The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor

Abstract

The selective non-competitive NMDA receptor antagonist, MK-801, potently blocked convulsions induced in the mouse by N-methyl-DL-aspartic acid (NMDLA) with an i.v. ED 50 dose of 0.2 mg/kg. Similar doses of MK-801 were also effective in blocking seizures induced by pentylenetetrazol (PTZ), electroshock and by sound in audiogenic seizure-prone animals. Other less selective non-competitive NMDA receptor antagonists including phencyclidine (PCP), thienylcyclohexylpiperidine (TCP), (+)-N-allylnormetazocine ((+)-NANM, (+)-SKF 10,047) and ketamine also blocked NMDLA-induced seizures with a rank order of potency of MK-801 > PCP > TCP = (+)-NANM > ketamine. The competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked NMDLA-induced seizures with an ED 50 of 4.5 mg/kg, 22- and 560-fold more potently than the competitive antagonists, 2-DL-amino-7-phosphonoheptanoic acid (2-APH) and 2-DL-amino-5-phosphonovaleric acid (2-APV), respectively. MK-801 was the most potent of the non-competitive antagonists to induce a motor syndrome including head weaving, body rolling, increased locomotion and ataxia, characteristic of the behavioural response to PCP in the mouse. The syndrome was also present following injection of the competitive NMDA receptor antagonists, although they were generally less potent (probably a reflection of poor brain penetration) and less efficacious than the non-competitive antagonists. For all compounds except CPP, the anticonvulsant ED 50 dose was close to the minimun effective dose to induce motor stimulation: CPP was 5- to 10-fold more potent as an anticonvulsant. In drug discrimination studies, MK-801 induced a highly discriminable interoceptive stimulus to which other non-competitive NMDA receptor antagonists dose dependently generalised. CPP partially generalised to the MK-801 stimulus. Overall, the results provide strong support for the hypothesis that antagonism of NMDA receptors is a major event in the genesis of many of the behavioural responses to MK-801 and phencyclidine.