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 Citations (Scopus)

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 1996
Externally publishedYes

Fingerprint

Dizocilpine Maleate
N-Methylaspartate
Dissociative Anesthetics
Memantine
Dextromethorphan
Phencyclidine
Ketamine
N-Methyl-D-Aspartate Receptors

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

Dizocilpine-like discriminative stimulus effects of low-affinity uncompetitive NMDA antagonists. / Grant, Kathleen A.; Colombo, Giancarlo; Grant, Julia; Rogawski, Michael A.

In: Neuropharmacology, Vol. 35, No. 12, 12.1996, p. 1709-1719.

Research output: Contribution to journalArticle

Grant, Kathleen A. ; Colombo, Giancarlo ; Grant, Julia ; Rogawski, Michael A. / Dizocilpine-like discriminative stimulus effects of low-affinity uncompetitive NMDA antagonists. In: Neuropharmacology. 1996 ; Vol. 35, No. 12. pp. 1709-1719.
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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.",
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