Poor inhibitory control is a known risk factor for drug abuse. Individuals with poor inhibitory control may be at risk because they have difficulty refraining from actions (e.g., drug use) despite known adverse consequences. However, recent evidence suggests that these individuals may also be at risk for another reason: that they experience more positive subjective, or euphorigenic, effects from drugs. The long-term goal is to identify the mechanisms underlying risk for drug abuse in individuals with poor inhibitory control, and ultimately to develop therapeutic agents to reduce this risk. The objective here is to investigate associations between impulsive action (i.e., poor inhibitory control) and subjective and behavioral measures of the rewarding effects of methamphetamine and alcohol in healthy young adults. The central hypothesis is that individuals high in impulsive action will be more sensitive to the rewarding effects of both of these drugs. The rationale for this proposal is that behavioral evidence linking poor inhibitory control and drug reward sensitivity will lay the foundation for investigations of common neurobiological mechanisms underlying both risk factors. Such neurobiological mechanisms would serve as potential targets for therapeutic agents aimed at reducing risk for drug abuse in individuals with poor inhibitory control. The central hypothesis will be tested by addressing two specific aims: 1) examine the degree to which impulsive action in humans predicts stimulant drug reward and 2) examine the degree to which impulsive action predicts alcohol reward. For both aims, participants will be pre-selected as exhibiting low or high impulsive action, and then we will compare these groups' responses to the rewarding effects of the two drugs. Impulsive action, defined as difficulty controlling or inhibiting behavior, will be measured using the stop signal task, a well-validated measure of behavioral control. Under the first aim, the rewarding effects of methamphetamine (20 mg) will be compared in high and low impulsive individuals, using both subjective self-report measures of euphoria and arousal, and behavioral measures of drug choice. Under the second aim, a similar approach will be taken in separate groups of subjects, to examine the rewarding effects of alcohol (0.8 g/kg) in relation to baseline impulsive action. Based on preliminary findings with the prototypic stimulant d-amphetamine, it is hypothesized that individuals high in impulsive action will report significantly greater euphoria and arousal than those low in impulsive action following both methamphetamine and alcohol. Based on findings from animal studies, it is hypothesized that high impulsive individuals will also exhibit greater choice for both methamphetamine and alcohol over placebo. This approach is innovative because it examines a novel association between two risk factors for drug abuse, that have until now been studied separately. This contribution is significant because it is the first step to developing targeted therapy, both pharmacological and behavioral, to prevent and treat drug abuse in individuals with poor inhibitory control.

R21DA037642

2015-04-01

2018-03-31