Nigrostriatal reduction of aromatic L-amino acid decarboxylase activity in MPTP-treated squirrel monkeys: in vivo and in vitro investigations.
Aromatic L-amino acid decarboxylase (AAAD) activity was examined in vivo with positron emission tomography (PET) using 6-[18F]fluoro-L-DOPA (FDOPA) in squirrel monkeys lesioned with graded doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In vitro biochemical determinations of AAAD activity in caudate, putamen, substantia nigra, and nucleus accumbens were performed in the same animals to establish a direct comparison of in vivo and in vitro measurements. In vivo and in vitro AAAD activities in caudate/ putamen were substantially reduced in animals treated with the highest dose of MPTP (2.0 mg/kg). The percent change in the striatal FDOPA uptake (K(i)) and decarboxylation rate constant (k3) values resulting from MPTP treatment showed highly significant correlations with in vitro-determined AAAD activities. However, decarboxylase rates within individual animals presented as approximately 10-fold difference between in vivo and in vitro values. Lower in vivo k3 measurements may be attributed to several possibilities, including transport restrictions limiting substrate availability to AAAD within the neuron. In addition, reductions in AAAD activity in the substantia nigra did not parallel reductions in AAAD activity within the striatum, supporting the notion of a nonlinear relationship between nigrostriatal cell degeneration and terminal losses. This work further explores the role of AAAD in Parkinson's disease, a more important factor than previously thought.
Yee
R E
RE
Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095-6948, USA.
Huang
S C
SC
Stout
D B
DB
Irwin
I
I
Shoghi-Jadid
K
K
Togaski
D M
DM
DeLanney
L E
LE
Langston
J W
JW
Satyamurthy
N
N
Farahani
K F
KF
Phelps
M E
ME
Barrio
J R
JR
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives; D015259:Dopamine Agents / Q000494:pharmacology*; D005260:Female; D008297:Male; D012453:Saimiri; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology*; D014055:Tomography, Emission-Computed
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D015259:Dopamine Agents; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D001142:Aromatic-L-Amino-Acid Decarboxylases