Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Memory Retrieval-Extinction to Prevent Drug Craving


Science 13 April 2012: Vol. 336 no. 6078 pp. 241-245

A Memory Retrieval-Extinction Procedure to Prevent Drug Craving and Relapse

Yan-Xue Xue, Yi-Xiao Luo, Ping Wu, Hai-Shui Shi, Li-Fen Xue, Chen Chen, Wei-Li Zhu, Zeng-Bo Ding, Yan-ping Bao, Jie Shi, David H. Epstein, Yavin Shaham, Lin Lu

1National Institute on Drug Dependence, Peking University, Beijing 100191, China.

2Department of Biochemistry and Molecular Biology, Basic Medical College, Hebei Medical University, Shijiazhuang 050017, China.

3Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.


Drug use and relapse involve learned associations between drug-associated environmental cues and drug effects. Extinction procedures in the clinic can suppress conditioned responses to drug cues, but the extinguished responses typically reemerge after exposure to the drug itself (reinstatement), the drug-associated environment (renewal), or the passage of time (spontaneous recovery). We describe a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts. In rats, daily retrieval of drug-associated memories 10 minutes or 1 hour but not 6 hours before extinction sessions attenuated drug-induced reinstatement, spontaneous recovery, and renewal of conditioned drug effects and drug seeking. In heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions attenuated cue-induced heroin craving 1, 30, and 180 days later. The memory retrieval-extinction procedure is a promising nonpharmacological method for decreasing drug craving and relapse during abstinence.

Conditioning plays a major role in drug addiction, and responses to drug-associated cues persist during prolonged abstinence. These findings led to the development of cue-exposure therapies to extinguish the craving- and relapse-provoking effects of drug cues. However, cue-exposure therapy in clinical settings does not usually prevent relapse when former drug addicts return to their previous drug environments. Animal learning studies predict that extinction responding is susceptible to renewal, reinstatement, and spontaneous recovery. Respectively, these terms refer to resumption of original learned responses after change of environmental context, acute exposure to the unconditioned stimulus (such as food or drug), or passage of time.

More recently, preclinical investigators have been able to decrease behavioral effects of drug-associated cues by pharmacologically interfering with reconsolidation of drug-cue memories. Reconsolidation refers to a time-dependent process in which consolidated memory items are rendered transiently unstable shortly after their reactivation. However, with the exception of the beta-adrenoceptor antagonist propranolol, which is approved for human use, the other pharmacological compounds used in these studies are not suitable for human use. Consequently, the results from rat reconsolidation studies have not yet “translated” to clinical use in addiction treatment.

A nonpharmacological alternative may be possible: the “memory retrieval-extinction” behavioral procedure to interfere with reconsolidation of fear cues in rats and humans. Reinstatement, renewal, and spontaneous recovery of fear responding are prevented by acute exposure to cues previously paired with footshock (a retrieval manipulation) if that exposure is followed 10 min or 1 hour later (but not 6 hours later) by repeated exposure to the same cues in extinction sessions. Thus, extinction experience within the timeframe of the “reconsolidation window” after cued retrieval of the fear memories mimicked the behavioral effect of a pharmacological manipulation on suppression of fear conditioning.

We used an extinction-reinstatement procedure in rats [an animal model of drug relapse] and a cue-induced–craving procedure in humans to assess whether the memory retrieval-extinction procedure can decrease drug- and cue-induced drug preference and relapse in rats and cue-induced drug craving in humans..

Investigators have identified several ways to disrupt cue-memory reconsolidation or strengthen extinction learning. However, their potential as preventive treatments for addiction is limited because they often rely on pharmacological agents that are either not approved for human use or that can cause problematic side effects. We used established animal models of drug relapse and a standard human laboratory procedure for drug-induced craving to assess a purely behavioral procedure to decrease the motivational effects of drug cues during abstinence. The memory retrieval-extinction procedure decreased cue-induced drug craving and (extrapolating from our rat data) perhaps could reduce the likelihood of cue-induced relapse during prolonged abstinence periods. If our procedure weakens the original drug-cue memories rather than solely facilitating extinction, it may overcome the contextual renewal problems that have limited the clinical effectiveness of traditional extinction procedures, although this possibility needs empirical evaluation in human addicts. Last, although the cellular mechanisms and brain circuits underlying the long-lasting effects of the retrieval-extinction procedure on drug relapse and craving remain to be elucidated, our data point to a role for PKMζ activity in the infralimbic cortex and basolateral amygdala.

[end of paraphrase]