Psychopharmacology (2011) 214:769–778 DOI 10.1007/s00213-010-2088-0 ORIGINAL INVESTIGATION Comparison of self-administration behavior and responsiveness to drug-paired cues in rats running an alley for intravenous heroin and cocaine Zu-In Su & Jennifer Wenzel & Rebeccah Baird & Aaron Ettenberg Received: 12 August 2010 / Accepted: 28 October 2010 / Published online: 18 November 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Rationale Evidence suggests that responsiveness to a drug- paired cue is predicted by the reinforcing magnitude of the drug during prior self-administration. It remains unclear, however, if this principle holds true when comparisons are made across drug reinforcers. Objective The current study was therefore devised to test the hypothesis that differences in the animals’ responsive- ness to a cocaine- or heroin-paired cue presented during extinction would reflect differences in the patterns of prior cocaine and heroin runway self-administration. Methods Rats ran a straight alley for single intravenous injections of either heroin (0.1 mg/kg/inj) or cocaine (1.0 mg/kg/inj) each paired with a distinct olfactory cue. Animals experienced 15 trials with each drug reinforcer in a counterbalanced manner. Start latencies, run times, and retreat behaviors (a form of approach-avoidance conflict) provided behavioral indices of the subjects’ motivation to seek the reinforcer on each trial. Responsiveness to each drug-paired cue was assessed after 7, 14, or 21 days of non- reinforced extinction trials. Other animals underwent conditioned place preference (CPP) testing to ensure that the two drug reinforcers were capable of producing drug– cue associations. Results While both drugs produced comparable CPPs, heroin served as a stronger incentive stimulus in the runway as evidenced by faster start and run times and fewer retreats. In contrast, cocaine- but not heroin-paired cues produced increases in drug-seeking behavior during subsequent extinction trials. Z.-I. Su : J. Wenzel : R. Baird : A. Ettenberg (*) Department of Psychology, University of California, Santa Barbara, CA 93106-9660, USA e-mail: ettenber@psych.ucsb.edu Conclusions The subjects’ responsiveness to drug-paired cues during extinction was not predicted by differences in the motivation to seek heroin versus cocaine during prior drug self-administration. Keywords Cocaine . Heroin . Runway . Drug reinforcement . i.v. self-administration . Drug seeking . Motivation . Response reinstatement Introduction Drug relapse (i.e., the re-emergence of drug seeking after a protracted period of drug withdrawal) is among the most prominent characteristics of addiction (Mendelson and Mello 1996; O'Brien 1997). Relapse of drug-seeking behaviors can occur as a consequence of several factors including re-exposure to the drug itself (de Wit and Stewart 1983; Jaffe et al. 1989), exposure to other drugs of abuse (de Vries et al. 1999; de Wit and Stewart 1981, 1983), to stress (Ahmed and Koob 1997; Shaham et al. 1997), and/or to cues previously associated with the drug reinforcer (Carter and Tiffany 1999; Fuchs et al. 2004; Grimm et al. 2001; Kruzich et al. 1999). Of these various factors, the role of conditioned cues has received considerable attention in both the human and animal literature (e.g., see reviews by Crombag et al. 2008; Rohsenow et al. 1990). In humans, exposure to cues that have been previously associated with drug consumption can induce an intense subjective craving for the drug that is highly correlated with renewed drug abuse (Childress et al. 1998; Rohsenow et al. 1990; Withers et al. 1995). Similarly in animal models, reinstatement of operant responding for drug reinforcers can be induced by presentation of drug-paired contextual or discrete cues even after long periods of non-reinforced responding (extinction)