Psychopharmacology (2011) 214:769–778 preference for the heroin-paired over the cocaine-paired compartment (t(12) = 1.2, p > 0.05). These results are depicted in Fig. 4 and clearly demonstrate that the doses of cocaine and heroin employed here were sufficiently salient to produce reliable drug–place associations even after only four 5-min drug–place pairings and that the initial impact of the drugs (during the first 5 min post-injection) was comparably rewarding for both compounds. Discussion The current data confirm and extend previous findings from our laboratory that the behavior of animals working for i.v. cocaine qualitatively differs from that of animals working for i.v. heroin (e.g., Ettenberg and Geist 1993). In the initial portion of self-administration testing, heroin-reinforced animals consistently produced faster start latencies and run times and exhibited little or no ambivalence about goal- box entry (i.e., very few retreats). In contrast, animals running for i.v. cocaine took comparatively longer to initiate runway responding (elevated start latencies) and longer to enter the goal box (elevated run times). The elevation in the run times of the cocaine-reinforced rats is likely due, in large part, to the progressive development of retreat behaviors since, to state the obvious, animals running back and forth in the alley will take longer to enter the goal box than animals that do not exhibit such behaviors. These retreats are thought to represent a form of approach–avoidance conflict behavior that stems from an ambivalence about entering a goal box with which the Fig. 4 Mean (+SEM) test days performance during a 5-min CPP test. Data reflect the time spent on the heroin-paired versus saline-paired side of a CPP apparatus during preference testing (left), on the cocaine-paired versus saline-paired side of the CPP apparatus (middle), and on the cocaine- versus heroin-paired sides of the preference apparatus (right). *p<0.01 (saline versus drug compartment) 775 subject has mixed positive and negative associations (see reviews by Ettenberg 2004, 2009). Thus, for example, the behavior of cocaine-reinforced rats in the runway is comparable to that exhibited by animals approaching a goal box whose entry has clearly discernible positive and negative consequences (e.g., where both food and foot- shock are delivered; Cohen et al. 2009; Geist and Ettenberg 1997; see also Miller 1944), and like other forms of conflict, retreat behaviors are dose-dependently reduced by pretreatment with compounds having known anxiolytic effects such as diazepam (Ettenberg and Geist 1991), busiprone, (Ettenberg and Bernardi 2006), or alcohol (Knackstedt and Ettenberg 2005). When CPP procedures are used, animals develop preferences for places paired with the immediate effects of i.v. cocaine, but aversions for environments paired with the effects present 15 min post- injection (e.g., Ettenberg et al. 1999; Ettenberg and Bernardi 2007; Knackstedt et al. 2002). Collectively, such findings suggest that acute administration of the drug has immediate positive (rewarding) and delayed negative (anxiogenic) consequences, a conclusion substantiated by subjective reports of human cocaine users (van Dyke and Byck 1982; Nelson et al. 2005; Lundahl and Lukas 2007). A novel aspect of the current study was the examination of the behavioral response of animals that were shifted from heroin to cocaine and vice versa. This permitted the determination of how discernable each reinforcer was from one another by examining whether or not and how quickly the animals would alter their pattern of runway behavior once the drug shift was made. The results clearly demonstrate that when rats are transitioned from one drug reinforcer to another, their runway responding quickly adopts the pattern associated with the “new” reinforcer (see Fig. 1). Thus, when animals were shifted from heroin to cocaine, they immediately exhibited slower start laten- cies, slower run times, and a progressive increase in retreat behaviors. The impact of the shift from cocaine to heroin was more complex since the animals had already estab- lished mixed positive and negative associations with the goal box prior to the reinforcer shift. Hence, one would expect such associations to have a continued impact even after the shift to heroin reinforcement. We know from previous work that retreat behaviors normally continue to rise during the first 3 weeks of daily testing and that an intervention that alters the negative impact of cocaine after retreats have already developed (e.g., the addition of heroin to the cocaine solution) truncates the further increase in retreats that would otherwise have occurred (Guzman and Ettenberg 2004). Similarly, in the current study, when animals were shifted from cocaine to heroin, a continued rise of retreats and further slowing of run times did not materialize and both measures remained stable or slightly improved. It therefore seems clear that rats readily