Wheel running as a predictor of cocaine self-administration and reinstatement in female rats Erin B. Larson a,b, * , Marilyn E. Carroll b,1 a Graduate Program in Neuroscience, University of Minnesota, MMC 392, Minneapolis, MN 55455, United States b Department of Psychiatry, University of Minnesota, MMC 392, Minneapolis, MN 55455, United States Received 9 June 2005; received in revised form 11 October 2005; accepted 25 October 2005 Abstract Avidity for behaviors mediated by nondrug rewards, such as novelty seeking or intake of sweets or fats, is predictive of enhanced vulnerability to the locomotor-activating and rewarding effects of drugs of abuse. The purpose of the present study was to determine whether avidity for wheel running was predictive of subsequent cocaine-induced locomotor activity, cocaine self-administration, and cocaine-seeking behavior in rats. Rats with high (HiR) and low (LoR) levels of wheel running were selected from an outbred sample of Wistar rats. These rats were first tested for their locomotor response to an acute injection of cocaine (10 mg/kg, i.p.). Subsequently, a multi-phase self-administration procedure was used to examine the effect of wheel running on the maintenance, extinction, and cocaine-induced reinstatement of cocaine-seeking behavior in HiR and LoR rats. The results indicate no significant differences between HiR and LoR rats in the cocaine-induced stimulation of locomotor activity. During maintenance, HiR rats self-administered more cocaine than LoR rats. While there were no group differences in saline self-administration behavior during extinction, HiR rats showed higher cocaine-induced reinstatement than LoR rats. Rats that were previously high responders to novelty (day 1 in locomotor track) also showed significantly higher reinstatement than low novelty responders. These results suggest that a propensity for wheel running is associated with increased vulnerability for cocaine self-administration and reinstatement and that HiR rats are more motivated than LoR rats to seek cocaine. D 2005 Elsevier Inc. All rights reserved. Keywords: Wheel running; Cocaine; Locomotor; Self-administration; Reinstatement; Relapse; Drug-seeking; Female 1. Introduction There is evidence that individual differences in drug abuse may reflect individual differences in endogenous character- istics, such as preference for sweets, activity, or novelty- seeking behavior. That is, individuals that strongly express these characteristics are more likely to abuse drugs than those that exhibit low occurrence of these traits (Carroll et al., 2001). In rats, high and low responders (e.g., rats that have high or low expression of a particular trait) can be selected from a population of outbred rats, and these animals can then be assessed on various aspects of drug-mediated behavior. The phenotype of interest can also be exaggerated by selective breeding (Dess et al., 1998). Studies using these methods show that high responders for palatable tastes (Gosnell, 2000; Gosnell and Krahn, 1992; Gosnell et al., 1995; Kampov-Polevoy et al., 1995; Dess et al., 1998; Carroll et al., 2002), novelty-seeking or novelty-induced locomotor activity (Piazza et al., 1989, 1990, 2000; Pierre and Vezina, 1997; Klebaur and Bardo, 1999; Sell et al., 2005), impulsivity (Poulos et al., 1995; Perry et al., 2005), and stress reactivity (Piazza et al., 1991; Piazza and Le Moal, 1996, 1998; Homberg et al., 2002) are more sensitive to the locomotor- activating effects of drugs of abuse, and they are more likely to self-administer drugs compared to their low-responding counterparts. While increased vulnerability for drug-mediated behavior has been demonstrated in high responders for palatable food, novelty, impulsivity, and stress, the relative vulnerability for drug abuse has not been investigated in rats that are high and low responders for wheel running. Wheel running is a nondrug, noningestive behavior that is actively engaged in by rats, and it 0091-3057/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2005.10.015 * Corresponding author. Tel.: +1 612 624 4406; fax: +1 612 624 8935. E-mail address: larso323@umn.edu (E.B. Larson). 1 Tel.: +1 612 686 6289; fax: +1 612 6248935. Pharmacology, Biochemistry and Behavior 82 (2005) 590 – 600 www.elsevier.com/locate/pharmbiochembeh