ABSTRACT
In previous studies, we reported that pretreatment with the antioxidant Tempol attenuated the development and expression of cocaine-induced psychomotor sensitization in rats and diminished cocaine-induced oxidative stress (OS) in the prefrontal cortex (PFC) and nucleus accumbens (NAc), suggesting a potential role for Tempol in interfering with cocaine-related psychomotor sensitization. The aim of the current study was to examine the role of Tempol in reward and reinforcement using the conditioned place preference (CPP) paradigm. We found that administration of Tempol during the conditioning session abolished the expression of cocaine-induced CPP. We also found that OS was significantly elevated following the establishment of CPP, and that cocaine-induced OS was significantly diminished by pretreatment with Tempol during conditioning. Furthermore, we found that repeated, but not single, administration of Tempol for seven days during withdrawal from CPP resulted in significant attenuation in the expression of CPP. Moreover, Tempol did not affect the expression of food reward. Taken together, these findings provide evidence for the involvement of Tempol in regulating cocaine rewarding properties without affecting natural rewards. Since Tempol was found to be effective in reducing OS and expression of CPP following withdrawal, it may be a potential treatment for cocaine addiction.
Subject(s)
Cocaine-Related Disorders/metabolism , Cocaine-Related Disorders/psychology , Cocaine/metabolism , Conditioning, Psychological , Cyclic N-Oxides/pharmacology , Oxidative Stress/drug effects , Reward , Animals , Cocaine/adverse effects , Cocaine-Related Disorders/therapy , Disease Models, Animal , Lipid Peroxidation , Male , Nitric Oxide/metabolism , Nitrites/metabolism , Prefrontal Cortex/metabolism , Prefrontal Cortex/physiopathology , Rats , Reinforcement, Psychology , Spin Labels , Treatment OutcomeABSTRACT
The association between cocaine administration and induction of oxidative stress in different brain regions suggests that oxidative damage is an important factor participating in cocaine disruption of normal central nervous system functions. In order to deal with this topic, brain penetrating exogenous antioxidants were suggested as a tool to prevent cocaine-induced oxidative damage and behavioral changes. Lately, we have shown that Tempol, a stable nitroxide radical reduced oxidative damage and attenuated the development and expression of cocaine psychomotor sensitization. To examine whether nitroxides, represented by Tempol, can exhibit protective effects against cocaine-induced cell death and to elucidate the molecular mechanism of cocaine-induced oxidative damage, we used the well established PC12 cell line model. The results showed that (1) cocaine induced cell death in a dose-dependent manner (2) and that it was reduced significantly by the stable nitroxide radical Tempol. Furthermore, (3) Tempol significantly inhibited oxidative damage induced by cocaine as reflected by mitochondrial superoxide radical and peroxide enhancement. Finally, (4) Tempol restored the total scavenging capacity which was reduced by cocaine in PC12 cells. Cumulatively, these results suggest that nitroxides such as Tempol can attenuate oxidative damage and cell death induced by cocaine and that PC12 cells can be used as an in vitro model to further investigate the precise molecular mechanism of these compounds.
Subject(s)
Biomimetic Materials/pharmacology , Cell Death/drug effects , Cocaine/toxicity , Cyclic N-Oxides/pharmacology , Free Radical Scavengers/pharmacology , Oxidative Stress/drug effects , Animals , Fluorescent Dyes/metabolism , Intracellular Space/drug effects , Intracellular Space/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , PC12 Cells , Rats , Spin Labels , Superoxide Dismutase/metabolism , Superoxides/metabolismABSTRACT
BACKGROUND: Heavy cocaine abusers are known to develop adverse skin manifestations, however, a possible mechanism for such damages has not yet been proposed. OBJECTIVE: The present study was designed to investigate whether a systemic cocaine administration affects skin characteristics by elucidating modifications of reactive oxygen species (ROS) production, antioxidant defense and iNOS and XO activity. METHODS: Two models were used: an in vivo rat model (male Sabra), in which skin specimens were taken 20 days after i.p. cocaine injection (15 mg/kg) and an in vitro model based on HaCaT cells representing human keratinocytes. RESULTS: Our findings clearly showed that cocaine promoted skin oxidation via the involvement of the enzymes inducible nitric oxide synthase (iNOS) and xanthine oxidase (XO). Cocaine administration significantly increased iNOS expression in rats' skin. It also decreased total scavenging capacity (TSC), as well as reduced glutathione (GSH) and ascorbic acid (AA). HaCaT cells treatment with a cocaine concentration of 2 mM for 24 h (as was chosen by dose-response experiments) markedly enhanced superoxide radicals and peroxides formation. It also decreased TSC and GSH levels. Addition of iNOS and XO inhibitors completely abolished these findings. This study indicates for the first time that systemic cocaine administration affects skin condition, even after a long period of withdrawal. CONCLUSION: Our study therefore, suggests additional metabolic outcomes of cocaine due to its ability to enhance oxidative stress in skin.
