776 discriminate between the impact of heroin and cocaine and adjust their approach behavior accordingly. If run times reflect the undrugged subjects’ motivation to seek the goal box reinforcer each day (as numerous studies over many decades have suggested; see review by Ettenberg 2009), then the distinctive patterns of responding in animals running for cocaine versus heroin suggest that the under- lying positive incentive properties of the drug (i.e., those aspects of a stimulus that induce an animal to approach) may be stronger for heroin than they are for cocaine. Such a conclusion is consistent with reports that the administration of the opiate drug, buprenorphine, can reduce cocaine self-administration in rats (Comer et al. 1996; Winger et al. 1992) and decrease preferences for cocaine in human addicts (Foltin and Fischman 1994, 1996). However, it has also been shown that animals given a direct choice between responding for cocaine (on one lever) or heroin (on an alternate lever) demonstrate strong preferences for the cocaine (Ward et al. 2005). Of course the current runway procedure does not offer animals a direct choice between the two drugs (a choice that is very likely affected by differences in the pharmacokinetics of cocaine and heroin). So while the initial positive/rewarding effects of cocaine might be stronger than those of heroin, thereby producing preferences for cocaine over heroin in a two-lever choice situation, the current runway data suggest that when the animal is tested in a non-drugged state, its motivation to seek heroin (as indicated by all three behavioral runway measures) appears to be more positive (or less mixed) than that for cocaine. The authors recognize that the observed differences in the response patterns of heroin- and cocaine-reinforced runway behavior may stem in part from the particular doses that were selected for study. Of course, as noted above, these doses were selected because we have in the past found them to produce the fastest start and run times and the fewest retreats for each drug (see “Materials and methods” for reference citations). However, the issue being addressed here is not whether or not the particular doses employed here generalize to other heroin and cocaine doses but rather whether the apparent enhanced motivation to seek one drug over another (at any dose) during self- administration, serves as a reliable predictor of the animals’ later responsiveness to cues paired with each of those drugs following periods of non-reinforced extinction responding. As discussed in the “Introduction” of this paper, several reports have shown that the pattern of responding during self-administration can serve as a predictor of the subjects’ vulnerability to factors that induce a reinstatement of drug- seeking following a period of drug withdrawal (e.g., Ahmed and Cador 2006; Kippin et al. 2006; Knackstedt and Kalivas 2007). A novel finding in the current study is that despite what appears to be a stronger motivation to Psychopharmacology (2011) 214:769–778 seek heroin versus cocaine during self-administration, the cocaine cue was more effective at potentiating responding during extinction than was the heroin-paired cue. Once again it might be suggested that heroin dose in the current study was less salient than the cocaine dose (due to heroin’s slower onset and longer duration of action), and hence, the strength of the resulting association between the external cue and the drug was weaker for heroin that it was for cocaine. This explanation, however, seems unlikely for two reasons: First, the almost immediate shift in the pattern of responding that occurred when animals were transitioned to or from heroin suggests that its presence was clearly discernible by the animals, and second, the demonstration that the same heroin dose employed in the runway was effective at producing significant conditioned place prefer- ences (even after only four drug–place pairings) suggests that the animals were capable of forming associations between external cues and the dose of the heroin reinforcer used in the current study. A more parsimonious explanation for the present results is that the pattern and strength of responding during self-administration may not always predict a subject’s responsiveness to those drug-paired cues that have been shown to induce a reinstatement of drug-seeking behavior after a period of non-reinforced responding. One might question why, if heroin is in fact a more potent incentive stimulus than cocaine at the doses employed here, did it not produce a stronger CPP when directly compared to cocaine (Fig. 4, right panel)? This may simply be a consequence of the fact that four drug–place pairings over 8 days was insufficient for such differences to emerge. Indeed, even in the runway, the conflict behavior (retreats) in cocaine animals do not develop until at least 9 days of consecutive testing. We would therefore predict that a more prolonged CPP conditioning protocol would ultimately reveal the differences between heroin and cocaine that the runway has identified in this and prior studies. Several aspects of the current experimental protocol differ from those typically employed in animal studies of cue-induced reinstatement of drug-seeking behavior. Most prominent among these is that fact that the rats in the current study drug self-administration involved single daily exposure to the drug reinforcer over a 30-day period. In typical response-reinstatement studies, the initial lever-press self-administration experience results in numerous drug infusions per day (for a review of reinstatement methodol- ogies, see Shaham et al. 2003). As a result, although run times slowed for all groups over the course of extinction (see Fig. 2), the effect was modest and not statistically significant. This may account for why there was no reliable response potentiation observed upon presentation of the heroin-paired cue—a finding that contrasts with the results of other studies that employed traditional lever-press self-