6-[18F]fluoro-L-DOPA-PET studies show partial reversibility of long-term effects of chronic amphetamine in monkeys.
The acute and long-term effects of chronic amphetamine administration on the striatal dopamine system in monkeys were assessed with 6-[18F]fluoro-L-DOPA (FDOPA) and positron emission tomography (PET). Vervet monkeys (Cerecopithecus aethiops) were administered amphetamine doses, i.m., that increased from 4 mg/kg/d to 18 mg/kg/d over a 10 day period. Post-amphetamine FDOPA-PET scans at 1-2, 3-4, and 6 week time points in individual subjects showed persistent decrements in dopamine synthesis capacity as reflected by FDOPA influx rate constant (Ki) values being approximately 30% that of pre-drug assessment. In other animals that were administered the same drug regimen, biochemical analysis of striatal regions at 1-2 weeks post-drug indicated that dopamine concentrations were decreased by approximately 95% throughout caudate and putamen regions, while the homovanillic acid/dopamine level ratio was increased 3-10-fold. Post-drug FDOPA-PET Ki values remained consistently low up to 6 weeks; however, at the 5-6 month time point, relative increases in FDOPA-Ki values (approximately 53% of pre-drug values) were observed for all subjects, indicative of partial recovery of striatal dopamine synthesis capacity. These results demonstrate that FDOPA-PET can reveal temporal activity changes within the striatal dopamine system of individual subjects. The apparent, partial reversibility of amphetamine's neurotoxic effects suggests a plasticity of dopaminergic function that may include regeneration of dopaminergic terminals and compensatory increases in residual dopamine synthesis rates. The persistence of the partial decrement in dopamine synthesis capacity, however, may indicate a long term component of amphetamine's toxic effects.
Melega
W P
WP
Department of Molecular and Medical Pharmacology, UCLA School of Medicine 90095-1735.
Quintana
J
J
Raleigh
M J
MJ
Stout
D B
DB
Yu
D C
DC
Lin
K P
KP
Huang
S C
SC
Phelps
M E
ME
D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D006719:Homovanillic Acid / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D014055:Tomography, Emission-Computed
D015259:Dopamine Agents; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D000661:Amphetamine; D004298:Dopamine; D006719:Homovanillic Acid