NMDA antagonist effects on striatal dopamine release: Positron emission tomography studies in humans

• Published in: Synapse (New York, N.Y.) Vol. 43; no. 1; pp. 19 - 29
• Main Authors: Kegeles, Lawrence S., Martinez, Diana, Kochan, Lisa D., Hwang, Dah-Ren, Huang, Yiyun, Mawlawi, Osama, Suckow, R. F., Van Heertum, Ronald L., Laruelle, Marc
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01-01-2002
• Subjects: [11C]raclopride; Adult; Antipsychotic Agents - pharmacokinetics; Behavior - drug effects; Behavior - physiology; Binding, Competitive - drug effects; Binding, Competitive - physiology; Cerebellum - diagnostic imaging; Cerebellum - drug effects; dopamine; Dopamine - metabolism; Dopamine - secretion; Drug Interactions - physiology; Excitatory Amino Acid Antagonists - adverse effects; Excitatory Amino Acid Antagonists - blood; Excitatory Amino Acid Antagonists - pharmacology; Female; glutamate; Humans; ketamine; Ketamine - adverse effects; Ketamine - blood; Ketamine - pharmacokinetics; Male; Middle Aged; Neostriatum - diagnostic imaging; Neostriatum - drug effects; Neurons - diagnostic imaging; Neurons - drug effects; Nucleus Accumbens - diagnostic imaging; Nucleus Accumbens - drug effects; PET; raclopride; Raclopride - pharmacokinetics; Receptors, Dopamine D2 - drug effects; Receptors, Dopamine D2 - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; schizophrenia; Tomography, Emission-Computed
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.10010

Previous brain imaging studies with [11C]raclopride have suggested that the psychotogenic effects of the noncompetitive N‐methyl‐D‐aspartate antagonist ketamine in humans might be mediated by increased dopamine (DA) release and increased stimulation of DA D2 receptors in the striatum. The goal of the present study was to assess the effect of ketamine on D2 receptor availability in subregions of the striatum (dorsal caudate, DCA; dorsal putamen, DPU; ventral striatum, VST) in humans. Ten healthy subjects were studied twice. In a first group of five subjects, PET scanning was obtained twice for 90 min during bolus plus constant infusion of [11C]raclopride. No significant differences were observed in [11C]raclopride specific‐to‐nonspecific activity ratios (V ″3) measured during an early interval (30–50 min) and late interval (70–90 min), confirming that a state of sustained equilibrium had been established from 30–90 min (end of infusion). In a second group of five subjects, a similar experiment was performed twice, except that ketamine was administered beginning at 50 min (0.12 mg/kg i.v. bolus followed by 0.65 mg/kg/h i.v. infusion for 70 min). Raclopride V ″3 measured before ketamine (30–50‐min interval) was compared to [11C]raclopride V ″3 measured during ketamine infusion (70–90‐min interval). Ketamine induced a robust dissociative state. However, no significant differences were observed in D2 receptor availability measured before and during the ketamine infusion (n = 10) in any of the regions examined (DCA, DPU, and VST). These data fail to demonstrate an effect of ketamine on [11C]raclopride BP and are consistent with microdialysis studies in rodents and nonhuman primates which reported only small effects of acute NMDA receptor blockade on extracellular striatal DA concentration. Synapse 43:19–29, 2002. © 2002 Wiley‐Liss, Inc.