Tags

Type your tag names separated by a space and hit enter

Evaluation of NMDA receptor models of schizophrenia: divergences in the behavioral effects of sub-chronic PCP and MK-801.

Abstract

The hypothesis of hypo-functionality of NMDA receptors in schizophrenia originates from the observation that administration of the NMDA antagonist phencyclidine (PCP) induces psychotic states that closely resemble schizophrenic symptoms and that persist after drug discontinuation. A large number of animal studies have used PCP and the NMDA antagonist dizocilpine (MK-801) almost interchangeably to model schizophrenia. However, PCP interacts with pharmacological targets other than NMDA receptors that are not affected by MK-801. In addition, although acute administration of either compound produces similar effects in animals, there is little information whether withdrawal from chronic MK-801 causes behavioral deficits that mimic schizophrenia symptoms as in the case of PCP. To clarify this issue, we compared the following behaviors in rats subjected to withdrawal from sub-chronic administration (2 x 7 days) of either PCP (5 mg/kg, i.p.) or MK-801 (0.5 mg/kg, i.p.): (1) working memory in a variable-delayed alternation task in a T-maze, (2) social interaction, and (3) motor activity in response to a (a) novel environment, (b) mild stressor, and (c) d-amphetamine challenge. Withdrawal from sub-chronic PCP caused a delay-dependent impairment of working memory, reduced social interaction and enhanced d-amphetamine-induced motor activity. These results were not replicated in animals sub-chronically treated with MK-801, which displayed only a slight decrease in social interaction. These data suggest that pharmacological antagonism at NMDA receptors is not sufficient to explain the full spectrum of PCP psychotomimetic properties.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. seillier@uthscsa.edu

    Source

    Behavioural brain research 204:2 2009 Dec 07 pg 410-5

    MeSH

    Animals
    Body Weight
    Disease Models, Animal
    Dizocilpine Maleate
    Male
    Memory, Short-Term
    Motor Activity
    Phencyclidine
    Rats
    Rats, Wistar
    Receptors, N-Methyl-D-Aspartate
    Schizophrenia
    Social Behavior
    Substance Withdrawal Syndrome

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    19716985

    Citation

    Seillier, Alexandre, and Andrea Giuffrida. "Evaluation of NMDA Receptor Models of Schizophrenia: Divergences in the Behavioral Effects of Sub-chronic PCP and MK-801." Behavioural Brain Research, vol. 204, no. 2, 2009, pp. 410-5.
    Seillier A, Giuffrida A. Evaluation of NMDA receptor models of schizophrenia: divergences in the behavioral effects of sub-chronic PCP and MK-801. Behav Brain Res. 2009;204(2):410-5.
    Seillier, A., & Giuffrida, A. (2009). Evaluation of NMDA receptor models of schizophrenia: divergences in the behavioral effects of sub-chronic PCP and MK-801. Behavioural Brain Research, 204(2), pp. 410-5. doi:10.1016/j.bbr.2009.02.007.
    Seillier A, Giuffrida A. Evaluation of NMDA Receptor Models of Schizophrenia: Divergences in the Behavioral Effects of Sub-chronic PCP and MK-801. Behav Brain Res. 2009 Dec 7;204(2):410-5. PubMed PMID: 19716985.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Evaluation of NMDA receptor models of schizophrenia: divergences in the behavioral effects of sub-chronic PCP and MK-801. AU - Seillier,Alexandre, AU - Giuffrida,Andrea, Y1 - 2009/02/14/ PY - 2008/10/16/received PY - 2009/02/05/revised PY - 2009/02/06/accepted PY - 2009/9/1/entrez PY - 2009/9/1/pubmed PY - 2009/9/26/medline SP - 410 EP - 5 JF - Behavioural brain research JO - Behav. Brain Res. VL - 204 IS - 2 N2 - The hypothesis of hypo-functionality of NMDA receptors in schizophrenia originates from the observation that administration of the NMDA antagonist phencyclidine (PCP) induces psychotic states that closely resemble schizophrenic symptoms and that persist after drug discontinuation. A large number of animal studies have used PCP and the NMDA antagonist dizocilpine (MK-801) almost interchangeably to model schizophrenia. However, PCP interacts with pharmacological targets other than NMDA receptors that are not affected by MK-801. In addition, although acute administration of either compound produces similar effects in animals, there is little information whether withdrawal from chronic MK-801 causes behavioral deficits that mimic schizophrenia symptoms as in the case of PCP. To clarify this issue, we compared the following behaviors in rats subjected to withdrawal from sub-chronic administration (2 x 7 days) of either PCP (5 mg/kg, i.p.) or MK-801 (0.5 mg/kg, i.p.): (1) working memory in a variable-delayed alternation task in a T-maze, (2) social interaction, and (3) motor activity in response to a (a) novel environment, (b) mild stressor, and (c) d-amphetamine challenge. Withdrawal from sub-chronic PCP caused a delay-dependent impairment of working memory, reduced social interaction and enhanced d-amphetamine-induced motor activity. These results were not replicated in animals sub-chronically treated with MK-801, which displayed only a slight decrease in social interaction. These data suggest that pharmacological antagonism at NMDA receptors is not sufficient to explain the full spectrum of PCP psychotomimetic properties. SN - 1872-7549 UR - https://www.unboundmedicine.com/medline/citation/19716985/Evaluation_of_NMDA_receptor_models_of_schizophrenia:_divergences_in_the_behavioral_effects_of_sub_chronic_PCP_and_MK_801_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-4328(09)00100-4 DB - PRIME DP - Unbound Medicine ER -