Effects of Nicotine Exposure and Anxiety on Motivation for Gambling-like Cues

Introduction: More than half of disordered gamblers (60.4%) report comorbid tobacco dependence (compared to only 16.8% of the general population), suggesting a common mechanism for the pathology of these disorders. Furthermore, 41.3% of disordered gamblers report the diagnosis of an anxiety disorder (compared to only 10% of the general population), which is implicated as a risk factor for relapse, and is thought to promote the maintenance of maladaptive gambling and smoking behaviors. One of the most important characteristics common to all gambling games is the uncertainty associated with the probability of reward delivery and the magnitude of the reward. Evidence suggests that this uncertainty may powerfully enhance attraction to cues, such as the flashing lights and celebratory sounds of casino slot machines, and at times, may sensitize reward pathways in the brain. Nicotine is implicated in attention, particularly for cues. However, it is unknown how nicotine or anxiety might contribute to cue-attraction. Methods: In the present study, we investigate the effects of nicotine (0.3 mg/kg, s.c.) on the desire for cues associated with uncertain rewards in male and female Long-Evans rats. Rats received injections of either nicotine or saline 15-minutes prior to each conditioning session. In an autoshaping task, rats learned to associate lever and tone cues (CS) with the delivery of sucrose pellet rewards (UCS) on either a certain or uncertain reward contingency. Under certain reward conditions, each CS presentation was immediately followed by the delivery of a single sucrose pellet (100%-1). In contrast, under uncertain conditions, only half of all CS presentations were rewarded by a sucrose pellet, with the remaining half being unrewarded. When the CS presentation was followed by UCS delivery, the reward was either 1, 2 or 3 pellets (with equal probability) (50%-1-2-3), which resulted in the same total number of CS and UCS presentations as in the certain condition. Sign-tracking and goal-tracking behaviors were recorded as a measure of attraction to either the lever cue or the sucrose delivery dish. Subsequently, we tested the ability of gambling-like cues to serve as a conditioned reinforcer, and to promote motivation for the sucrose reward during a progressive ratio task. Finally, the Elevated Plus Maze was used to measure the effects of anxiety and its interaction with nicotine and uncertainty. Results: Here, we demonstrate differences in cue attraction and motivation for certain versus uncertain rewards in the presence of nicotine. For example, during the autoshaping task, nicotine enhanced attraction to CS cues for certain conditions, but not for uncertain ones. Conversely, in the progressive ratio task, nicotine enhanced motivation to obtain the reward in uncertain conditions, but not for certain conditions. Females, in particular, appear to be vulnerable to the combined effects of nicotine and reward uncertainty on motivation to obtain rewards. While not significant, anxiety appears to play a role in moderating attraction-related behaviors, as rats in the uncertain condition exhibited higher levels of anxiety compared to rats in the certain condition. Discussion: Understanding the effects of nicotine and uncertainty on cue-reactivity might provide insight into the comorbid relationship between pathological gambling and tobacco use. Here, nicotine increased attraction for cues associated with certain reward outcomes, and increased motivation to obtain rewards associated with uncertain outcomes. Since motivation to obtain rewards appears to be greater in females injected with nicotine, comorbidity rates may be sex specific rather than uniform across both sexes. Future studies should consider these sex-dependent effects when developing successful intervention programs for comorbid disordered gambling and tobacco behaviors. Additionally, the finding that uncertainty increases anxiety behavior suggests an interplay between anxiety and nicotine, which should be considered when treating patients with a comorbid anxiety diagnosis, GD diagnosis, and nicotine dependence. Since anxiety is a known contributor to the relapse and maintenance of maladaptive behaviors, it is crucial to understand its ability to promote attraction to uncertain rewards in the presence of nicotine.