as pomaglumetad methionil and LY404,039 do not have any antipsychotic efficacy. A four-week trial had little or no efficacy against positive symptoms or negative signs when compared with olanzapine.…”

Section: Clozapine and Glutamate Receptorsmentioning

confidence: 99%

Clozapine, a Fast-Off-D2 Antipsychotic

Seeman

2013

ACS Chem. Neurosci.

106

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Ever since clozapine was first synthesized and tested, it showed the unique property of having antipsychotic action but no Parkinson-like motor side effects. The antipsychotic basis of clozapine is to transiently occupy dopamine D2 receptors in the human striatum, in contrast to haloperidol and chlorpromazine, which have a prolonged occupation of D2 receptors. The chemical structure of clozapine facilitates a relatively rapid dissociation from D2 receptors. After short-term occupation of D2 receptors, peak neural activity raises synaptic dopamine, which then displaces clozapine. While clozapine also occupies other types of receptors, they may not have a significant role in preventing parkinsonism. Clozapine's transient occupation of D2 receptors permits patients to move easily and comfortably.

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Comparison of Chlorpromazine, Haloperidol and Pimozide in the Treatment of Phencyclidine Psychosis: Da-2 Receptor Specificity

Cited by 30 publications

References 15 publications

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

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

NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors—implications for models of schizophrenia

Clozapine, a Fast-Off-D2 Antipsychotic

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