Effects of antioxidants on nicotine recognition in rats

According to the CDC, nicotine addiction accounts for over 7 million deaths a year worldwide, twice that of narcotics and alcohol combined (11). Most adults need 30 attempts to quit smoking for a year or longer, and this is likely an underestimate (1). The addictive properties of nicotine are thought to involve activation by acetylcholine of brain reward pathways of the Ventral tegmental area and nucleus accumbens (see Figure 1) (8). Drugs like bupropion and varenicline target monoamine and cholinergic nicotinic receptor mechanisms involved in these pathways and have been approved to treat nicotine addiction, although their success has been limited (19). Because of this, novel approaches of treating nicotine addiction are necessary. The goal of current studies will be to evaluate redox signals as a target for development of new interventional approaches to smoking cessation. A variety of approaches have been used to treat addiction. The nicotine patch is an example of a substitution approach for which the goal of treatment is to maintain a sustained low level of the addicting substance for the purpose of reducing craving for the drug (12). Varenicline and bupropion also represent examples of substitution-based approaches targeting a reduction of craving (18). A second approach which could be characterized as an antagonist approach involves preventing activation of neural systems involved in the addicting process (6). The following is a proposal to test blockers of redox signaling as potential treatment medications for addiction using the antagonist approach.In the current study, we will evaluate the hypothesis that redox signaling-related effects on neurotransmission participate in the subjective effects of nicotine using a drug discrimination paradigm. In this paradigm, rat subjects learn to recognize the effects of a drug and report its presence or absence using behavioral responses emitted to obtain food reward or avoid aversive stimuli (17). If the hypothesis is correct, then interference with redox signals should fully or partially block the nicotine discriminate stimulus effects. Vitamin C, vitamin E, apocynin, and FSNY-1 were chosen as potential antagonists for this study to evaluate multiple sources and targets of reactive oxygen species (ROS). Vitamin C is a cytosolic antioxidant, vitamin E is a membrane antioxidant, apocynin is a NADPH oxidase inhibitor, and FSNY-1 is thought to inhibit hydrogen peroxide and hydroxide radical. As positive controls, the proposed studies will evaluate the nonselective NN receptor antagonist mecamylamine for the ability to antagonize nicotine discrimination (see preliminary data in subsequent sections). The NN receptor antagonist hexamethonium will also be included as a negative control for mecamylamine, because it has same mechanism of action but does not cross the blood brain barrier. It is expected that mecamylamine, but not hexamethonium, will block the discriminative stimulus produced by nicotine.