Exposure to conditions of uncertainty promotes the pursuit of amphetamine.

Prior exposure to abused drugs leads to long-lasting neuroadaptations culminating in excessive drug intake. Given the comorbidity between substance use and gambling disorders, surprisingly little is known about the effects of exposure to reinforcement contingencies experienced during games of chance. As it is a central feature of these games, we characterized the effects of exposure to uncertainty on biochemical and behavioral effects normally observed in rats exposed to amphetamine. Rats in different groups were trained to nose-poke for saccharin under certain [fixed-ratio (FR)] or uncertain conditions [variable-ratio (VR)] for 55 1-h sessions. Ratios were escalated on successive sessions and rats maintained on the last ratio (FR/VR 20) for 20-25 days. Two to three weeks later, rats were tested for their locomotor or nucleus accumbens dopamine (NAcc DA) response to amphetamine or self-administration of the drug using a lever press operant. NAcc DA overflow was also assessed in additional rats during the saccharin sessions. Rats exposed to uncertainty subsequently showed a higher locomotor and NAcc DA response to amphetamine and self-administered more drug infusions relative to rats exposed to predictable reinforcement. NAcc DA levels during the saccharin sessions tracked the variance of the scheduled ratios (a measure of uncertainty). VR rats showed escalating DA overflow with increasing ratios. Exposure to uncertainty triggered neuroadaptations similar to those produced by exposure to abused drugs. As these were produced in drug naive rats both during and after exposure to uncertainty, they provide a novel common pathway to drug and behavioral addictions.