Age-related changes in the striatal dopaminergic system in the living brain: a multiparametric PET study in conscious monkeys.
In the present study, age-related changes in the striatal dopaminergic system were examined in the living brains of conscious young (6.2 +/- 1.5 years old) and aged (20.2 +/- 2.6 years old) monkeys (Macaca mulatta) using positron emission tomography (PET). L-[beta-(11)C]DOPA and [(11)C]beta-CFT were applied to determine dopamine presynaptic functions such as synthesis rate and transporter (DAT) availability, respectively. Striatal dopamine D(1)- (D(1)R) and D(2)-like receptor (D(2)R) binding were measured with [(11)C]SCH23390 and [(11)C]raclopride, respectively. Although the markers of presynaptic terminals showed parallel age-related declines, the reduction of dopamine synthesis rate measured with L-[beta-(11)C]DOPA was slightly smaller than that of DAT determined with [(11)C]beta-CFT. The binding of [(11)C]raclopride to D(2)R in vivo was significantly reduced with aging, while that of [(11)C]SCH23390 to D(1)R showed no such marked age-related reduction. When the DAT inhibitor GBR12909 (0.5 and 5 mg/kg) was administered, DAT availability, dopamine synthesis, and D(2)R binding were significantly decreased in a dose-dependent manner in both age groups; however, the degrees of the decreases in these parameters were significantly higher in young rather than in aged animals. Dopamine concentration in the striatal extracellular fluid (ECF), as measured by microdialysis, was increased by administration of GBR12909 in a dose-dependent manner and the degree of the increase in dopamine level decreased with age. These results demonstrate that age-related changes of dopamine neuronal functions were not limited to the resting condition but were also seen in the functional responses to the neurotransmitter modulation.
Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka 434-8601, Japan.
Norihiro
N
Harada
Shingo
S
Nishiyama
Kengo
K
Satoh
Dai
D
Fukumoto
Takeharu
T
Kakiuchi
Hideo
H
Tsukada
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000493:pharmacokinetics; D003042:Cocaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D007980:Levodopa / Q000493:pharmacokinetics; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D017551:Microdialysis; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D020891:Raclopride / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed
D001552:Benzazepines; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D020891:Raclopride; D007980:Levodopa; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; C043425:vanoxerine; D003042:Cocaine; D004298:Dopamine