L-701,324, a glycine/NMDA receptor antagonist, blocks the increase of cortical dopamine metabolism by stress and DMCM.
Dopamine metabolism, as reflected by the concentration of dihydroxyphenylacetic acid (DOPAC), in the medial prefrontal cortex was significantly increased following 30 min immobilisation stress or systemic administration of the benzodiazepine/GABA(A) receptor inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). The response to stress was attenuated by pretreatment of rats with the benzodiazepine/GABA(A) receptor agonists diazepam and zolpidem. Furthermore, pretreatment with R-(+)-3-amino-1-hydroxypyrrolid-2-one (R-(+)-HA-966), a low efficacy partial agonist, and 7-chloro-4-hydroxy-3(3-phenoxy) phenylquinolin-2-(H)-one (L-701,324) a novel, high affinity, full antagonist at the glycine/NMDA receptor attenuated the response to both stress and DMCM. These results demonstrate that antagonists at the glycine/NMDA receptor complex are comparable with benzodiazepine/GABA(A) receptor agonists in their ability to prevent activation of the mesocortical dopamine system by stress and GABA(A) receptor inverse agonists. Results are discussed in relation to the interaction between glycine/NMDA receptor antagonists, the mesocorticolimbic dopamine system and stress related disorders.
Hutson
P H
PH
MSD Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK. Peter_Hutson@Merck.com
Barton
C L
CL
D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000378:metabolism; D000077334:Zolpidem
D002243:Carbolines; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D011725:Pyridines; D011760:Pyrrolidinones; D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D000077334:Zolpidem; C001369:1-hydroxy-3-amino-2-pyrrolidone; C094635:L 701324; D003975:Diazepam; D004298:Dopamine