Prior Exposure to Salient Win-Paired Cues in a Rat Gambling Task Increases Sensitivity to Cocaine Self-Administration and Suppresses Dopamine Efflux in Nucleus Accumbens: Support for the Reward Deficiency Hypothesis of Addiction

Abstract

Rats trained to perform a version of the rat gambling task (rGT) in which salient audiovisual cues accompany reward delivery, similar to commercial gambling products, show greater preference for risky options. Given previous demonstrations that probabilistic reinforcement schedules can enhance psychostimulant-induced increases in accumbal DA and locomotor activity, we theorized that performing this cued task could perpetuate a proaddiction phenotype. Significantly more rats developed a preference for the risky options in the cued versus uncued rGT at baseline, and this bias was further exacerbated by cocaine self-administration, whereas the choice pattern of optimal decision-makers was unaffected. The addition of reward-paired cues therefore increased the proportion of rats exhibiting a maladaptive cognitive response to cocaine self-administration. Risky choice was not associated with responding for conditioned reinforcement or a marker of goal/sign-tracking, suggesting that reward-concurrent cues precipitate maladaptive choice via a unique mechanism unrelated to simple approach toward, or responding for, conditioned stimuli. Although "protected" from any resulting decision-making impairment, optimal decision-makers trained on the cued rGT nevertheless self-administered more cocaine than those trained on the uncued task. Collectively, these data suggest that repeated engagement with heavily cued probabilistic reward schedules can drive addiction vulnerability through multiple behavioral mechanisms. Rats trained on the cued rGT also exhibited blunted locomotor sensitization and lower basal accumbal DA levels, yet greater cocaine-induced increases in accumbal DA efflux. Gambling in the presence of salient cues may therefore result in an adaptive downregulation of the mesolimbic DA system, rendering individuals more sensitive to the deleterious effects of taking cocaine. Impaired cost/benefit decision making, exemplified by preference for the risky, disadvantageous options on the Iowa Gambling Task, is associatedwithgreaterriskofrelapseandtreatmentfailureinsubstanceusedisorder.Understandingfactorsthatenhancepreferencefor risk may help elucidate the neurobiological mechanisms underlying maladaptive decision making in addiction, thereby improving treatment outcomes. Problem gambling is also highly comorbid with substance use disorder, and many commercial gambling products incorporate salient win-paired cues. Here we show that adding reward-concurrent cues to a rat analog of the IGT precipitates a hypodopaminergic state, characterized by blunted accumbal DA efflux and attenuated locomotor sensitization, which may contribute to the enhanced responsivity to uncertain rewards or the reinforcing effects of cocaine we observed.

Dopamine neurons gate the intersection of cocaine use, decision making, and impulsivity

“…It is therefore difficult to draw a link between indicators of motor slowing and decreases in motor impulsivity or risky decisionmaking patterns, as the former are clearly present in female rats without the latter. In concordance with our initial hypothesis, we demonstrated a critical role for VTA dopamine neurons in cocaine-induced deficits in decision making (9). Specifically, we showed that self-administration of cocaine within the same diurnal period no longer resulted in an increase in risky choice when VTA dopamine neurons were inhibited during the crGT test session, even though rats were still self-administering ample cocaine.…”

“…Specifically, we aseptically implanted catheters constructed of Silastic silicone tubing (Dow Corning via VWR International, Edmonton, AB, Canada), attached to back-mounted cannulae (Plastics One, Roanoke, VA, USA), into the right jugular vein as per our previous published methods (9). We passed the catheters through the skin subcutaneously and externalized the cannulae between the scapulae.…”

“…Much like in real-world casinos, and in experimental gambling tasks for humans (6,7), adding casino-inspired sound and light cues to wins in the rGT causes more rats to choose the risky options (8). The addition of these casino-like cues to the rGT also enhances the ability of volitionally self-administered cocaine to sway choice toward the risky options (9). Moreover, rats trained in the cued rGT appear more motivated to take cocaine in general.…”

“…As such, the ability of rewardconcurrent cues to promote cocaine use and problem gambling may be underpinned by similar neurobiological mechanisms, partly explaining why GD and SUD are highly comorbid. Animals that learned the cued rGT (in which risk taking is more prevalent) also exhibited lower levels of tonic dopamine in the nucleus accumbens (NAc) at the end of training (9). Similarly, repeated administration of cocaine reduces tonic NAc dopamine levels, as well as phasic NAc dopamine responses to cues and cocaine (10)(11)(12)(13).…”

Relative insensitivity to time-out punishments induced by win-paired cues in a rat gambling task

“…Risky decision making is also predictive of greater severity and poor treatment response in substance use disorder (Bechara et al, 2001;Gonzalez et al, 2015;Stevens et al, 2013Stevens et al, , 2015. Basal extracellular dopamine levels are lower on average in the nucleus accumbens of rats trained on the cued rGT, as compared to those trained in the absence of win-paired cues, in addition to exhibiting either enhanced risky decision making following cocaine self-administration, or greater levels of cocaine intake (Ferland et al, 2019). Understanding the mechanism through which sensory enhancement of wins can promote risky choice could therefore provide valuable insight into the neurocognitive basis of addiction vulnerability.…”