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Recent advances in the phencyclidine model of schizophrenia.

Abstract

OBJECTIVE

Phencyclidine (PCP, "angel dust") induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding of schizophrenic pathophysiology.

METHOD

Twenty-five papers were identified that described the clinical dose and serum and CSF levels at which PCP induces its psychotomimetic effects. The dose range of PCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission.

RESULTS

It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation of its receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition.

CONCLUSIONS

These findings suggest that endogenous dysfunction of NMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models of schizophrenia are discussed in relationship to the diagnosis and etiology of schizophrenia.

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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, N.Y.

    Source

    The American journal of psychiatry 148:10 1991 Oct pg 1301-8

    MeSH

    Animals
    Dose-Response Relationship, Drug
    Humans
    Memory
    Mice
    Paired-Associate Learning
    Phencyclidine
    Phencyclidine Abuse
    Receptors, N-Methyl-D-Aspartate
    Receptors, Neurotransmitter
    Receptors, Phencyclidine
    Schizophrenia
    Schizophrenic Psychology

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.
    Review

    Language

    eng

    PubMed ID

    1654746

    Citation

    Javitt, D C., and S R. Zukin. "Recent Advances in the Phencyclidine Model of Schizophrenia." The American Journal of Psychiatry, vol. 148, no. 10, 1991, pp. 1301-8.
    Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;148(10):1301-8.
    Javitt, D. C., & Zukin, S. R. (1991). Recent advances in the phencyclidine model of schizophrenia. The American Journal of Psychiatry, 148(10), pp. 1301-8.
    Javitt DC, Zukin SR. Recent Advances in the Phencyclidine Model of Schizophrenia. Am J Psychiatry. 1991;148(10):1301-8. PubMed PMID: 1654746.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Recent advances in the phencyclidine model of schizophrenia. AU - Javitt,D C, AU - Zukin,S R, PY - 1991/10/1/pubmed PY - 1991/10/1/medline PY - 1991/10/1/entrez SP - 1301 EP - 8 JF - The American journal of psychiatry JO - Am J Psychiatry VL - 148 IS - 10 N2 - OBJECTIVE: Phencyclidine (PCP, "angel dust") induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding of schizophrenic pathophysiology. METHOD: Twenty-five papers were identified that described the clinical dose and serum and CSF levels at which PCP induces its psychotomimetic effects. The dose range of PCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission. RESULTS: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation of its receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition. CONCLUSIONS: These findings suggest that endogenous dysfunction of NMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models of schizophrenia are discussed in relationship to the diagnosis and etiology of schizophrenia. SN - 0002-953X UR - https://www.unboundmedicine.com/medline/citation/1654746/full_citation L2 - https://ajp.psychiatryonline.org/doi/full/10.1176/ajp.148.10.1301?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -