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.
Bristow
L J
LJ
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Thorn
L
L
Tricklebank
M D
MD
Hutson
P H
PH
D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004347:Drug Interactions; D005998:Glycine / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010875:Pipecolic Acids / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D010875:Pipecolic Acids; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; C053672:selfotel; D004295:Dihydroxyphenylalanine; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D000661:Amphetamine; D005998:Glycine