Relapse to cocaine use persists following extinction of drug-primed craving
Introduction
Cocaine not only evokes intense pleasurable sensations but also induces an overwhelming desire or craving for more cocaine. This latter process is especially obvious in individuals with a diagnosis of cocaine use disorder and is thought to contribute, together with other factors, to precipitate or favor relapse after abstinence (Jaffe et al., 1989; Mahoney et al., 2007; Volkow et al., 2005). Cocaine-induced craving can be approached and studied in animals using the classic drug reinstatement model (Epstein and Preston, 2003; Epstein et al., 2006). In this model, operant responding for the drug (e.g., pressing a lever) is first extinguished by discontinuing drug reinforcement and then reinstated by drug priming (i.e., passive or non-contingent drug administration). Importantly, after drug priming, reinstated operant responding continues to be non-reinforced as during extinction and, therefore, is thought to be a behavioral expression of genuine drug seeking (Ahmed and Koob, 1997; Grimm et al., 2001). This standard animal model has been extensively used to study the neural correlates and substrates of cocaine seeking and to develop potential anti-craving interventions for relapse prevention (Kalivas et al., 2005; Schmidt et al., 2005; Shalev et al., 2002).
Using this model, we found that the reinstating effect of cocaine on previously extinguished cocaine seeking is not an unconditioned effect as it can itself be extinguished with repeated drug priming – a phenomenon dubbed extinction of drug priming to distinguish it from extinction of operant drug responding (Mihindou et al., 2011). Extinction of cocaine priming was also observed after escalation of cocaine self-administration in rats with extended drug access (Mihindou et al., 2011). Such extinction was largely unanticipated by most theories on the mechanisms underlying cocaine priming-induced reinstatement, except by the drug interoceptive conditioning hypothesis (Ahmed and Koob, 1997; Keramati et al., 2017; Mihindou et al., 2011). According to this hypothesis, the priming effect of cocaine on reinstatement of cocaine seeking would result from an interoceptive drug conditioning mechanism whereby the interoceptive cues of cocaine are associated with the availability of cocaine reinforcement and become conditioned Pavlovian stimuli (Ahmed and Koob, 1997; Mihindou et al., 2011; Wang et al., 2013; Wise et al., 2008). During cocaine priming, perception of these conditioned cues would induce reinstatement of responding. In other words, according to this view, cocaine priming would be a special form of cue-induced reinstatement. In theory, the interoceptive cues of cocaine could reinstate responding via a simple stimulus-response mechanism, a goal-directed mechanism, or an incentive salience attribution mechanism. For instance, perception of these interoceptive cues after instrumental extinction could lead rats to expect, albeit falsely, that the cocaine outcome is again available for self-administration, thereby prompting them to reinstate responding. This goal-directed account of cocaine priming seems to be consistent with the critical role of the prelimbic cortex in cocaine-primed reinstatement (Capriles et al., 2003; McFarland and Kalivas, 2001; Vassoler et al., 2013) – a brain region that is also involved in goal-directed instrumental behavior (Gourley and Taylor, 2016; Killcross and Coutureau, 2003). Regardless of the underlying mechanisms, however, after repeated priming, these cues would progressively lose their conditioned effects, thereby explaining extinction of cocaine priming.
Recently, we suggested that extinction of drug priming could represent a potential cocaine exposure therapy for relapse prevention (Mihindou et al., 2011). The validity of this proposal ultimately depends, however, on whether the mechanisms involved in cocaine priming significantly overlap with those involved in cocaine self-administration when the drug is available. Previous research has shown that these mechanisms can be dissociated, at least partly, by some specific pharmacological or neurobiological interventions (Bachtell et al., 2008; Baker et al., 2003; Chauvet et al., 2015; Fletcher et al., 2002; Moussawi et al., 2011; Peng et al., 2008; Pentkowski et al., 2010; Schroeder et al., 2010; Sun and Rebec, 2005). In addition, extinction of drug cues, albeit exteroceptive ones, has so far been relatively ineffective in preventing relapse in human addicts (Conklin and Tiffany, 2002). Thus, it is not clear whether and to what extent extinction of cocaine priming should impact relapse to cocaine self-administration.
The overarching goal of the present series of experiments was to directly assess this question. To this end, we developed a within-session, multiple drug priming procedure (i.e., 3 per session) to promote a rapid extinction of cocaine priming in rats with relatively long prior histories of intravenous cocaine self-administration (i.e., > 24 daily sessions) (see Section 2). Importantly, to avoid limitations due to the context-specificity of extinction (Conklin and Tiffany, 2002; Mihindou et al., 2011), this procedure was applied in the same environmental context where cocaine self-administration originally took place and where relapse-like behavior will occur. After extinction of cocaine priming, cocaine was again made available for self-administration under the same operant conditions as before extinction. Relapse-like behavior was then measured by comparing in the same individuals their pre- versus post-extinction patterns and rates of cocaine self-administration. To avoid confusion, the term relapse-like behavior is strictly defined here as a return to the pre-extinction pattern and rate of cocaine self-administration – an operational definition that is close to the clinical definition of relapse (Epstein and Preston, 2003; Miller et al., 2011). In contrast and as already defined above, the term reinstatement is exclusively used to refer to the reinstatement of non-reinforced cocaine seeking by cocaine priming.
Section snippets
Initial cocaine self-administration training
In all experiments, young adult, male Wistar rats (n = 171, weighing 225–250 g at the beginning of experiments) were first habituated during 2 3-h daily sessions to the experimental chambers (see also Supplementary Data (Appendix A). During habituation, no lever or light cue was presented, and rats were allowed to move freely and explore the cage. After habituation, rats were progressively trained to press a lever to self-administer cocaine intravenously (0.25 mg per injection) under a final
Experiment 1: Effects of extinction of non-contingent cocaine priming on relapse-like behavior
On the first session of extinction, all priming doses of cocaine reinstated responding above the non-primed level of responding but this effect rapidly decreased within-session with repeated priming (i.e., from the first to the third priming dose) (F3,57 = 27.57, p < 0.01) (Fig. 1a). A higher-resolution time course of the within-session extinction of cocaine priming is shown in Supplementary Fig. S1. After repeated session of extinction, there was a further extinction of cocaine priming
Discussion
The present study demonstrates that extinction of cocaine priming, whether administered contingently or non-contingently, has no major effect on subsequent relapse-like behavior in rats. Importantly, this lack of effectiveness could not be due to the context-specificity of extinction of cocaine priming (Mihindou et al., 2011) since relapse-like behavior occurred in the same environmental context. The lack of effectiveness of extinction of cocaine priming on subsequent relapse-like behavior
Declaration of interest
None.
Acknowledgments
This research was supported by funding from the Centre National de la Recherche Scientifique, the Agence Nationale de la Recherche (ANR- 2010-BLAN-1404-01), the Université de Bordeaux, the Conseil Regional d’Aquitaine (CRA11004375/11004699), the Labex BRAIN (ANR-10-LABX-43), and the NRJ Foundation. We thank Jean-Philippe Fougères and Eric Wattelet for administrative assistance. We also thank Sandra Dovero, Evelyne Doudnikoff, and Matthieu Bastide for technical advice, and Etienne Gontier from
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