Elsevier

Brain Research

Volume 766, Issues 1–2, 22 August 1997, Pages 113-120
Brain Research

Research report
Recovery of striatal dopamine function after acute amphetamine- and methamphetamine-induced neurotoxicity in the vervet monkey

https://doi.org/10.1016/S0006-8993(97)00548-9Get rights and content

Abstract

In six vervet monkeys, presynaptic striatal dopamine function was assessed longitudinally by [18F]fluoro-l-DOPA (FDOPA)–positron emission tomography (PET) after administration (2×2 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.

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

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