Ketamine decreased striatal [(11)C]raclopride binding with no alterations in static dopamine concentrations in the striatal extracellular fluid in the monkey brain: multiparametric PET studies combined with microdialysis analysis.
The effects of ketamine, a noncompetitive antagonist of NMDA receptors, on the striatal dopaminergic system were evaluated multiparametrically in the monkey brain using high-resolution positron emission tomography (PET) in combination with microdialysis. L-[beta-(11)C]DOPA, [(11)C]raclopride, and [(11)C]beta-CFT were used to evaluate dopamine synthesis rate, D(2) receptor binding, and transporter availability, respectively, in conscious and ketamine-anesthetized animals. Dopamine concentrations in the striatal extracellular fluid (ECF) were simultaneously measured by PET. Thirty minutes prior to PET scan, intravenous administration of ketamine was started by continuous infusion at a rate of 3 or 10 mg/kg/h. Ketamine infusion dose-dependently decreased [(11)C]raclopride binding, but induced no significant changes in dopamine concentration in the striatal ECF as measured by microdialysis at any dose used. In contrast, ketamine increased both dopamine synthesis and DAT availability as measured by L-[beta-(11)C]DOPA and [(11)C]beta-CFT, respectively, in a dose-dependent manner. These results suggest that the inhibition of glutamatergic neuronal activity modulates dopamine turnover in the striatum by simultaneous enhancement of the dynamics of dopamine synthesis and DAT availability to the same extent, resulting in no apparent changes in ECF dopamine concentration as measured by microdialysis. It also suggests that the alteration of [(11)C]raclopride binding in vivo as measured by PET might not simply be modulated by the static synaptic concentration of dopamine.
Tsukada
H
H
Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan. tsukada@crl.hpk.co.jp
Harada
N
N
Nishiyama
S
S
Ohba
H
H
Sato
K
K
Fukumoto
D
D
Kakiuchi
T
T
D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism*; D015259:Dopamine Agents / Q000378:metabolism; D018492:Dopamine Antagonists / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology*; D007980:Levodopa / Q000378:metabolism; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D017551:Microdialysis; D009419:Nerve Tissue Proteins; D009994:Osmolar Concentration; D020891:Raclopride / Q000378:metabolism*; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D020891:Raclopride; D007980:Levodopa; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D007649:Ketamine; D003042:Cocaine; D004298:Dopamine