Recovery of striatal dopamine function after acute amphetamine- and methamphetamine-induced neurotoxicity in the vervet monkey.
In six vervet monkeys, presynaptic striatal dopamine function was assessed longitudinally by [18F]fluoro-L-DOPA (FDOPA)-positron emission tomography (PET) after administration (2 x 2 mg/kg, i.m., 4 h apart) of either amphetamine (Amp), n = 3, or methamphetamine (MeAmp), n = 3. At 1-2 weeks postdrug, both Amp and MeAmp exposure effected similar decreases (60-70%) in the FDOPA influx rate constant (FDOPA Ki), an index of striatal dopamine synthesis capacity. Subsequent studies in these subjects showed that FDOPA Ki values were decreased by 45-67% at 3-6 weeks, by 25% at 10-12 weeks and by 16% in one Amp-treated subject at 32 weeks. Biochemical analysis showed that striatal dopamine concentrations were decreased by 75% at 3-4 weeks and by 55% at 10-12 weeks. These results indicate that in vervet monkey striatum, an acute Amp or MeAmp drug dosage produces extensive striatal dopamine system neurotoxicity. However, these effects were reversible; observed time-dependent recovery in both FDOPA Ki and dopamine concentrations indicates that neurochemical plasticity remains active in the adult primate striatum. At 3-4 and 10-12 weeks postdrug, the concurrent characterization of the striatal FDOPA Ki and dopamine concentrations for individual subjects showed that Ki decreases between 24 and 67% corresponded to dopamine depletions of 55-85%. These relatively larger postdrug decrements in steady-state striatal dopamine concentrations suggest that compensatory increases in dopamine synthesis capacity develop in the partially lesioned striatum. In contrast to the dopamine depletion in striatum, substantia nigra concentrations remained unchanged from referent values at both 3-4 and 10-12 weeks postdrug. Thus, the integrity of the substantia nigra could not be inferred from decreases in the striatal FDOPA Ki parameter. This disparity between striatum and substantia nigra reactivity to systemic administration of amphetamines suggests that each has unique dopamine system regulatory mechanisms.
Melega
W P
WP
Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095-1735, USA. bmelega@v401.nuc.ucla.edu
Raleigh
M J
MJ
Stout
D B
DB
Lacan
G
G
Huang
S C
SC
Phelps
M E
ME
D000208:Acute Disease; D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D002522:Chlorocebus aethiops; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D015259:Dopamine Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006719:Homovanillic Acid / Q000032:analysis / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity; D013378:Substantia Nigra / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D014055:Tomography, Emission-Computed
D015259:Dopamine Agents; D009498:Neurotoxins; D008694:Methamphetamine; D000661:Amphetamine; D004298:Dopamine; D006719:Homovanillic Acid