Continuous phencyclidine treatment induces schizophrenia-like hyperreactivity of striatal dopamine release.
Functional dopaminergic hyperactivity is a key feature of schizophrenia. Recent in vivo imaging studies have demonstrated greater striatal dopamine release in response to amphetamine challenge in schizophrenia subjects than in normal controls. N-methyl-D-aspartate (NMDA) receptors are known to play a prominent role in regulation of striatal dopamine release. In humans, NMDA antagonists induce a psychotic state that closely resembles schizophrenia. The present study investigates the degree to which chronic continuous administration of the NMDA antagonist phencyclidine (PCP) induces schizophrenia-like hyperreactivity of striatal dopamine release to amphetamine in rodents. Rats were treated with 10 or 15 mg/kg/d PCP for two weeks by osmotic minipump, and striatal dopamine release to amphetamine challenge (1 mg/kg) was monitored by microdialysis. PCP-treated rats showed significant enhancement in amphetamine-induced dopamine release, along with significantly enhanced locomotor activity. These findings support the concept that NMDA receptor dysfunction may contribute to dopaminergic dysfunction in schizophrenia.
Balla
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A
Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
Koneru
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R
Smiley
J
J
Sershen
H
H
Javitt
D C
DC
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010622:Phencyclidine / Q000008:administration & dosage* / Q000494:pharmacology*; D011595:Psychomotor Agitation / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism*
D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D015102:3,4-Dihydroxyphenylacetic Acid; D000661:Amphetamine; D010622:Phencyclidine; D004298:Dopamine; D006719:Homovanillic Acid