Over the last two decades, a growing body of evidence has revealed that reward uncertainty, a major component of human gambling, stimulates the brain similarly to addictive drugs. However, many questions relative to the exact neuronal, psychological, and behavioral effects of uncertainty remain unanswered, especially after prolonged exposure. In this issue of Neuropsychopharmacology, Mascia et al. (2018) provide important insights into the role played by reward uncertainty in creating behavioral and neural changes associated with addiction. Two groups of rats were trained to nose-poke for a non-caloric saccharin reward under an increasing variable- (VR) or a fixed-ratio (FR) schedule (1–20) across 55 days. Although the rats performed similarly under the VR and FR schedules, exposure to a VR schedule resulted in a sensitized locomotor response and greater dopamine release in the Nucleus Accumbens (NAc) following amphetamine. It also induced greater drug-seeking and amphetamine self-administration under a progressive ratio.

Interestingly, the authors reported larger dopamine outflows during training under VR (uncertain) conditions that exponentially increased in conjunction with the growing variability associated with larger response ratios. However, this uncertainty-induced increase in dopamine outflow occurred despite no apparent behavioral change during training, suggesting that it did not directly affect motivated behavior. Instead this increased dopamine outflow appears to be a consequence of the training conditions, which raises interesting questions regarding the role of dopamine in encoding this form of uncertainty. Although the authors highlight that dopamine tracks the variability of ratios, it remains to be determined how what appears to be something more akin to an error prediction-like signal, turns into enhanced incentive motivation when animals are later tested on a progressive ratio reinforcement schedule for a drug. Indeed, prediction error does not account for the uncertainty-induced sensitization of dopamine neurons or the increases in locomotion in response to amphetamine and in self-administration of amphetamine. In the current study, microdialysis does not provide the precise temporal resolution that might help answer some of these questions, which is why techniques such as fast-scan cyclic voltammetry or even very recent dopamine-targeted neural imaging techniques might be useful to further probe at these questions [1].

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