Neurobiology of the incubation of drug craving: An update.

Relapse to drug use is often preceded by drug craving. Clinical observations in the 1980s led clinical investigators to postulate that cue-induced cocaine craving may increase during abstinence. Over 2 decades ago, investigators identified an analogous phenomenon in rats of time-dependent increases in drug-seeking behavior during homecage abstinence and termed it incubation of cocaine craving. In 2011, we reviewed the first decade of studies on brain mechanisms of incubation of drug craving. In this review, we provide an update on incubation-related brain mechanisms from studies published since 2011. We first review studies using the standard method of incubation after homecage-forced abstinence from cocaine, methamphetamine, opioid drugs, and nicotine. Next, we review studies using newer methods to study incubation after voluntary abstinence in the drug environment. In these studies, abstinence is achieved by either providing rats alternative nondrug rewards in a choice setting or introducing rats to adverse consequences to drug seeking or taking. We then discuss translational human studies on incubation of cue-induced drug craving. We conclude by discussing several emerging topics, including sex differences in incubation of drug craving, role of sleep patterns, and similarities and differences in mechanisms of incubation of craving across drug classes and abstinence conditions. Our 2 main conclusions are as follows: (1) across drug classes, there are both similarities and differences in mechanisms of incubation of drug craving after forced abstinence, and (2) the method used to achieve abstinence (forced or voluntary) can influence the mechanisms controlling incubation of drug craving or its expression. SIGNIFICANCE STATEMENT: This article reviews results from preclinical and clinical studies published since 2011 on neurobiological mechanisms of incubation of drug craving after homecage-forced abstinence or voluntary abstinence in the drug environment. This article also reviews translational human studies on incubation of cue-induced subjective drug craving and brain response during abstinence. The results of the studies reviewed indicate that multiple brain mechanisms control incubation of drug craving after homecage-forced abstinence or voluntary abstinence.