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Selective interaction of nitric oxide synthase inhibition with phencyclidine: behavioural and NMDA receptor binding studies in the rat.

Abstract

The psychotomimetic drugs, phencyclidine (PCP) and MK-801, are non-competitive antagonists of the N-methyl-d-aspartate (NMDA) receptor and used as pharmacological tools to mimic a possible NMDA receptor hypofunction in schizophrenia. These drugs were tested in two behavioural paradigms in the present study: prepulse inhibition (PPI) of acoustic startle and locomotor activity (LMA) in an open field. Recent studies show that several behavioural and biochemical effects of PCP are blocked by nitric oxide synthase (NOS) inhibition. Hence, it is likely that some effects of PCP are mediated via an increase in NO production, an assumption not in accordance with the NMDA receptor antagonistic effect of PCP. Experiments were conducted in rats to further elucidate the involvement of NO-dependent mechanisms in the effects of PCP and MK-801, and how these effects may involve the NMDA receptor. The NOS inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) (10 mg/kg) normalised the disruptive effect of PCP (2 mg/kg) on PPI and the stimulatory effect of PCP (4 mg/kg) on LMA. In contrast to these observations, the deficit in PPI induced by MK-801 (0.1 mg/kg) was not affected by L-NAME (10, 20 or 40 mg/kg). MK-801 (0.15 mg/kg)-induced hyperlocomotion was not affected by L-NAME (10 mg/kg), but attenuated by L-NAME (40 mg/kg). Furthermore, receptor binding studies aimed at investigating the influence of L-NAME on the binding of PCP to the MK-801-sensitive NMDA receptor binding site failed to show such an influence. These results suggest that the NO-sensitive effects of PCP are not sufficiently explained by its antagonistic effect at the NMDA receptor channel complex.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, The Sahlgrenska Academy at Göteborg University, Göteborg University, P.O. Box 431, SE 40530 Göteborg, Sweden.

    , ,

    Source

    Behavioural brain research 159:1 2005 Apr 15 pg 95-103

    MeSH

    Acoustic Stimulation
    Animals
    Dizocilpine Maleate
    Dose-Response Relationship, Drug
    Enzyme Inhibitors
    Excitatory Amino Acid Antagonists
    Exploratory Behavior
    Male
    Motor Activity
    NG-Nitroarginine Methyl Ester
    Neural Inhibition
    Nitric Oxide
    Nitric Oxide Synthase
    Phencyclidine
    Rats
    Rats, Sprague-Dawley
    Receptors, N-Methyl-D-Aspartate
    Reflex, Startle

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    15795002

    Citation

    Klamer, Daniel, et al. "Selective Interaction of Nitric Oxide Synthase Inhibition With Phencyclidine: Behavioural and NMDA Receptor Binding Studies in the Rat." Behavioural Brain Research, vol. 159, no. 1, 2005, pp. 95-103.
    Klamer D, Zhang J, Engel JA, et al. Selective interaction of nitric oxide synthase inhibition with phencyclidine: behavioural and NMDA receptor binding studies in the rat. Behav Brain Res. 2005;159(1):95-103.
    Klamer, D., Zhang, J., Engel, J. A., & Svensson, L. (2005). Selective interaction of nitric oxide synthase inhibition with phencyclidine: behavioural and NMDA receptor binding studies in the rat. Behavioural Brain Research, 159(1), pp. 95-103.
    Klamer D, et al. Selective Interaction of Nitric Oxide Synthase Inhibition With Phencyclidine: Behavioural and NMDA Receptor Binding Studies in the Rat. Behav Brain Res. 2005 Apr 15;159(1):95-103. PubMed PMID: 15795002.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Selective interaction of nitric oxide synthase inhibition with phencyclidine: behavioural and NMDA receptor binding studies in the rat. AU - Klamer,Daniel, AU - Zhang,Jianhua, AU - Engel,Jörgen A, AU - Svensson,Lennart, PY - 2004/09/27/received PY - 2004/10/11/revised PY - 2004/10/13/accepted PY - 2005/3/30/pubmed PY - 2005/7/13/medline PY - 2005/3/30/entrez SP - 95 EP - 103 JF - Behavioural brain research JO - Behav. Brain Res. VL - 159 IS - 1 N2 - The psychotomimetic drugs, phencyclidine (PCP) and MK-801, are non-competitive antagonists of the N-methyl-d-aspartate (NMDA) receptor and used as pharmacological tools to mimic a possible NMDA receptor hypofunction in schizophrenia. These drugs were tested in two behavioural paradigms in the present study: prepulse inhibition (PPI) of acoustic startle and locomotor activity (LMA) in an open field. Recent studies show that several behavioural and biochemical effects of PCP are blocked by nitric oxide synthase (NOS) inhibition. Hence, it is likely that some effects of PCP are mediated via an increase in NO production, an assumption not in accordance with the NMDA receptor antagonistic effect of PCP. Experiments were conducted in rats to further elucidate the involvement of NO-dependent mechanisms in the effects of PCP and MK-801, and how these effects may involve the NMDA receptor. The NOS inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) (10 mg/kg) normalised the disruptive effect of PCP (2 mg/kg) on PPI and the stimulatory effect of PCP (4 mg/kg) on LMA. In contrast to these observations, the deficit in PPI induced by MK-801 (0.1 mg/kg) was not affected by L-NAME (10, 20 or 40 mg/kg). MK-801 (0.15 mg/kg)-induced hyperlocomotion was not affected by L-NAME (10 mg/kg), but attenuated by L-NAME (40 mg/kg). Furthermore, receptor binding studies aimed at investigating the influence of L-NAME on the binding of PCP to the MK-801-sensitive NMDA receptor binding site failed to show such an influence. These results suggest that the NO-sensitive effects of PCP are not sufficiently explained by its antagonistic effect at the NMDA receptor channel complex. SN - 0166-4328 UR - https://www.unboundmedicine.com/medline/citation/15795002/Selective_interaction_of_nitric_oxide_synthase_inhibition_with_phencyclidine:_behavioural_and_NMDA_receptor_binding_studies_in_the_rat_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-4328(04)00390-0 DB - PRIME DP - Unbound Medicine ER -