Competitive NMDA receptor antagonists attenuate the behavioural and neurochemical effects of amphetamine in mice.

We have previously reported that the glycine/NMDA receptor antagonist, R-(+)-HA-966 (R-(+)-3-amino-1-hydroxypyrrolid-2-one), attenuates amphetamine-induced activation of mesocorticolimbic dopamine neurones. In the present study, the effects of the competitive NMDA receptor antagonists, CGS 19755 (cis-4-(phosphonomethyl)piperidine-2-carboxylic acid) and (+/-)-CPP ((+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) were examined in mice. In the absence of any neurochemical effects per se, both compounds (2 or 5 mg/kg) significantly attenuated amphetamine-induced 3,4-dihydroxyphenylalanine (DOPA) accumulation in the nucleus accumbens and striatum. Furthermore, amphetamine-induced hyperlocomotion was also antagonised following pretreatment with CGS 19755 (ED50 = 2.4 mg/kg) or (+/-)-CPP (ED50 = 5.8 mg/kg) at doses which did not impair spontaneous locomotor activity. Thus, in addition to blockade of the glycine modulatory site, competitive antagonism at the NMDA receptor also attenuates psychostimulant-induced activation of forebrain dopamine neurones.