2008b, 2010, 2013). Following training, exposure to a second, alternate context without cues or alcohol was conducted to establish the second context as an environment in which alcohol was never available. Evidence for this association is seen in the across-session decrease

in spontaneous entries into the fluid port during this phase (Figs. 2C, S1). At test, responding Inhibitors,research,lifescience,medical to both cues was assessed in several different contexts. It is important to note that cue responding had not been extinguished before Test 1, thereby paralleling human studies that examine craving and physiological reactivity induced by discrete drug cues that have not been systematically extinguished (Staiger and White 1991; Thomas et al. 2005). Consistent with previous data, rats continued to discriminate between the CS+ and CS− when the cues were presented without alcohol in a nonalcohol context (Chaudhri et al. 2010). Inhibitors,research,lifescience,medical Discrimination remained intact when the cues were presented in the PDT context where alcohol had previously been consumed: however, alcohol-seeking behavior driven by the CS+ was invigorated in the alcohol-associated context, compared to either the nonalcohol or novel contexts. This effect was consistent across two separate experiments conducted using different concentrations of ethanol during PDT. Thus, the context in which a discrete drug cue is experienced Inhibitors,research,lifescience,medical can be a critical determinant of the level of drug

seeking elicited by that cue (Zironi et al. 2006; Tsiang

and Janak 2006; Chaudhri et al. 2008a; Nees et al. 2012,). When translated to the human condition these results imply that craving may be more vigorous when discrete drug cues are encountered in a drug-associated context, and that the combination of discrete Inhibitors,research,lifescience,medical and contextual drug cues may be the more potent trigger for relapse, compared to either type Inhibitors,research,lifescience,medical of cue independently. There was no difference in the level of alcohol seeking driven by the CS+ in either a nonalcohol context or a novel context, indicating that removal from a nonalcohol context per se is not sufficient to invigorate Pavlovian-conditioned alcohol seeking. That the CS+ triggered alcohol seeking in a novel context parallels data from human studies in which reactivity to drug-predictive cues can be evoked in novel laboratory settings that may not resemble environments in which participants normally consume drugs (Litt and Cooney 1999; de Wit 2000; Field and Duka 2002). The present findings suggest Anacetrapib that the strength of cue reactivity measured in human studies may be underestimated in laboratory environments. By extension, cue-reactivity estimates might be more accurate if tests could be conducted either in drug-use environments, or in laboratory settings that incorporated contextual elements that might be found in drug-use environments. The use of virtual reality to create drug contexts may prove useful for such investigations (Bordnick et al. 2008; Paris et al. 2011; Traylor et al. 2011).