Oxygen radicals diminish dopamine transporter function in rat striatum

doi:10.1016/S0014-2999(97)01175-8

European Journal of Pharmacology

Volume 334, Issue 1, 3 September 1997, Pages 111-114

https://doi.org/10.1016/S0014-2999(97)01175-8 Get rights and content

Abstract

Incubation of striatal synaptosomes with the oxygen radical generating enzyme, xanthine oxidase, decreased [ $^{3} H$ ]dopamine uptake: an effect attributable to a decreased V_max. Concurrent incubation with the superoxide radical scavenger, superoxide dismutase, abolished the xanthine oxidase-induced decrease. These results indicate that, like methamphetamine administration in vivo, reactive oxygen species diminish dopamine transporter function in vitro. The significance of these findings to mechanisms responsible for effects of methamphetamine is discussed.

Introduction

Administration of the amphetamine analog, methamphetamine, causes both oxygen radical formation (Kondo et al., 1994; Giovanni et al., 1995; Fleckenstein et al., 1997a) and a rapid and reversible decrease in dopamine transporter function (Fleckenstein et al., 1997b; Fleckenstein et al., 1997c). An association between these phenomena is suggested by findings that reactive oxygen species may alter the activity of a variety of aminergic transporters (Braughler, 1985; Debler et al., 1986; Volterra et al., 1994; Tarrant and Williams, 1995), including the dopamine transporter (Pögün et al., 1994; Berman et al., 1996). Because of its potential role in mediating methamphetamine-induced decreases in dopamine uptake, the purpose of this study was to characterize the effect of reactive oxygen species on dopamine transporter function. To elucidate the direct effect of oxygen radicals on dopamine transport, xanthine oxidase was used to generate reactive oxygen species as described previously (Braughler, 1985; Debler et al., 1986; Berman et al., 1996). The results reveal that oxygen radicals, like methamphetamine administration (Fleckenstein et al., 1997c), diminish dopamine transporter V_max. Consistent with a role in effecting methamphetamine-induced dopaminergic neuronal impairment (Hirata et al., 1996), superoxide radicals contribute to this decrease. The significance of these findings to the effects of methamphetamine, and for the physiological regulation of monoaminergic systems, is discussed.

Section snippets

Animals

Male Sprague–Dawley rats (200–300 g; Simonsen laboratories, Gilroy, CA) were maintained under conditions of controlled temperature and lighting, with food and water provided ad libitum. Rats were killed by decapitation. All procedures were conducted in accordance with approved national institutes of health guidelines.

Drugs and chemicals

(−)cocaine hydrochloride and (±)methamphetamine hydrochloride were supplied by the national institute on drug abuse (USA). Pargyline hydrochloride was supplied by Abbott

Results

Results presented in Fig. 1 demonstrate that [ $^{3} H$ ]dopamine uptake into striatal synaptosomes, prepared from rats decapitated 1 h after methamphetamine administration (15 mg/kg, s.c.), was decreased by 52% relative to saline controls. This effect is unrelated to residual levels of methamphetamine introduced by the in vivo treatment, as evidenced, in part, by the finding that methamphetamine concentrations in the synaptosomal preparations are less than 1% of the concentration required to decrease

Discussion

Previous studies have demonstrated that methamphetamine administration causes both oxygen radical formation in vivo (Kondo et al., 1994; Giovanni et al., 1995; Fleckenstein et al., 1997a), and a rapid and reversible decrease in dopamine transporter function (Fleckenstein et al., 1997b; Fleckenstein et al., 1997c). By demonstrating an oxygen radical-mediated impairment of dopamine transporters, this study demonstrates a possible association between these phenomena. Results reveal that

Acknowledgements

This research was supported by PHS grants DA00869, DA04222 and DA05780.

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View full text

Oxygen radicals diminish dopamine transporter function in rat striatum

Abstract

Introduction

Section snippets

Animals

Drugs and chemicals

Results

Discussion

Acknowledgements

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Eur. J. Pharmacol.

Modification of dopamine transporter function: Effect of reactive oxygen species and dopamine

J. Neurochem.

Selective dopamine transport inhibition by cocaine analogs

Neurorep.

Lipid peroxidation-induced inhibition of γ-aminobutyric acid uptake in rat brain synaptosomes: Protection by glucocorticoids

J. Neurochem.

Superoxide radical-mediated alteration of synaptosome membrane structure and high-affinity γ-[14C]aminobutyric acid uptake

J. Neurochem.

Superoxide radical-mediated alteration of synaptosome membrane structure and high-affinity γ-[ $^{14} C$ ]aminobutyric acid uptake