TABLE 2

Incubation of drug craving: behavioral measures and learning processes

Initial incubation procedureTime-dependent increases in drug seeking after cessation of drug self-administration were initially observed in studies that used the so-called between-within reinstatement procedure (Shalev et al., 2002). In this procedure, the extinction and reinstatement test phases are performed during a single session on different days after drug self-administration training (Tran-Nguyen et al., 1998; Neisewander et al., 2000; Grimm et al., 2001; Shalev et al., 2001). In the first study, in which this time-dependent drug-seeking phenomenon was termed “incubation of craving,” Grimm et al. (2001) assessed cocaine seeking at different time points after forced abstinence (1 day to 60 days) in two ways. They first exposed rats to six to eight 1-h extinction sessions in the absence of a discrete tone-light cue previously paired with cocaine infusions during training. The authors then tested the rats immediately after the last extinction session for cue-induced reinstatement in a single 1-h session in which lever presses resulted in contingent presentations of the discrete cue. They found that lever presses in the extinction and cue-induced reinstatement tests follow a similar time course.
Current incubation procedureOver the years, several studies used the between-within reinstatement procedure and showed robust incubation of extinction responding (without the discrete cue) and subsequent cue-induced reinstatement (Grimm et al., 2003; Lu et al., 2004; Kerstetter et al., 2008). However, most subsequent mechanistic studies on incubation of drug craving after forced or voluntary abstinence have primarily used a simplified procedure in which rats were tested at different time points after cessation of drug self-administration in a single extinction session in the presence of contextual cues previously paired with drug effects (the self-administration chambers) and lever presses or nose pokes result in contingent presentations of the discrete cue (Pickens et al., 2011; Wolf, 2016; Dong et al., 2017; Szumlinski and Shin, 2018). In the studies described in the current review, investigators have used the simplified procedure to study mechanisms of incubation after voluntary abstinence.
Learning processes of incubationAn unresolved question is the learning processes involved in the observed incubation of drug seeking in the simplified single-session procedure. This question was addressed by Adhikary et al. (2017) who used a variation of the between-within procedure and two different contexts to determine the unique contribution of the discrete cues, the contextual cues, and the learned operant response to the incubated methamphetamine seeking response, as typically assessed in the single-session procedure. They trained rats to self-administer methamphetamine in a distinct context (context A) for 14 days; lever presses were paired with a discrete light cue. Next, they tested groups of rats in context A or a different nondrug context (context B) after 1 day, 1 week, or 1 month for extinction responding with or without the discrete cue. The authors found that operant responding in the extinction sessions in contexts A or B was higher after 1 week and 1 month than after 1 day; this effect was context-independent. Independent of the forced-abstinence period, operant responding in the extinction sessions was somewhat higher when responding led to contingent delivery of the discrete cue. After extinction in context B in the absence of the discrete cue, cue-induced reinstatement in context B was modestly higher after 1 month than after 1 day or 1 week. After extinction in context B in the presence of the discrete cue, context-induced reinstatement in context A was similar after 1 day, 1 week, and 1 month. These results demonstrate that the incubation of drug craving phenomenon is primarily mediated by time-dependent increases in context-independent nonreinforced operant responding, and this incubation effect is modestly increased by exposure to discrete cues previously paired with drug infusions.