Acute or repeated cocaine administration generates reactive oxygen species and induces antioxidant enzyme activity in dopaminergic rat brain structures
Introduction
Cocaine and methamphetamine (METH) are psychostimulants abused by man, that eventually lead to drug dependence. They both increase extracellular level of the monoamines dopamine, serotonin and noradrenaline, although by distinct mechanisms. Cocaine binds with high affinity to transporter sites for the monoamines and inhibits monoamine uptake into presynaptic neurons (Ritz et al., 1990, Ross and Renyi, 1969). METH induces the release of even greater amounts of the monoamines from vesicles to the cytoplasm and extracellular space. Increase in neurotransmitter concentrations in the synaptic cleft subsequently results in the over-stimulation of the corresponding receptors. METH administration to rodents has been shown to provoke significant neurotoxicity in vitro (Cubells et al., 1994) and in vivo (Cadet et al., 2003, Fumagalli et al., 1999). Neurotoxicity of amphetamines is thought to result essentially from reactive oxygen species (ROS) that are formed by the oxidation of dopamine. Toxicity involves dopaminergic nerve terminal degeneration, as assessed by reductions in dopamine, dopamine transporter and tyrosine hydroxylase, and is accompanied by reactive gliosis. However, little information on the effect of cocaine on ROS production and neurotoxicity in the brain is currently available.
In order to identify the molecular events underlying neuro-adaptations occurring in rat cingulate cortex in response to cocaine administration, we recently searched for genes, the expression of which is modified in this dopaminergic projection area by this drug. Using the differential display technique, we found that acute administration of cocaine down-regulated several transcripts encoded by the mitochondrial genome, including NADH dehydrogenase subunits and cytochrome c oxidase subunits (Dietrich et al., 2004). Given the well documented role of mitochondria in ROS formation, this mitochondria dysfunction we characterized prompted us to study the effect of cocaine on the expression of ROS in dopaminergic rat brain structures. The study was conducted after both single and repeated cocaine administration. We also investigated whether cocaine induced neuronal apoptosis, as has been described for METH. Furthermore, we measured the effect of cocaine on the activity of antioxidant enzymes such as glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), and also on the activity of the proteasome.
Section snippets
Animals
Male Wistar rats (250–300 g) were housed with a fixed 12-h light–dark cycle and free access to food and water. All experiments were conducted in conformity with the European Community Council guidelines. Rats were injected intraperitoneally (i.p.) with either 20 mg/kg cocaine hydrochloride (Sigma, St Louis, MO) or an equivalent volume of saline (NaCl 0.9%). For chronic treatment, rats were injected with the same dose for 10 days (1 injection/day). d-amphetamine (5 mg/kg) was administered i.p. for 3
Cocaine reduces mitochondrial ND4 gene expression
Using the differential display technique, we previously showed that several transcripts encoded by the mitochondrial genome were down-regulated in rat cingulate cortex following a single cocaine administration (Dietrich et al., 2004). Table 1 shows a real-time PCR quantification of NADH dehydrogenase subunit 4 (ND4) in frontal cortex 15 h after an acute cocaine injection. ND4 mRNA level was found to be reduced by 44% in response to cocaine administration, thus confirming that this mitochondrial
Discussion
We report here that administration of cocaine to rats was found to increase the formation of hydrogen peroxide in mitochondria prepared from frontal cortex. Either acute or repeated injection of cocaine was also found to increase hydroperoxide and lipid peroxide production in frontal cortex and striatum, two brain structures that contain numerous dopaminergic nerve terminals. It is well known that the mitochondrial respiratory chain produces ROS as by-products of normal respiration (Boveris et
Acknowledgements
We thank Dr. L. Caumont for help with immunohistological techniques, and Dr. K. Langley for critical reading of the manuscript.
References (34)
- et al.
Methamphetamine causes lipid peroxidation and an increase in superoxide dismutase activity in the rat striatum
Brain Research
(1998) - et al.
Mitochondrial phospholipid hydroperoxide glutathione peroxidase plays a major role in preventing oxidative injury to cells
Journal of Biological Chemistry
(1999) - et al.
Import into mitochondria of phospholipid hydroperoxide glutathione peroxidase requires a leader sequence
Biochemical and Biophysical Research Communications
(1996) - et al.
Assaying for superoxide dismutase activity: some large consequences of minor changes in conditions
Analytical Biochemistry
(1987) - et al.
Methamphetamine induces apoptosis in an immortalized rat striatal cell line by activating the mitochondrial cell death pathway
Neuropharmacology
(2002) - et al.
Methamphetamine causes widespread apoptosis in the mouse brain: evidence from using an improved TUNEL histochemical method
Molecular Brain Research
(2001) - et al.
Co-involvement of mitochondria and endoplasmic reticulum in regulation of apoptosis: changes in cytochrome c, Bcl-2 and Bax in the hippocampus of aluminum-treated rabbits
Brain Research
(2001) - et al.
The Fenton reagents
Free Radicals in Biology and Medicine
(1993) - et al.
Long-term effects of repeated methylamphetamine administration on monoamine neurons in the rhesus monkey brain
Brain Research
(1985) - et al.
Mitochondria, oxygen free radicals, disease and ageing
Trends in Biochemical Sciences
(2000)
Inhibition of the uptake of tritiated 5-hydroxytryptamine in brain tissue
European Journal of Pharmacology
Ubiquitin conjugation is not required for the degradation of oxidized proteins by proteasome
Journal of Biological Chemistry
Isolation of subcellular organelles
Methods in Enzymology
The cellular production of hydrogen peroxide
Biochemical Journal
Speed kills: cellular and molecular bases of methamphetamine-induced nerve terminal degeneration and neuronal apoptosis
The FASEB Journal
Methamphetamine neurotoxicity involves vacuolation of endocytic organelles and dopamine-dependent intracellular oxidative stress
Journal of Neuroscience
Cocaine down-regulates the expression of the mitochondrial genome in rat brain
Annals of the New York Academy of Sciences
Cited by (144)
The ubiquitin-proteasome system and learning-dependent synaptic plasticity – A 10 year update
2023, Neuroscience and Biobehavioral ReviewsLithium engages autophagy for neuroprotection and neuroplasticity: Translational evidence for therapy
2023, Neuroscience and Biobehavioral ReviewsMechanism of drug-induced neurotoxicity and its management
2023, Essentials of Pharmatoxicology in Drug Research: Toxicity and Toxicodynamics: Volume 1Evidence of methylphenidate effect on mitochondria, redox homeostasis, and inflammatory aspects: Insights from animal studies
2022, Progress in Neuro-Psychopharmacology and Biological PsychiatryCYP3A1 metabolism-based neurotoxicity of strychnine in rat
2022, Toxicology