Elsevier

Brain Research

Volume 885, Issue 2, 8 December 2000, Pages 283-288
Brain Research

Research report
Increased striatal dopamine turnover following acute administration of rotenone to mice

https://doi.org/10.1016/S0006-8993(00)02960-7Get rights and content

Abstract

Because of the potential role of mitochondrial dysfunction in nigrostriatal degeneration in Parkinson’s disease, the effects of rotenone (an inhibitor of mitochondrial NADH dehydrogenase and a naturally occurring toxicant) on the levels of striatal dopamine (DA) and DA metabolites were evaluated after acute and subchronic administration to mice. Systemic acute treatment with relatively high doses of rotenone did not affect DA concentration, but caused a significant increase in both DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). DOPAC and HVA changes were measured at 1 day and were reversed within 1 week, paralleling the time course of rotenone-induced increase in striatal lactate levels. Subchronic administration with a relatively mild dose of rotenone did not significantly alter the striatal levels of DA and DOPAC, while it slightly reduced HVA concentration. No neurochemical signs of dopaminergic damage were seen when mice were co-exposed to rotenone and diethyldithiocarbamate, a compound known to enhance nigrostriatal injury caused by the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Also, rotenone did not cause additional injury to animals previously lesioned by MPTP. Taken together, data indicate that rotenone is not capable of causing overt dopaminergic toxicity under the testing paradigms used in this study. Rather, an increase in DA turnover, as indicated by a higher (DOPAC+HVA)/DA ratio, seems to be associated to rotenone-induced striatal energy impairment.

Introduction

The neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduce neurochemical and pathological features of human parkinsonism such as the reduction of striatal dopamine (DA) and the loss of dopaminergic cell bodies in the substantia nigra (SN) [3], [14], [17], [29]. Thus, studies on MPTP toxicity are likely to provide valuable insight into mechanisms of nigrostriatal degeneration in Parkinson’s disease (PD). Several lines of experimental evidence suggest that MPTP-induced cell death, mediated by its toxic 1-methyl-4-phenylpyridinium metabolite (MPP+), involves the inhibition of complex I activity of the mitochondrial respiratory chain [23], [24], [25], with consequent ATP depletion and a loss of mitochondrial transmembrane potential [3], [5], [12], [14], [16], [28]. Similar toxic events may play a role in neurodegeneration in PD since a decrease in complex I activity has been measured post mortem in both the SN and the striatum of PD patients as compared to control subjects [22], [27].

Findings with the MPTP model and in PD patients raise the possibility that the nigrostriatal system may be particularly vulnerable to an impairment of mitochondrial energy metabolism. Rotenone is a ‘classic’ inhibitor of mitochondrial complex I and could therefore be used to further evaluate the relationship between energy deficiency and dopaminergic injury. Furthermore, since rotenoid compounds are widely used as pesticides, studies with rotenone may provide clues on environmental exposures that could increase the risk for PD. Particularly intriguing is the possibility that chemical interactions may play a role in nigrostriatal degeneration. The fungicide diethyldithiocarbamate (DDC) has been shown to enhance dramatically MPTP-induced neurotoxicity [6], [13], [31]. However, whether DDC can also act synergistically with other compounds, including rotenoid derivatives, in damaging dopaminergic neurons is unknown. A limited number of studies has evaluated the effects of rotenone on dopaminergic neurons both in vitro and in vivo. Treatment of mesencephalic cultures and striatal synaptosomes with rotenone has been shown to cause neurotoxicity as measured by a decreased uptake of neurotransmitters [20], [21]. Interestingly, DA uptake was significantly more affected than the uptake of serotonin, GABA or noradrenaline, thus supporting the hypothesis of a selective vulnerability of dopaminergic cells. In the in vivo setting, Heikkila and colleagues have reported a substantial depletion of striatal DA and its metabolites after the stereotaxic injection of rotenone into the median forebrain bundle of rats [11]. More recently, histological, but not biochemical, evidence of selective tissue damage has been shown in the striatum and globus pallidus of rats treated for 7–9 days with high doses of rotenone as a continuous intravenous infusion [8]. However, the possibility that nigrostriatal injury may be induced by rotenone under less severe experimental conditions and different paradigms of administration remains to be further evaluated. In the present study, changes in DA levels and metabolism were determined in the mouse striatum following a single subcutaneous injection of various doses of rotenone (acute treatment). The effects of the toxicant were also evaluated after multiple systemic administrations of a relatively mild dose (subchronic treatment). Finally, mice were exposed to both rotenone and DDC to test the hypothesis that, similar to its effect with MPTP, DDC may promote or enhance dopaminergic damage by rotenone.

Section snippets

Chemicals

Rotenone and sodium diethyldithiocarbamate were purchased from Sigma (St. Louis, MO). MPTP (hydrochloride salt) was obtained from Research Biochemicals International BI (Natick, MA). All other reagents were of the highest purity available commercially.

Animals and treatments

Seven- to 8-week-old male C57BL/6 mice (20–25 g, from Simonsen Laboratories, Gilroy, CA) were maintained under a 13:11-h light/dark cycle in a temperature-controlled room with access to food and water ad libitum. All experiments were performed in

Results

When mice were killed 24 h after a single subcutaneous injection of either 5, 10 or 15 mg/kg rotenone, striatal dopamine levels were the same in controls as in rotenone-treated animals. However, rotenone caused a dose-dependent increase in striatal DOPAC and HVA concentrations (Fig. 1a). At 7 days, DA remained unchanged while the increase in DA metabolites seen at 24 h was reversed. In fact, DOPAC and HVA levels were slightly reduced in mice treated with 5 or 10 mg/kg rotenone as compared to

Discussion

In the present study, the effects of energy metabolism impairment on striatal dopaminergic terminals were assessed after exposure of mice to rotenone, a known inhibitor of mitochondrial complex I. Administration of relatively high doses of rotenone using an acute systemic model caused metabolic changes consistent with a shift from aerobic to anaerobic glucose utilization, as indicated by increased striatal lactate levels. These changes were present immediately after rotenone exposure at 1 day,

Acknowledgements

The authors are grateful to Drs R. Quirion and J.P. Bennett, Jr. for their constructive criticisms of an earlier version of the manuscript. This work was supported by the NIEHS Grant no. 1R03 ES 08627-01 (D.D.) and by a fellowship from the Fonds de la Recherche en Santé du Québec (C.T.).

References (31)

Cited by (119)

  • Neuroprotective effects of catechin and quercetin in experimental Parkinsonism through modulation of dopamine metabolism and expression of IL-1β, TNF-α, NF-κB, IκKB, and p53 genes in male Wistar rats

    2022, NeuroToxicology
    Citation Excerpt :

    Rats in groups 3–5 were post-treated with catechin (5, 10, and 20 mg/kg) after rotenone administration while groups 6–8 rats were post-treated with quercetin (5, 10, and 20 mg/kg) after rotenone administration. Administration of rotenone (1.5 mg/kg) (product number: R8875–1 G, purity: ≥ 95%, stored at room temperature, prepared freshly in corn oil for administration) was carried out subcutaneously for 10 days, followed by post-treatment with varying doses of catechin (product number: C1788–500MG, purity: ≥ 96%, stored at 4 °C, prepared freshly in corn oil for administration), and quercetin (product number: 337951-25G, purity: ≥ 95%; stored at room temperature, prepared freshly in corn oil for administration), for 3 days through the same route (Akinmoladun et al., 2018; Thiffault et al., 2000). Neurobehavioral evaluation of the animals was carried out 3 h after the last treatment while animals were sacrificed 24 h after the last treatment.

  • Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice

    2020, Neurobiology of Disease
    Citation Excerpt :

    Intriguingly, the significant decrease in dopamine is not accompanied by concomitant reductions in the dopamine catabolites DOPAC and HVA. Currently, we have not clarified the reason, but abnormal mitochondrial accumulations may induce a partially modified DA metabolism (Thiffault et al., 2000). Great progress has been made toward understanding the pathogenesis of familial PD, mainly due to the discovery of PINK1/Parkin-mediated mitophagy.

  • Co-administration of TiO<inf>2</inf>-nanowired DL-3-n-butylphthalide (DL-NBP) and mesenchymal stem cells enhanced neuroprotection in Parkinson's disease exacerbated by concussive head injury

    2020, Progress in Brain Research
    Citation Excerpt :

    In animal studies, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and herbicide rotenone model of PD cause selective neurodegeneration by diminishing the mitochondrial function (Betarbet et al., 2000, 2002; Fornai et al., 2005; Meredith and Rademacher, 2011; Prediger et al., 2011). Rotenone and MPTP are selective inhibitors of mitochondrial complex I (Betarbet et al., 2000; Fornai et al., 2005; Thiffault et al., 2000). Administration of MPTP triggers free radical production, increases O2 utilization, diminishes mitochondrial function, and lowers energy generation (Acuna-Castroviejo et al., 2007; Boengler et al., 2013; Halliwell, 2001; Mancuso et al., 2007; Obata, 2002).

View all citing articles on Scopus
View full text