770 or simply after the passage of time from previous drug exposure (e.g., Di Ciano and Everitt 2002; Kelamangalath and Wagner 2009; Lu et al. 2004; Shaham et al. 1997; Weiss et al. 2001). Several aspects of the initial self-administration experi- ence itself have been identified in animals as reliable predictors of subsequent renewed responding (including cue-induced reinstatement) after a period of drug with- drawal. These include the dose of the self-administered drug (Mantsch et al. 2001, 2004), the length of the training period (Deroche et al. 1999), and the initial schedule of reinforcement (Acosta et al. 2008; Valles et al. 2006). For example, Ahmed and Koob (1998) have shown that animals permitted 6 h of daily access to intravenous (i.v.) cocaine demonstrate escalating rates of self-administration over days (compared to animals provided 1 h of daily cocaine access) and are more responsive to factors that induce a reinstatement of drug seeking following periods of drug withdrawal (Ahmed and Cador 2006; Kippin et al. 2006; Knackstedt and Kalivas 2007). Thus, animals exhibiting higher rates of drug self-administration appear to be more likely to re-engage drug seeking after the drug reinforcer has been removed. However, it remains unknown whether or not such conclusions generalize to comparisons between drug reinforcers. To address this question, the authors have employed an operant runway model that assesses a subject’s motivation to seek goal-box incentive stimuli, including drugs of abuse (see review by Ettenberg 2009). In this model, the time required to run a straight alley and enter a goal box for an i.v. injection of a drug reinforcer serves as an index of the subjects’ motivation to seek the drug reinforcer in question. In previous work, i.v. heroin and cocaine have been shown to produce highly distinct patterns of runway behavior. When heroin serves as the reinforcer, animals initiate trials quickly, run fast, and proceed directly into the goal box. In contrast, rats running for cocaine, while initiating trials quickly, develop a distinct pattern of approach–avoidance conflict about goal box entry that gets progressively stronger over trials (e.g., Ettenberg and Geist 1993). The conflict is operationally quantified by the number of “retreat behav- iors” that occur, i.e., the number of times an animal runs quickly to the threshold of the goal but then stops, turns, and retreats back toward the start box. Such behavior is prototypical of animals approaching a goal box with which they have concurrent positive and negative associations such as a goal box where both food + shock are delivered upon entry (Cohen et al. 2009; Geist and Ettenberg 1997; Miller 1944). Indeed, cocaine administration is now well- known to have dual and opposing affective consequences where the initial rewarding/euphoric state is followed by a “crash” associated with anxiety, anhedonia, restlessness, and cravings (e.g., Childress et al. 1988; Van Dyke and Psychopharmacology (2011) 214:769–778 Byck 1982; see review by Ettenberg 2004). The slow development of cocaine-induced retreat behaviors over several trials is thought to stem from this delay in the onset of the drug’s aversive effects and the consequent need for additional runway drug pairings in order for the animal to adequately form the association between such effects and the goal box (Ettenberg 2009). In any event, the runway data clearly suggest that the motivation of subjects to seek heroin and cocaine are qualitatively different from one another, with heroin having more purely positive behavioral effects (approach) and cocaine having mixed positive and negative effects (approach and avoidance). It was of interest, therefore, to test the hypothesis that such differences during self-administration would extend to differences in the rats’ responsiveness to a cocaine- or heroin-paired cue after varying periods of non-reinforced trials (i.e., extinction). Materials and methods Subjects The subjects were male Sprague-Dawley rats (n = 50) weighing 330–360 g at the time of surgery (Charles River Laboratories, Wilmington, MA, USA). Rats were individ- ually housed in plastic cages within a temperature- controlled (23°C) vivarium maintained on a reverse 12- h light–dark cycle (lights off at 0800 hours). Free access to food (Purina Rat Chow) and water was provided through- out the duration of the study. All animal handling and experimental procedures adhered to the NIH Guide for the Care and Use of Laboratory Animals and were reviewed and approved by the University of California at Santa Barbara’s Institutional Animal Care and Use Committee. Surgery Rats were acclimated to human handling for 1 week prior to i.v. catheterization. Each rat was then deeply anesthetized via isoflurane inhalation (4% for induction and 1.5–2.5% for maintenance) and fitted with a catheter (13 mm of polyethylene tubing, 0.3 mm inner and 0.64 mm outer diameters; Dow Corning Corp, Midland, MI, USA) that was inserted into the right jugular vein and secured by silk sutures. The open end of the catheter was passed subcutaneously to a 2-mm hole located on the midline of the animal’s back. This end of the catheter has been preassembled to fit into a stainless steel guide cannula (Item 313G; Plastics One, Roanoke, VA, USA) that was in turn affixed with dental cement to a 2-cm square of Mersilene surgical mesh (Bard; Warwick, RI, USA). The surgical mesh was laid flat on the animal’s back and secured by