Research reportRecovery of striatal dopamine function after acute amphetamine- and methamphetamine-induced neurotoxicity in the vervet monkey
Introduction
Amphetamine (Amp)- and methamphetamine (MeAmp)-induced neurotoxic effects have been extensively characterized in the striatum. With the application of appropriate dosage protocols, a long-term loss of phenotypic markers has been consistently observed without an apparent cell loss in the substantia nigra. After administration of Amp or MeAmp, significant reductions of striatal dopamine integrity indices, e.g., tyrosine hydroxylase activities [9], dopamine concentrations [30]and transporter densities [4]have been measured in mice [33], rats [25]and monkeys [31]. Degeneration of axonal processes and terminals within the striatum has also been observed and attributed to nigrostriatal dopaminergic afferents, based on corresponding dopamine system biochemical deficits [26]. Although alterations in other striatal neurotransmitter systems have also been demonstrated (e.g. serotonin and norepinephrine), their low concentrations in striatum relative to that of dopamine make it unlikely that they contribute significantly to the observed morphological neurotoxicity.
As part of our series of longitudinal studies on the effects of amphetamines in primates, we previously used 6-[18F]fluoro-l-DOPA (FDOPA)–positron emission tomography (PET) studies in the vervet monkey to demonstrate that long-term striatal dopamine neurotoxicity resulted from daily administration of Amp (incremental increases from 4 to 18 mg/kg/day over 10 days). However, in contrast to the apparent irreversible effects observed in other monkey studies [39], our FDOPA–PET results at 6 months postdrug showed that a partial recovery of striatal dopamine function had occurred [21]. At 12 months, further improvement was observed and by 24 months, FDOPA uptake had returned to predrug values [17]. These results indicated that the adult primate brain had endogenous restorative mechanisms that were activated after an Amp-induced neurotoxicity.
Presently, human drug abuse patterns indicate that MeAmp rather than Amp is the drug of choice and it may be that MeAmp has a unique neurotoxicity profile in the primate striatal dopamine system. Accordingly, the present studies were designed to determine whether Amp and MeAmp were of different neurotoxic potency in the vervet monkey. Rather than use the previous high-dosage, chronic (10 days) drug protocol, we designed an acute protocol with lower dosage (2×2 mg/kg, 4 h apart) that might better allow for the actions of the two drugs to be differentiated. Although complete Amp and MeAmp dose–response studies were not conducted, preliminary results with this lower dosage had indicated that striatal neurotoxicity occurred, but was of shorter duration. Accordingly, after drug administration, multiple FDOPA–PET studies were conducted at 1–2, 3–6 and 10–12 weeks to determine the magnitude and duration of the striatal deficits. In the striatum and substantia nigra, dopamine and homovanillic concentrations were also determined to establish whether these measures could be correlated to the FDOPA–PET assessment of a compromised striatal dopamine system.
Section snippets
Housing and feeding
Six, adult male vervet monkeys (Cercopithecus aethiops sabaeus), age 5–11 years, and weight 6–8 kg, were used for this study. Except for routine veterinary care, subjects were drug-free prior to the onset of the current study and lived as members of species-typical social groups. Subjects were fed isoniazid-free commercial monkey chow and water ad libitum. They received fresh fruit twice weekly. Referent subjects were also adult males and were similarly maintained.
Drug administration
During drug administration,
Results
After administration of either Amp or MeAmp, multiple postdrug PET studies were obtained. One subject's pre- and post-Amp FDOPA Ki parametric images are shown in Fig. 1. Each reported FDOPA Ki value represents the average of left and right striatal activities obtained from the plane that contained the highest activity. FDOPA Ki values were decreased by 64% at 1 week, by 39% at 8 weeks and by 16% at 32 weeks post-Amp.
The summary for each subject's drug treatment and FDOPA–PET study time points
Discussion
Non-invasive in-vivo PET methods and concepts [37]provide the framework for the elucidation and interpretation of the Amp- and MeAmp-induced changes revealed in these longitudinal FDOPA studies. In particular, the FDOPA–PET index is based both on the biochemical characteristics of FDOPA and its tracer kinetic model [1]. Analogous to l-DOPA, FDOPA enters into the striatal dopamine synthesis pathway via aromatic amino acid decarboxylase (AAAD) facilitated conversion to [18F]fluorodopamine (FDA).
Acknowledgements
The authors thank Dr. Satyamurthy and his cyclotron staff for synthesis of FDOPA; Dr. Michael McGuire, Deborah Pollack, Grenvill Morton, Jill Cullen, and Brain Stauffer of the Sepulveda VAMC Research Service-Nonhuman Primate Research Laboratory for supervision of monkey care; Dr. Waldemar Ladno and Judy Edwards of the UCLA Animal PET center for expert technical assistance with the PET studies. This research was supported in part by US Department of Energy (DOE) DE-FC03-87ER60615 and by the
References (41)
Monoamine metabolites: their relationship and lack of relationship to monoaminergic neuronal activity
Biochem. Pharmacol.
(1985)- et al.
MPTP-induced parkinsonism: relative changes in dopamine concentration in subregions of substantia nigra, ventral tegmental area, and retrorubral field of symptomatic and asymptomatic vervet monkeys
Brain Res.
(1990) - et al.
Effect of acute and chronic methamphetamine treatment on tyrosine hydroxylase activity in brain and adrenal medulla
Eur. J. Pharmacol.
(1971) - et al.
Injury of nigral neurons exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: a tyrosine hydroxylase immunocytochemical study in monkey
Neuroscience
(1986) - et al.
Longitudinal behavioral and 6-[18F]Fluoro-l-DOPA–PET assessment in MPTP-hemiparkinsonian monkeys
Exp. Neurol.
(1996) - et al.
Ethological and 6-[18F]Fluoro-l-DOPA–PET profiles of long term vulnerability to chronic amphetamine
Behav. Brain Res.
(1997) - et al.
6-[18F]fluoro-l-dopa metabolism in MPTP-treated monkeys: assessment of tracer methodologies for positron emission tomography
Brain Res.
(1991) - et al.
Comparative in vivo metabolism of 6-[18F]fluoro-l-dopa and [3H]l-dopa in rats
Biochem. Pharmacol.
(1990) - et al.
Dopamine nerve terminal degeneration produced by high doses of methylamphetamine in the rat brain
Brain Res.
(1982) - et al.
Further evidence that amphetamines produce long-lasting dopamine neurochemical deficits by destroying dopamine nerve fibers
Brain Res.
(1984)