Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach.
Agents that antagonize the glutamatergic N-methyl-d-aspartate (NMDA) receptor, such as phenylcyclidine (PCP) and ketamine, produce a behavioral state in healthy volunteers that resembles some aspects of schizophrenia. A dysfunction in NMDA-dopaminergic interactions has been proposed as a mechanism for these behavioral effects. In this study, we examined the effects of ketamine on striatal dopamine release in healthy human subjects with a novel 11C-raclopride/PET displacement paradigm and compared these effects to administration of saline and the direct-acting dopamine agonist amphetamine. We found that the percent decreases (mean +/- SD) in specific 11C-raclopride binding from baseline for ketamine (11.2 +/- 8.9) was greater than for saline (1.9 +/- 3.7) (t = 2.4, df = 13, P = 0.003) indicating that ketamine caused increases in striatal synaptic dopamine concentrations. Ketamine-related binding changes were not significantly different than the decreases in percent change (mean +/- SD) in specific 11C-raclopride binding caused by amphetamine (15.5 +/- 6.2) (t = 1.3, df = 19, P = 0.21). Ketamine-induced changes in 11C-raclopride-specific binding were significantly correlated with induction of schizophrenia-like symptoms. The implications of this brain imaging method for studies of schizophrenia and the mechanism of action of antipsychotic drugs are discussed.
Breier
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Experimental Therapeutics Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA. Breier_Alan@Lilly.com
Adler
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Weisenfeld
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Su
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Elman
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Picken
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Malhotra
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AK
Pickar
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D
D000328:Adult; D000661:Amphetamine / Q000494:pharmacology; D001519:Behavior / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D011569:Psychiatric Status Rating Scales; D011605:Psychoses, Substance-Induced / Q000000981:diagnostic imaging / Q000523:psychology; D020891:Raclopride; D012457:Salicylamides; D014055:Tomography, Emission-Computed
D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D012457:Salicylamides; D020891:Raclopride; D016202:N-Methylaspartate; D000661:Amphetamine; D004298:Dopamine