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Gambling disorder is an impairing condition confounded by psychiatric co-morbidity, particularly with substance use and anxiety disorders. Yet, our knowledge of the mechanisms that cause these disorders to coalesce remains limited. The Incentive Sensitization Theory suggests that sensitization of neural "wanting" pathways, which attribute incentive salience to rewards and their cues, is responsible for the excessive desire for drugs and cue-triggered craving. The resulting hyper-reactivity of the "wanting' system is believed to heavily influence compulsive drug use and relapse. Notably, evidence for sensitization of the mesolimbic dopamine pathway has been seen across gambling and substance use, as well as anxiety and stress-related pathology, with stress playing a major role in relapse. Together, this evidence highlights a phenomenon known as cross-sensitization, whereby sensitization to stress, drugs, or gambling behaviors enhance the sensitivity and dopaminergic response to any of those stimuli. Here, we review the literature on how cue attraction and reward uncertainty may underlie gambling pathology, and examine how this framework may advance our understanding of co-mordidity with substance-use disorders (e.g., alcohol, nicotine) and anxiety disorders. We argue that reward uncertainty, as seen in slot machines and games of chance, increases dopaminergic activity in the mesolimbic pathway and enhances the incentive value of reward cues. We propose that incentive sensitization by reward uncertainty may interact with and predispose individuals to drug abuse and stress, creating a mechanism through which co-mordidity of these disorders may emerge.

Background We recently reported that operant social choice–induced voluntary abstinence prevents incubation of methamphetamine craving. Here, we determined whether social choice–induced voluntary abstinence would prevent incubation of heroin craving. We also introduce a fully automatic social reward self-administration model that eliminates the intense workload and rat–human interaction of the original semiautomatic model. Methods In experiment 1, we trained male and female rats for social self-administration (6 days) and then for heroin self-administration (12 days). Next, we assessed relapse to heroin seeking after 1 and 15 abstinence days. Between tests, the rats underwent either forced or social choice–induced abstinence. In experiment 2, we developed a fully automatic social self-administration procedure by introducing a screen between the self-administration chamber and the social-peer chamber; the screen allows physical contact but prevents rats from crossing chambers. Next, we compared incubation of craving in rats with a history of standard (no-screen) or automatic (screen) social self-administration and social choice–induced abstinence. Results The time-dependent increase in heroin seeking after cessation of drug self-administration (incubation of craving) was lower after social choice–induced abstinence than after forced abstinence. There were no differences in social self-administration, social choice–induced abstinence, and incubation of craving in rats trained in the standard semiautomatic procedure versus the novel fully automatic procedure. Conclusions Our study demonstrates the protective effect of rewarding social interaction on heroin self-administration and incubation of heroin craving and introduces a fully automatic social self-administration and choice procedure to investigate the role of volitional social interaction in drug addiction and other psychiatric disorders.

Background Studies using continuous-access drug self-administration showed that cocaine seeking increases during abstinence (incubation of cocaine craving). Recently, studies using intermittent-access self-administration showed increased motivation to self-administer and seek cocaine. We examined whether intermittent cocaine self-administration would potentiate incubation of craving in male and female rats and examined the estrous cycle’s role in this incubation. Methods In experiment 1, male and female rats self-administered cocaine either continuously (8 hours/day) or intermittently (5 minutes ON, 25 minutes OFF × 16) for 12 days, followed by relapse tests after 2 or 29 days. In experiments 2 and 3, female rats self-administered cocaine intermittently for six, 12, or 18 sessions. In experiment 4, female rats self-administered cocaine continuously followed by relapse tests after 2 or 29 days. In experiments 3 and 4, the estrous cycle was measured using a vaginal smear test. Results Incubation of cocaine craving was observed in both sexes after either intermittent or continuous drug self-administration. Independent of access condition and abstinence day, cocaine seeking was higher in female rats than in male rats. In both sexes, cocaine seeking on both abstinence days was higher after intermittent drug access than after continuous drug access. In female rats, incubation of craving after either intermittent or continuous drug access was significantly higher during estrus than during non-estrus; for intermittent drug access, this effect was independent of the training duration. Conclusions In both sexes, intermittent cocaine access caused time-independent increases in drug seeking during abstinence. In female rats, the time-dependent increase in drug seeking (incubation) is critically dependent on the estrous cycle phase.

The flashing lights and celebratory sounds that dominate slot-machine gambling are believed to promote engagement and motivation to keep playing. However, these cues are often presented in the absence of reward, and previous research suggests that this reward uncertainty, which degrades their predictive value, also increases their incentive value. Here, we used autoshaping to tease apart the impact of reward uncertainty on the predictive and incentive value of a conditioned stimulus (CS) using serial cues. Each CS trial began with the presentation of a predictive CS1, followed by a CS2, holding primarily incentive value, because of its proximity to sucrose reward delivery, under Certain (100%-1) or Uncertain (50%-1- 2-3) reward conditions. Subsequently, we tested the impact of amphetamine and nicotine on cue attraction, and the ability of these cues to either serve as a conditioned reinforcer, or promote motivation for sucrose during a progressive ratio task. Finally, we measured anxiety behavior, and examined its interaction with each cue and uncertainty. Our results suggest that reward uncertainty increases attraction to the incentive CS2 and its ability to trigger motivation and reward-seeking. However, although the CS2 is largely ignored under Certain conditions, both CS1 and CS2 become conditioned reinforcers for both groups. Finally, amphetamine reduced the attraction of the CS1 for both groups but had no effect on the attraction of the CS2. These results suggest that reward uncertainty recruits and increases the incentive value of cues with limited predictive value and highlights the distinction between cue attraction, reward-seeking and conditioned reinforcer properties.