COMPETITIVE NMDA RECEPTOR ANTAGONISTS ATTENUATE THE BEHAVIORAL 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 amph etamine-induced activation of mesocorticolimbic dopamine neurones. In the present study, the effects of the competitive NMDA receptor antago nists, 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 p er se, both compounds (2 or 5 mg/kg) significantly attenuated amphetam ine-induced 3,4-dihydroxyphenylalanine (DOPA) accumulation in the nucl eus accumbens and striatum. Furthermore, amphetamine-induced hyperloco motion was also antagonised following pretreatment with CGS 19755 (ED( 50) = 2.4 mg/kg) or (+)-CPP (ED(50) = 5.8 mg/kg) at doses which did no t impair spontaneous locomotor activity. Thus, in addition to blockade of the glycine modulatory site, competitive antagonism at the NMDA re ceptor also attenuates psychostimulant-induced activation of forebrain dopamine neurones.