N-methyl-D-aspartate antagonism and phencyclidine-like activity: a drug discrimination analysis.
W. Koek, James H Woods, Françis C. Colpaert
Journal of Pharmacology and Experimental Therapeutics June 1, 1990 DOI: 10.1016/s0022-3565(25)13197-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Rats trained to discriminate NMDA or PCP from saline, and mice tested for NMDA-induced lethality |
| Interventions | CPP CGS 19755 phencyclidine (PCP) ketamine MK-801 ifenprodil PK 26124 pentobarbital chlordiazepoxide NMDA |
| Dose | NMDA 40 mg/kg (discrimination), NMDA 160 mg/kg (lethality), PCP 2.5 mg/kg (discrimination) |
| Key points | Competitive NMDA antagonists (CPP, CGS 19755) blocked NMDA's discriminative stimulus effects and fully protected against NMDA-induced lethality, whereas noncompetitive antagonists (PCP, ketamine, MK-801) and other drugs only partially antagonized these effects. The authors suggest that the extent of NMDA antagonism and PCP-like discriminative effects may depend on the behavioral measure and the receptor site involved. |
Abstract
The experiments examined the ability of competitive N-methyl-D-aspartate (NMDA) antagonists (CPP, CGS 19755), noncompetitive NMDA antagonists [phencyclidine (PCP), ketamine, MK-801], other putative excitatory amino acid antagonists (ifenprodil, PK 26124), and anticonvulsants (pentobarbital, chlordiazepoxide) to antagonize the discriminative stimulus (DS) effects of NMDA and to produce PCP-like DS effects. Rats were trained to discriminate NMDA (40 mg/kg) from saline. The DS effects of NMDA were blocked by the competitive NMDA antagonists but were antagonized at best partially by the other drugs tested. The response rate decreasing effects of NMDA were attenuated to varied extents by both the competitive and the noncompetitive NMDA antagonists. Some competitive and noncompetitive NMDA antagonists partially mimicked NMDA. To further examine their NMDA-antagonist properties, the compounds were also tested for antagonism of NMDA (160 mg/kg)-induced lethality in mice; only the competitive and noncompetitive NMDA antagonists completely protected against NMDA-induced lethality. In rats discriminating PCP (2.5 mg/kg) from saline, the competitive NMDA antagonists produced less drug-appropriate responding than the noncompetitive NMDA antagonists but more than was produced by the other drugs tested. The extent to which compounds antagonize behavioral effects of NMDA and produce PCP-like DS effects may depend partly on the effect measured and on the component of the NMDA receptor complex with which they interact. Although the competitive NMDA antagonists were more effective in blocking NMDA than the other drugs tested, they failed to act as pure antagonists of the DS effects of NMDA.