Tempol diminishes cocaine-induced oxidative damage and attenuates the development and expression of behavioral sensitization.
A variety of mechanisms has been suggested for cocaine toxicity, including the possibility that cocaine induces an increase in oxidative stress (OS) due to excessive oxidation of dopamine (e.g. dopamine quinine), or by redox cycling of cocaine oxidized metabolites. However, the association between oxidative status in the brain and cocaine induced-behavior is poorly understood. Therefore, we examined the ability of the unique antioxidant tempol to attenuate cocaine-induced oxidative damage and behavioral response. Acute cocaine treatment significantly elevated OS markers in prefrontal cortex (PFC) and nucleus accumbens (NAc) in rats, both in slices and following a single cocaine injection, which corresponded with a decrease in total antioxidant capacity (TAC). Tempol, at the optimal concentration we determined that was needed to observe an antioxidant non-toxic effect in vitro (1 mM) and in vivo (200 mg/kg), completely abolished the elevation of OS markers and prevented the reduction in TAC in these areas. Importantly, tempol injections, at a dose that does not affect the basal levels of locomotor activity, attenuated both the development and expression of cocaine-induced locomotor sensitization. Finally, in cocaine-sensitized animals, tempol prevented the elevation of OS markers in both PFC and NAc. Our findings suggest that oxidation of specific sites in the brain reward system by cocaine is accompanied with behavioral changes. Tempol has a neuro-protective effect against cocaine toxicity in these regions, and it may be beneficial in the treatment of cocaine addiction.
Numa
R
R
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel.
Kohen
R
R
Poltyrev
T
T
Yaka
R
R
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004347:Drug Interactions; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013113:Spin Labels; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; D003497:Cyclic N-Oxides; D018765:Dopamine Uptake Inhibitors; D009573:Nitrites; D017382:Reactive Oxygen Species; D013113:Spin Labels; D017392:Thiobarbituric Acid Reactive Substances; D008315:Malondialdehyde; D003042:Cocaine; C001803:tempol