NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans.
Previous brain imaging studies with [(11)C]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 D(2) receptors in the striatum. The goal of the present study was to assess the effect of ketamine on D(2) 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 [(11)C]raclopride. No significant differences were observed in [(11)C]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 [(11)C]raclopride V(")(3) measured during ketamine infusion (70-90-min interval). Ketamine induced a robust dissociative state. However, no significant differences were observed in D(2) 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 [(11)C]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.
Kegeles
Lawrence S
LS
Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY 10032, USA. lsk5@columbia.edu
Martinez
Diana
D
Kochan
Lisa D
LD
Hwang
Dah-Ren
DR
Huang
Yiyun
Y
Mawlawi
Osama
O
Suckow
R F
RF
Van Heertum
Ronald L
RL
Laruelle
Marc
M
D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics; D001519:Behavior / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000187:drug effects*; D009474:Neurons / Q000000981:diagnostic imaging / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000000981:diagnostic imaging / Q000187:drug effects; D020891:Raclopride / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014055:Tomography, Emission-Computed
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D020891:Raclopride; D007649:Ketamine; D004298:Dopamine