Reversal of phencyclidine-induced dopaminergic dysregulation by N-methyl-D-aspartate receptor/glycine-site agonists.
N-methyl-D-aspartate (NMDA) receptors may play a critical role in the pathophysiology of schizophrenia. In rodents, NMDA receptor antagonists, such as phencyclidine (PCP), induce dopaminergic dysregulation that resembles the pattern observed in schizophrenia. The present study investigates the degree to which concurrent treatment with NMDA modulators, such as glycine and the recently developed glycine transport antagonist N[3-(4"-fluorophenyl)-3-(4"-phenylphenoxy)propyl]sarcosine (NFPS) prevents dopaminergic dysregulation observed following chronic (3 months) or subchronic (2 weeks) PCP administration. Both chronic and subchronic treatment with PCP in the absence of glycine or NFPS led to significant potentiation of amphetamine-induced dopamine release in the prefrontal cortex and striatum, similar to that observed in schizophrenia. Treatment with either high-dose glycine or NFPS along with PCP prevented PCP effects. These findings demonstrate effective doses of glycine for use in animal models of schizophrenia, and support recent clinical studies showing the effectiveness of NMDA agonists in the treatment of persistent symptoms of schizophrenia.
Javitt
Daniel C
DC
Nathan Kline Institute for Psychiatric Research, NYU School of Medicine, Orangeburg, NY, USA. Javitt@nki.rfmh.org
Balla
Andrea
A
Burch
Sarah
S
Suckow
Ray
R
Xie
Shan
S
Sershen
Henry
H
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004563:Electrochemistry; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005998:Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D010622:Phencyclidine / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
D000697:Central Nervous System Stimulants; D018690:Excitatory Amino Acid Agonists; C435025:N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine; D016194:Receptors, N-Methyl-D-Aspartate; D000661:Amphetamine; D010622:Phencyclidine; D005998:Glycine; D004298:Dopamine; D012521:Sarcosine