Drug Abuse Etiology: A Translational Analysis of Impulsivity

Aims

Impulsivity, a biologically based trait composed of independent behavioral processes of reinforcement-based activation and punishment-based inhibition, has been linked to drug abuse vulnerability. Impulsive individuals initiate drug use at earlier ages, escalate to heavy use and transition to abuse and dependence more quickly, and are less likely to remain abstinent following treatment than non-impulsive individuals. Ongoing preclinical and clinical studies in our Center for Drug Abuse Research Translation examine the effects of individual differences in activation (sensation-seeking status) and inhibition on self-administration and other behavioral effects of stimulant drugs.

Methods

Preclinical rat studies measured individual differences in activation and inhibition using performance tasks (i.e., activity levels in novel environment, novel place preference, delay discounting performance). Clinical studies assessed activation and inhibition using personality measures (e.g., Zuckerman-Kuhlman Personality Questionnaire, UPPS). Groups of rats and humans varying in activation and inhibition were then tested for d-amphetamine self-administration. Acquisition of intravenous drug self-administration and amount of drug intake were assessed across groups in preclinical studies. Break points on a modified progressive-ratio procedure were used to assess group differences in oral d-amphetamine self-administration in human studies. Supplemental behavioral measures of drug effects, including verbal-report, performance and cardiovascular assessments were completed before and at regular intervals after dose administration in humans. Data were analyzed using ANOVA.

Results

Preclinical drug self-administration studies demonstrated that individual differences in response to novelty and delay discounting were related to acquisition of d-amphetamine self-administration. In clinical studies, break points (i.e., the amount of drug self-administered) increased as a function of dose (0, 8, 16 mg), demonstrating that d-amphetamine functions as a reinforcer. Dose-related increases in break point were consistently observed in individuals high but not low in activation, independent of inhibition. Drug effects on other behavioral measures did not vary as a function of impulsivity.

Conclusions

Results demonstrate that the reinforcing effects of stimulant drugs are greater in high novelty seeking (activation) and high impulsive (inhibition) rats. However, in humans, the reinforcing effects of stimulants and other drugs, including marijuana and alcohol, appear more closely related to activation.

Supported by DA-05312.