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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    855—Behavioral Flexibility and Response Inhibition

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    855.03: Effect of methylphenidate on temporal discounting in impulsive and calm rhesus monkeys

    Location: Halls B-H

    *A. RAJALA1, S. WEBER2, A. ANDERSON2, L. POPULIN2;
    2Neurosci., 1Univ. of Wisconsin, Madison, MADISON, WI

    Abstract Body: Subjective reward value can be influenced by many factors, including reward magnitude and timing. When given a choice, humans and animals prefer a smaller reward immediately over a larger reward that is delayed in time, a phenomenon known as temporal discounting. Dopamine (DA) neurotransmission is central to reward processing and encodes delayed reward value. Impulsivity, the tendency to act without forethought, is associated with impaired DA transmission and excessive discounting of rewards, which has been documented in patients with attention deficit hyperactivity disorder combined type (ADHD-C). Methylphenidate (MPH), which blocks the DA transporter and increases extracellular DA in the basal ganglia and prefrontal cortex, is a primary treatment for ADHD and, at low doses, ameliorates impulsivity in both humans and animals. We tested the hypothesis that low doses of MPH will reduce temporal discounting in both impulsive and calm subjects.
    Two male rhesus monkeys, one impulsive and one calm, were tested in a reward preference task that required them to choose between a smaller reward right away (SS) or a larger reward after a delay (LL). The task required fixating a red dot straight ahead, after which two images appear to the right and left of the fixation representing the SS and LL. When the fixation dot was turned off, the subject made an eye movement towards one of the images indicating his reward choice. Eight fractal images represented each of the 4 SS and LL conditions. The SS delay was constant at 0 sec with 4 reward magnitudes (0.2, 0.3, 0.4, and 0.5 mL) while the LL reward magnitude was constant at 0.59 mL with 4 delay times (2, 4, 8, and 16 sec). A set of 16 blocks of 20 trials each contained all possible combinations of SS and LL and were presented in either ascending or descending order. The inter-trial time was adjusted to have constant trial length within each block. Methylphenidate was administered orally, dissolved in 0.5 mL juice 45 min prior to testing; juice alone was delivered on control days.
    Both monkeys exhibited temporal discounting that was best fit by a hyperbolic model, demonstrating a constant decay of reward value over time. The impulsive subject had steeper discounting and chose the SS significantly more often compared to the calm. Low doses of MPH shifted the choices of both subjects toward the LL and reduced discounting of LL reward value. Importantly, low dose MPH reduced the SS choice of the impulsive subject to the level of the calm subject under control conditions. These results suggest that MPH could improve impulsive behavior by altering the processing of reward information.

    Lay Language Summary: Our research demonstrates that low doses of methylphenidate (MPH; Ritalin®) made both calm and impulsive rhesus monkeys more willing to wait for larger rewards as opposed to choosing smaller immediate ones. The results indicate that MPH alters reward choice and the specific differences in the way it affects the impulsive vs. the calm monkey suggest that the subjects differ in the way they process rewards.
    Eleven percent of American children aged 4 to 17 are now diagnosed with attention deficit hyperactivity disorder (ADHD), though that number reaches as high as 20% in teenage boys, and many are treated with low dose psychostimulants such as MPH. A common feature of the "combined type" ADHD, which specifically lists impulsivity among its diagnostic criteria, is the tendency to take a smaller reward right away rather than a larger, delayed reward, called "temporal discounting." Methylphenidate changes the elimination of dopamine, a "reward" neurotransmitter that is elevated by such drugs as cocaine and amphetamine. Our results suggest that as MPH inhibits the transporter that clears dopamine from the brain, more dopamine remains, and reward processing is altered in the medicated monkeys.
    This hypothesis was tested using two rhesus macaque monkeys with opposite behaviors. One was extremely calm, while the other was impulsive, nervous and fidgety. The monkeys were asked to choose between two images representing a small immediate reward and a larger delayed reward. We varied the size of the small reward and the delay of the large reward and measured how many times the monkeys chose the small reward for each condition.
    As expected, the calm monkey was more willing to wait for a larger reward than the impulsive one. When both monkeys were given a low dose of MPH, they chose the delayed reward more frequently than they did without the drug. The impulsive monkey actually showed the same preference for the larger delayed reward as the unmedicated calm monkey, but the pattern of discounting was very different. This suggests that the impulsive monkey processes rewards differently.
    Although there is no perfect animal model of ADHD, many studies are performed in rodents, which are very different from humans; this one was done in a non-human primate, which is the closest to humans available for this work.
    A common hypothesis for the cause of ADHD involves dysfunction of cognitive processing in the highly evolved frontal cortex of the brain. The results of this study, however, support an alternative explanation: that impulsivity is linked to a dysfunctional reward-processing mechanism, which also involves more primitive parts of the brain. By teasing apart one characteristic of ADHD, impulsivity, this study could help refine drug and/or behavioral treatments of a disorder whose diagnosis rate has grown by 16 percent just since 2007 among school aged children.