Research Article Selective Nitric Oxide Synthase Inhibitor 7-Nitroindazole Protects against Cocaine-Induced Oxidative Stress in Rat Brain Vessela Vitcheva, Rumyana Simeonova, Magdalena Kondeva-Burdina, and Mitka Mitcheva Laboratory of “Drug Metabolism and Drug Toxicity”, Department of “Pharmacology, Pharmacotherapy and Toxicology”, Faculty of Pharmacy, Medical University of Sofa, 2 “Dunav” Street, 1000 Sofa, Bulgaria Correspondence should be addressed to Vessela Vitcheva; vesselavitcheva@yahoo.com Received 30 December 2014; Revised 24 March 2015; Accepted 26 March 2015 Academic Editor: Joern Steinert Copyright © 2015 Vessela Vitcheva et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. One of the mechanisms involved in the development of addiction, as well as in brain toxicity, is the oxidative stress. Te aim of the current study was to investigate the efects of 7-nitroindazole (7-NI), a selective inhibitor of neuronal nitric oxide synthase (nNOS), on cocaine withdrawal and neurotoxicity in male Wistar rats. Te animals were divided into four groups: control; group treated with cocaine (15 mg/kg −1 , i.p., 7 days); group treated with 7-NI (25mg/kg −1 , i.p., 7 days); and a combination group (7- NI + cocaine). Cocaine repeated treatment resulted in development of physical dependence, judged by withdrawal symptoms (decreased locomotion, increased salivation and breathing rate), accompanied by an increased nNOS activity and oxidative stress. Te latter was discerned by an increased formation of malondialdehyde (MDA), depletion of reduced glutathione (GSH) levels, and impairment of the enzymatic antioxidant defense system measured in whole brain. In synaptosomes, isolated from cocaine- treated rats, mitochondrial activity and GSH levels were also decreased. 7-NI administered along with cocaine not only attenuated the withdrawal, due to its nNOS inhibition, but also reversed both the GSH levels and antioxidant enzyme activities near control levels. 1. Introduction Cocaine is a potent psychostimulant, recognized as one of the most signifcant examples of drug abuse due to intense feeling of euphoria and increased concentration and energy. Te psychostimulant efects of cocaine appear to be mediated by its ability to enhance the dopaminergic activity in the mesocorticolimbic circuit through binding to the dopamine, serotonin, and noradrenalin transport proteins and directly prevent their reuptake into presynaptic neurons [1]. Te repeat intake of cocaine is related to tolerance and development of dependence and serious injuries of the central nervous system, heart, and liver. One of the metabolic pathways of cocaine, N-oxidation mediated by cytochrome P 450 enzymes and favin adenine (FAD) containing monooxy- genases, leads to production of reactive oxygen species (ROS), namely, nitroxide, nitrosonium, and iminium ions, which have been recognized to be involved in cocaine- induced organ toxicity [2]. Increased reactive oxygen species production in the central nervous system has been identifed to play a pivotal role in the neuropathology induced by drugs of abuse, including cocaine [3]. Oxidative stress may occur during or afer drug exposure and/or during the withdrawal from the drug [4]. Not only has the role of nitric oxide and related N-methyl-D-aspartate (NO/NMDA) cascade been discussed in the process of development of tolerance and withdrawal from diferent drugs of abuse [5] but also it is considered an important source of oxidative stress, induced by psychostimulants [6]. Although nitric oxide (NO) plays an important physiological role as a neurotransmitter in the central nervous system (CNS), excessive neuronal nitric oxide synthase- (nNOS-) dependent NO release during high levels of NMDA receptor stimulation results in production of hydroxyl (HO ∙ ) and peroxynitrite (ONOO − ) radicals that are responsible for oxidative injury [7]. 7-Nitroindazole (7-NI) is a heterocyclic compound, which inhibits nNOS by competing with both L-arginine and tetrahydrobiopterin [8] and has been used extensively as Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2015, Article ID 157876, 8 pages http://dx.doi.org/10.1155/2015/157876