Dizocilpine-like discriminative stimulus effects of low-affinity uncompetitive NMDA antagonists

Kathleen A. Grant, Giancarlo Colombo, Julia Grant, Michael A. Rogawski

    Research output: Contribution to journalArticle

    53 Scopus citations

    Abstract

    The dizocilpine-like discriminative stimulus effects of a variety of channel blocking (uncompetitive) N-methyl-D-aspartate (NMDA) receptor antagonists were examined in rats trained to discriminate dizocilpine (0.17 mg/kg, i.p) from saline in a two-lever operant procedure. The dissociative anesthetic-type NMDA antagonists dizocilpine (ED50 0.05 mg/kg), phencyclidine (ED50 3.4 mg/kg) and ketamine (ED50 14 mg/kg) showed complete substitution without producing significant decreases in response rates, whereas dexoxadrol (ED50 4.3 mg/kg) also produced complete substitution with a concomitant decrease (35%) in response rate. Similarly, the low-affinity antagonist memantine resulted in complete substitution (ED50 9.7 mg/kg) at doses that significantly reduced (68%) the response rate. All other low-affinity antagonists resulted in either partial or no substitution for the discriminative stimulus effects of dizocilpine at doses that significantly decreased average response rates. These include (ED50 values in parentheses) remacemide (29 mg/kg), the remacemide metabolite 1,2-diphenyl-2-propylamine (ARL 12495) (14 mg/kg), phencylcyclopentylamine (25 mg/kg), dextromethorphan (46 mg/kg), (±)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-im ine (ADCI; no substitution) and levoxadrol (no substitution). We conclude that low affinity uncompetitive NMDA antagonists have discriminative stimulus properties distinct from dissociative anesthetic-type uncompetitive NMDA antagonists. The lowest-affinity antagonists show virtually no substitution for dizocilpine, whereas the relatively more potent low-affinity antagonists (such as memantine) exhibit greater substitution, but complete substitution is obtained only at rate-reducing doses.

    Original languageEnglish (US)
    Pages (from-to)1709-1719
    Number of pages11
    JournalNeuropharmacology
    Volume35
    Issue number12
    DOIs
    StatePublished - Dec 1 1996

    Keywords

    • N-methyl-D-aspartate antagonist
    • N-methyl-D-aspartate receptor
    • dizocilpine (MK-801)
    • drug discrimination
    • glutamate receptor
    • ketamine
    • phencyclidine
    • rat

    ASJC Scopus subject areas

    • Pharmacology
    • Cellular and Molecular Neuroscience

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