Neurobiology of the incubation of drug craving

It was suggested in 1986 that cue-induced drug craving in cocaine addicts progressively increases over the first several weeks of abstinence and remains high for extended periods. During the past decade, investigators have identified an analogous incubation phenomenon in rodents, in which time-dependent increases in cue-induced drug seeking are observed after withdrawal from intravenous cocaine self-administration. Such an incubation of drug craving is not specific to cocaine, as similar findings have been observed after self-administration of heroin, nicotine, methamphetamine and alcohol in rats. In this review, we discuss recent results that have identified important brain regions involved in the incubation of drug craving, as well as evidence for the underlying cellular mechanisms. Understanding the neurobiology of the incubation of drug craving in rodents is likely to have significant implications for furthering understanding of brain mechanisms and circuits that underlie craving and relapse in human addicts.

Introduction

Relapse to drug use in humans can occur after prolonged abstinence [1] and is often precipitated by exposure to drug-associated cues that provoke drug craving [2] (see Glossary). In an attempt to account for this persistent relapse, it was hypothesized that cue-induced cocaine craving progressively increases over the first weeks of abstinence and remains high over extended periods [3]. An analogous incubation phenomenon, termed ‘incubation of drug craving’ [4], was subsequently identified in rats, based on observations that time-dependent increases in cue-induced cocaine or heroin seeking occurred after withdrawal from the drug 4, 5, 6.

Incubation of craving has also been observed in rats with a history of methamphetamine [7], alcohol [8], nicotine [9] or oral sucrose self-administration 10, 11 (Figure 1; see [12] for an early demonstration of ‘incubation of food craving’). Such a phenomenon has been demonstrated using several established procedures to assess the motivational impact of reward cues and cue-induced relapse to drug seeking 13, 14, 15, including extinction 16, 17, 18, 19, cue-induced reinstatement 4, 8, 9, 20, 21 and acquisition of a new response [22].

In humans, drug craving is induced not only by drug cues, but also by re-exposure to the drug itself or exposure to stress 23, 24. These stimuli are known to cause reinstatement of drug seeking in non-human laboratory animals 25, 26, 27, 28, 29; however, unlike drug cues, evidence for ‘incubation’ of the response of the rat to drug re-exposure (often termed ‘drug priming’) is mixed, with reports of time-dependent increases [30], decreases [31] or no change 18, 32 in cocaine priming-induced reinstatement of drug seeking. However, there is evidence for time-dependent changes in intermittent footshock stress-induced reinstatement after withdrawal from heroin or cocaine 6, 17. This ‘stress incubation’ effect, however, was not observed in reinstatement of methamphetamine seeking by the pharmacological stressor yohimbine [7].

Several factors influence the magnitude of incubation of cocaine craving in rodents, including age, housing conditions, exercise and sex hormones. Incubation of craving was observed to be weaker in adolescent rats than in adult rats [33]. Housing in an enriched environment during abstinence was found to decrease the magnitude of incubation of craving for cocaine in rats 34, 35 (see also [36] for similar results observed for the reinstatement of sucrose seeking). Exercise during abstinence decreased extinction responding and cue-induced reinstatement of cocaine seeking in rats [37] under self-administration training conditions that led to incubation of cocaine craving [38]. Finally, incubation of cocaine craving was more pronounced in female rats during estrus than in non-estrus females or in males [39].

In this review, we discuss recent studies that have investigated neurobiological mechanisms underlying the incubation of drug craving. Earlier studies on the incubation of cocaine craving have been covered in previous reviews [40]. Because of space limitations, we do not review correlational studies in which changes in gene expression and proteins were assessed in the absence of experimental manipulations to assess a causal role of the molecular changes in incubation of craving for cocaine 41, 42, 43, 44, 45 or other drugs 9, 46, 47, 48, 49.