Weakening of negative relative to positive associations with cocaine-paired cues contributes to cue-induced responding after drug removal

Abstract

Cocaine has been shown to have initial positive (euphoric) and delayed negative (anxiogenic) effects in both humans and animals. Cocaine-paired cues are consequently imbued with mixed positive and negative associations. The current study examines the relative roles of these dual associations in the enhanced drug-seeking observed upon presentation of cocaine-paired cues. Rats ran a straight alley once/day for a single i.v. injection of cocaine (1.0 mg/kg/inj) in the presence of a distinctive olfactory cue (scented cotton swabs placed under the apparatus). An alternate scent was presented in a separate cage 2-h prior to runway testing. After 15 trials/days, the scents and cocaine reinforcer were removed and a series of extinction trials (lasting for 1 or 3 weeks) was initiated. Immediately following extinction, runway responding was tested during a single trial in the presence of the cocaine-paired or non-paired cue. As previously reported, while subjects initiated responding faster over trials (reduced latencies to leave the start box), they exhibited a progressive increase in approach–avoidance conflict behavior (“retreats”) regarding goal-box entry, reflecting cocaine's dual positive + negative effects. Once established, retreat behaviors persisted over the course of 1 or 3 weeks days of extinction. However, both run times and retreats decreased in response to presentation of the cocaine-paired but not the non-paired scent. These data suggest that, after reinforcer removal, cue-induced cocaine-seeking stems in part from a reduction in approach–avoidance conflict; i.e., a greater weakening of the negative relative to the positive associations that animals form with cocaine-paired stimuli.

Introduction

Human cocaine addicts report that once the initial drug-induced state of euphoria subsides, they experience profound levels of anxiety, agitation, depression, and fatigue (Resnick and Resnick, 1984, Smith, 1986, Washton and Gold, 1984, Williamson et al., 1987). These negative effects of cocaine occur even while plasma levels of the drug remain high, suggesting that the onset of such effects is not a result of drug withdrawal, but more directly related to the inherent mixed or opponent-process properties of cocaine (Van Dyke and Byck, 1982). The negative/aversive actions of cocaine have also been demonstrated in animal studies. Cocaine increases the reluctance of animals to explore an open field task (Simon et al., 1994, Yang et al., 1992) or enter the open arms of an elevated plus maze (Rogerio and Takahashi, 1992). Cocaine administration has been reported to potentiate an animal's avoidance of an inherently negative environment (Costall et al., 1989) and decrease responding in conflict tests (Fontana and Commissaris, 1989). While animals develop conditioned preferences for distinct environments paired with the immediate effects of i.v. cocaine, they exhibit aversions for environments paired with the effects present 15-min post-injection (Ettenberg et al., 1999, Ettenberg and Bernardi, 2007, Jhou et al., unpublished manuscript, Knackstedt et al., 2002, Pliakas et al., 2001). Additionally, cocaine has long been known to produce increases in plasma and/or brain levels of stress hormones such as adrenocorticotropin and corticotropin-releasing factor (Goeders, 2002, Goldstein, 1991, Koob, 1999, Moldow and Fischman, 1987, River and Vale, 1987) and more recently its negative effects have been associated with actions within structures of the extended-amygdala (e.g. Wenzel et al., 2011) that have themselves been implicated in fear, stress and anxiogenic states (e.g., de la Mora et al., 2010, Tanimoto et al., 2003, Walker and Davis, 2008). Collectively, these studies provide clinical, behavioral, and neurobiological evidence that demonstrates the presence of profound aversive/anxiogenic properties of cocaine administration.

The demonstration that cocaine produces dual and opposing actions would seem to suggest that the motivation of organisms to seek the drug must involve both positive (approach) and negative (avoidance) features. To assess the nature of these dual actions of cocaine, our laboratory has developed and employed a runway model of drug self-administration in which animals traverse a straight alley once a day to enter a goal box where they receive an i.v. injection of the drug reinforcer. In this model the time it takes the subject to re-enter the goal area each day provides an index of that subject's motivation to seek the drug. The runway has been successfully employed to assess the motivation of subjects to seek a variety of drug and natural reinforcers (e.g. for a review see Ettenberg, 2009). Early on, it was found that animals running for cocaine, exhibited a unique pattern of responding that had not and has not been observed with other drug reinforcers (e.g., Ettenberg and Geist, 1993, Su et al., 2011). While cocaine-reinforced animals initiate responding (leave the start box) more and more quickly as trials progress (demonstrating the positive motivational “pull” of the drug), they develop a progressive increase in “retreat behaviors” in which they approach the goal quickly, but then stop at the threshold, turn, and run back toward the start box (Ettenberg and Geist, 1991). These retreat behaviors have been shown to reflect an approach–avoidance conflict about goal-box entry that stems from the mixed positive (rewarding) and negative (anxiogenic) associations with the goal box that in turn stem from cocaine's opponent-process properties (see review by Ettenberg, 2004). Thus, the runway self-administration model provides a unique means of investigating the dual positive and negative actions of cocaine administration within the same subject on the same trial.

In the current study, we employed the self-administration runway to examine a topic of primary interest in the drug abuse field, namely the role of drug-paired environmental stimuli as a motivating factor for the return to drug-seeking behavior observed after a period of drug abstinence (Childress et al., 1987, O'Brien et al., 1992, Rescorla and Cunningham, 1978, Robbins and Ehrman, 1992). Previously we had reported that while heroin reinforcement supported more robust goal-directed performance in the runway (i.e., faster start and run times) compared to cocaine (in the same subjects), those animals were subsequently more responsive to the presentation of cocaine-paired cues than heroin-paired cues after the drug reinforcers had been removed (i.e., after a period of non-reinforced responding) (Su et al., 2011). More specifically, in animals with a history of both cocaine and heroin reinforcement, only the cocaine-paired cue (and not the heroin cue) induced a reduction in runway retreat behaviors during extinction. This decrease in retreats in the presence of the cocaine-cue suggests that the strength of the negative associations with that cue (i.e., the factor motivating avoidance of the goal box) weakens faster than the positive associations with the cue (the factor motivating approach behavior) — hence goal-directed behavior is potentiated. If correct, this would represent a novel explanation for cue-induced response reinstatement/relapse of drug-seeking behavior. Of course it remains unclear whether or not the results obtained by Su et al. (2011) were dependent upon the animals' prior comparative experience with both heroin and cocaine. The current study was therefore devised to extend these findings by focusing solely on cocaine and comparing the runway performance of animals presented with either a cocaine-paired or non-paired cue after varying periods of non-cued/non-reinforced trials. If the strength and/or persistence of the positive associations with a cocaine-paired cue are indeed stronger than that of the negative associations with that cue, then the impact of non-cued/non-reinforced responding should be a shift in the relative valence of the cue toward the positive — thereby resulting in a reduction in the frequency of approach–avoidance retreat behaviors when the cocaine-paired cue is again presented. The present experiment tested this prediction.