Exposure to conditions of uncertainty promotes the pursuit of amphetamine

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• In the present experiments, we found that prior exposure to conditions of uncertainty enhanced subsequent locomotor and NAcc DA responding to amphetamine and heightened self-administration of the drug. These effects, consistent with effects normally observed in rats previously exposed to psychostimulant drugs, were produced in drug naive animals, demonstrating direct effects of exposure to uncertainty on NAcc DA reactivity and drug intake that provide a novel pathway to drug abuse. The additional finding that NAcc DA tracked uncertainty during operant responding for saccharin provides a likely mechanism, again observed with abused drugs, whereby repeated intermittent increases in DA can lead to long-lasting changes in neurotransmission and behavior.

• These findings together with those reported here showing that exposure to uncertainty in and of itself can enhance subsequent NAcc DA responding to and self-administration of amphetamine, support a unified theory of addiction in which excessive incentive wanting drives the maintenance and progression of both drug and behavioral addictions, such as gambling disorder. Thus, repeated intermittent exposure to uncertainty, manipulated here not as a model of gambling but rather as a central feature of games of chance necessary to maintain their pursuit [19], led to incentive sensitization resulting in excessive drug intake.