Age differences in phosphodiesterase type-IV and its functional response to dopamine D1 receptor modulation in the living brain: a PET study in conscious monkeys.
The present study demonstrated the age-related changes in the striatal dopamine D1 receptor binding and its related cAMP second-messenger system in the living brains of conscious young (6.4 +/- 1.8 years old) and aged (19.5 +/- 3.3 years old) monkeys (Macaca mulatta) using positron emission tomography (PET). For quantitative analysis of D1 receptors, [11C]SCH23390 was used and phosphodiesterase type-IV (PDE-IV) activity, as an index of cAMP system, was estimated by two scans with R- and S-[11C]rolipram. Significant age-related decreases in D1 receptor binding were observed in the striatum and frontal cortex. Analysis of uptake of R- and S-[11C]rolipram indicated age-related decreases in PDE-IV activity showing 22.0 and 25.2% decreases in the striatum and frontal cortex, respectively, while no significant changes were observed in the cerebellum. With systemic preadministration of the dopamine D1 receptor antagonist SCH23390 (0.2, 0.6, and 2 mg/kg), the PDE-IV activities in the striatum and frontal cortex were dose-dependently suppressed in both age groups. However, the degree of suppression by SCH23390 was more marked in young than in aged monkeys. These results demonstrate that the striatal cAMP second-messenger system activity as well as its functional response to dopamine D1 antagonist showed age-related impairment in the brain.
Harada
Norihiro
N
Central Research Laboratory, Hamamatsu Photonics K. K., Shizuoka 434-8601, Japan.
Nishiyama
Shingo
S
Ohba
Hiroyuki
H
Sato
Kengo
K
Kakiuchi
Takeharu
T
Tsukada
Hideo
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism* / Q000502:physiology; D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000502:physiology; D002250:Carbon Radioisotopes / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D018492:Dopamine Antagonists / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D008297:Male; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D014055:Tomography, Emission-Computed / Q000379:methods*
D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4