title: L-701,324, a glycine/NMDA receptor antagonist, blocks the increase of cortical dopamine metabolism by stress and DMCM.
abstract: 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.
authors.affiliation: MSD Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK. Peter_Hutson@Merck.com
authors.forename: P H
authors.initials: PH
authors.lastname: Hutson
authors.forename: C L
authors.initials: CL
authors.lastname: Barton
mesh_terms: 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
chemical_list: 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