Figure 1. Mean adjusted delays (MAD, s) for each group during the baseline, sensitization, and washout periods.

1. Adjusting Delay Task Lever 1 Immediate Lever 2 Adjusting Delay Delay (initially 6 s) Mean Adjusted Delay (MAD) = quantitative measure of impulsivity Experimental Outline AM: Adjusting Delay Task Sensitization (10 days) Washout (14 days) Baseline PM: Locomotor Sensitization 1.0 mg/kg d-AMPH/saline d-AMPH challenge Delay discounting and sensitization to the locomotor-activating effects of d-amphetamine Jennifer L. Perry & Michael T. Bardo Department of Psychology, University of Kentucky Results Summary/Discussion Introduction • Locomotor Activity • HiI rats showed less locomotor activity following acute d-AMPH administration compared to LoI rats. This is similar to other research12 showing that HiI mice showed lower locomotor activity following a single injection of ethanol. • HiI rats showed faster sensitization to the locomotor-activating effects of d-AMPH compared to LoI rats. By Day 10 of locomotor testing, HiI rats had significantly greater locomotor activity compared to Day 1. Sensitization to the locomotor-activating effects of d-AMPH occurred in LoI rats; however, this did not occur until d-AMPH induced locomotor activity was tested following a 14-day washout period. These findings extend previous research12 showing that HiI mice had greater locomotor sensitization following chronic ethanol administration compared to LoI mice. • On the d-AMPH challenge day (2 weeks after washout of chronic d-AMPH/saline administration), there were no differences in HiI and LoI groups that previously received saline. This suggests that the novelty of the locomotor chamber may have played a role in the HiI/LoI differences in d-AMPH-induced locomotor activity on Day 1 of the sensitization period. Future studies should be conducted to characterize the relationship between novelty, delay discounting, and the response to drugs of abuse. • Delay Discounting • In LoI rats, repeated d-AMPH administration decreased MADs (increased impulsivity). Previous studies of the acute effects of d-AMPH on delay discounting have produced mixed results13,14,15,16,17,18, and it is possible that differences in baseline levels of impulsivity have contributed to the discrepancies in these results. Therefore, future studies should consider the role of individual differences in impulsivity when studying the effects of psychostimulants. • In HiI rats, repeated d-AMPH administration increased MADs (decreased impulsivity). Similarly,in humans with attention deficit hyperactivity disorder (ADHD), a disorder characterized by excessive impulsivity, d-AMPH also reduces impulsivity. Thus, HiI rats could potentially be used as an animal model of ADHD. • The MAD-altering effects of d-AMPH in HiI and LoI rats persisted after discontinuation of d-AMPH administration. However, MADs in the HiI and LoI saline groups were no longer significantly different during the washout period. The change in MADs in the saline groups may have been due to weight gain, aging, or long-term experience performing the adjusting delay task, and future studies are needed to clarify this issue. Research has suggested that delay discounting, a measure of impulsivity, and drug abuse are related. In humans, opioid users1, problem drinkers2, crack cocaine users3, and cigarette smokers4,5 discounted delayed rewards to a greater extent (i.e., were more impulsive) than nonusers. Impulsivity on a delay discounting task was associated with age of first alcohol, nicotine, and marijuana use6, and it was associated with reduced likelihood of maintaining smoking cessation7,8. While these studies suggest a relationship between delay discounting and drug abuse, they do not address whether impulsivity predicts enhanced vulnerability to drug abuse or, conversely, whether exposure to drugs of abuse increases impulsivity. In rats, impulsive choice on delay discounting tasks predicted elevated ethanol consumption9, greater acquisition of cocaine self-administration10, and greater reinstatement of cocaine-seeking behavior11. Additionally, mice screened for high impulsivity on a delay discounting task showed a lower locomotor response to an acute ethanol injection; however, they showed greater locomotor sensitization following repeated ethanol administration12. Combined, these results suggest that impulsive choice predicts enhanced vulnerability to drug abuse. The goals of the present experiment were: 1. To determine whether delay discounting predicts the locomotor response to acute or repeated d-amphetamine (d-AMPH). 2. To determine whether repeated d-AMPH exposure alters impulsive choice. B A Figure 1.Mean adjusted delays (MAD, s) for each group during the baseline, sensitization, and washout periods. C Method Figure 1.Total distance traveled (cm) over a 90 min locomotor testing period on Day 1 (A), Day 10 (B), and the d-AMPH challenge day (C) in LoI and HiI d-AMPH and saline groups. Subjects: Twenty-nine experimentally-naïve adult female Sprague Dawley rats Procedure: Briefly,rats were screened for high (HiI) or low (LoI) impulsivity based on a median split of stable mean adjusted delays (MADs) on an adjusting delay task (see procedure outline below). Over the subsequent 10 days, rats continued to perform the adjusting delay task, and they were also given 1.0 mg/kg d-amphetamine (d-AMPH) or saline(i.p.). Locomotor activity in an open field was monitored for 90 min following each d-AMPH or saline injection. Delay discounting continued to be measured for 14 days following repeated d-AMPH exposure. On the 14th day, all rats were administered a challenge injection of 1.0 mg/kg d-AMPH and locomotor activity was measured for the subsequent 90 min. References • Madden et al. (1997) Impulsive and self-control choices in opioid-dependent patients and non-drug-using control participants: drug and monetary rewards. Exp Clin Psychopharmacol, 5:258-62. • Vuchinich & Simpson (1998) Hyperbolic temporal discounting in social drinkers and problem drinkers. Exp Clin Psychopharmacol, 6:292-305. • Coffey et al. (2003) Impulsivity and rapid discounting of delayed hypothetical rewards in cocaine-dependent individuals. Exp Clin Psychopharmacol, 11:18-25. • Bickel et al. (1999) Impulsivity and cigarette smoking: delay discounting in current, never, and ex-smokers. Psychopharmacol, 146:447-54. • Mitchell (1999) Measures of impulsivity in cigarette smokers and non-smokers. Psychopharmacol, 146:455-64. • Kollins (2003) Delay discounting is associated with substance use in college students. Addict Behav, 28:1167-73. • Dallery & Raiff (2007) Delay discounting predicts cigarette smoking in a laboratory model of abstinence reinforcement. Psychopharmacol, 190:485-96. • Krishnan-Sarin et al. (2007) Behavioral impulsivity predicts treatment outcome in a smoking cessation program for adolescent smokers. Drug Alcohol Depend, 88:79-82. • Poulos et al. (1995) Impulsivity predicts individual susceptibility to high levels of alcohol self-administration. Behav Pharmacol, 6:810-14. • Perry et al. (2005) Impulsivity (delay discounting) as a predictor of acquisition of iv cocaine self-administration in female rats. Psychopharmacol, 178:193-201. • Perry, et al. unpublished data. • Mitchell et al. (2006) Delay discounting predicts behavioral sensitization to ethanol in outbred WSC mice. Alcohol Clin Exp Res, 30:429-37. • Cardinal et al. (2000) The effects of d-amphetamine, chlordiazepoxide, alpha-flupenthixol and behavioral manipulations on choice of signalled and unsignalled delayed reinforcement in rats. Psychopharmacol, 152:362-75. • Charrier & Thiebot (1996) Effects of psychotropic drugs on rat responding in an operant paradigm involving choice between delayed reinforcers. Pharmacol Biochem Behav, 54:149-57. • Evenden & Ryan (1999) The pharmacology of impulsive behaviour in rats VI: The effects of ethanol and selective serotonergic drugs on response choice with varying delays of reinforcement. Psychopharmacol, 146:413-21. • Van Gaalen et al. (2006) Critical involvement of dopaminergic neurotransmission in impulsive decision making. Biol Psychiatry, 60:66-73. • Wade et al. (2000) Effects of dopaminergic drugs on delayed reward as a measure of impulsive behavior in rats. Psychopharmacol, 150: 90-101. • Winstanley et al. (2005) Interactions between serotonin and dopamine in the control of impulsive choice in rats: Therapeutic implications for impulse control disorders. Neuropsychopharmacol, 30:669-82. Figure 3.Mean adjusted delays (MAD, s) during the baseline, sensitization, and washout periods in LoI and HiI d-AMPH and saline groups. * significant LoI/HiI difference; # significantly different from baseline Figure 2.Total distance traveled (cm) on Day 1, Day 10, and the d-AMPH challenge day in LoI and HiI d-AMPH and saline groups. # significantly higher than the saline group; * significantly higher than Day 1; † significant LoI/HiI difference. Acknowledgements The authors would like to thank Jason T. Ross, M.S. and Matthew Wethington for their technical assistance. Supported by USPHS grants DA05312 (MTB) and DA007304 (JLP).