Dose-response and duration effects of acute administrations of cocaine and GBR12909 on dopamine synthesis and transporter in the conscious monkey brain: PET studies combined with microdialysis.
The dose-response and duration effects of acute administration of the dopamine transporter (DAT) blocker cocaine and GBR12909 on dopamine synthesis and transporter availability were evaluated in the brains of conscious monkeys using high-resolution positron emission tomography (PET) in combination with microdialysis. Rate of dopamine synthesis and DAT availability were evaluated using L-[beta-11C]DOPA and [11C]beta-CFT (WIN35,428), respectively. Administration of cocaine (0.5, 2 and 5 mg/kg) resulted in dose-dependent elevation of dopamine level in the striatal extracellular fluid (ECF) at 0.5 h after injection, and returned to the baseline level within 1.5 h post-injection. At 0.5 post-injection, cocaine reduced dopamine synthesis rate and DAT availability in a dose-dependent manner. The reduction of DAT availability by cocaine (2 mg/kg) returned to baseline level at 3 h post-injection and thereafter. Interestingly, dopamine synthesis rate was significantly higher at 3 h than baseline level and returned to baseline level 5.5 h post-injection. When GBR12909 (0.5, 2 and 5 mg/kg) was administered 0.5 h before tracer injection, dopamine synthesis rate and DAT availability were significantly decreased in a dose-dependent manner. These reductions induced by GBR12909 (2 mg/kg) lasted at least until 5.5 h post-injection. GBR12909 induced dose-dependent elevation of dopamine level in ECF, and the elevation lasted up to 7 h. The present results indicated that cocaine and GBR12909 affect dopamine synthesis rate and DAT availability in the striatum with difference time courses as measured by PET in the conscious monkey brains.
Tsukada
H
H
Central Research Laboratory, Hamamatsu Photonics, 5000 Hirakuchi, Hamakita, Japan. tsukuda@cr1.hpk.co.jp
Harada
N
N
Nishiyama
S
S
Ohba
H
H
Kakiuchi
T
T
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008253:Macaca mulatta / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D017551:Microdialysis; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014055:Tomography, Emission-Computed
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; C043425:vanoxerine; D003042:Cocaine; D004298:Dopamine