R-(+)-HA-966, a glycine/NMDA receptor antagonist, selectively blocks the activation of the mesolimbic dopamine system by amphetamine.
1. The effects of the glycine/NMDA receptor antagonist, (+)-HA-966 on the neurochemical and behavioural responses to amphetamine have been determined in the mouse and rat. 2. In vehicle-treated control mice, (+)-HA-966 (30-100 mg kg-1) did not affect dopamine synthesis in either the nucleus accumbens or striatum and was without marked effect on spontaneous locomotor activity. 3. In the mouse, (+)-HA-966 (30 and 100 mg kg-1) dose-dependently blocked the enhancement of dopamine synthesis induced in the nucleus accumbens by amphetamine, but was without effect on the increase in dopamine synthesis in the striatum. 4. Intracerebroventricular administration of the glycine/NMDA receptor antagonist, 5,7-dichlorokynurenic acid, in the mouse (10 micrograms) also significantly attenuated amphetamine-enhanced DOPA accumulation in the nucleus accumbens, but not in the striatum. 5. The decrease of dopamine synthesis in striatum and nucleus accumbens induced by the dopamine receptor agonist, apomorphine, was unaffected by (+)-HA-966 (100 mg kg-1). 6. (+)-HA-966 (30 mg kg-1) failed to attenuate the hyperactivity induced by the systemic administration of amphetamine in the mouse, but totally prevented the hyperlocomotion following infusion of amphetamine into the rat nucleus accumbens. In contrast, stereotyped behaviour induced by infusion of amphetamine into the rat striatum was not altered following pretreatment with (+)-HA-966 (30 mg kg-1). 7. The results are consistent with a selective facilitatory role of glycine/NMDA receptors on mesolimbic dopaminergic neurones.
Hutson
P H
PH
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
Bristow
L J
LJ
Thorn
L
L
Tricklebank
M D
MD
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000032:analysis; D004298:Dopamine / Q000032:analysis*; D005998:Glycine / Q000378:metabolism*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009714:Nucleus Accumbens / Q000187:drug effects; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D017981:Receptors, Neurotransmitter / Q000187:drug effects*
D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D004295:Dihydroxyphenylalanine; D000661:Amphetamine; C001369:1-hydroxy-3-amino-2-pyrrolidone; D005998:Glycine; D004298:Dopamine