A memory retrieval-extinction procedure to prevent drug craving and relapse

Abstract

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.

Fig. 1

In rats, retrieval of drug-cue memories 10 min or 1 hour before extinction sessions prevented drug-priming–induced reinstatement of morphine CPP. (A) During CPP training, rats learned to associate one environmental context with the effect of morphine injections (10 mg/kg, subcutaneous) and to associate another context with saline injections. Next, all rats were tested for their place preference (CPP test 1). Twenty-four hours later, rats were divided into four groups and given different memory retrieval-extinction manipulations: 55-min extinction training (in one group), or 10-min memory retrieval + 45 min extinction training (in the other three groups—with either a 10-min, 1-hour, or 6-hour delay between memory retrieval and extinction training). All rats were tested for reinstatement of morphine CPP induced by a priming injection of morphine (5 mg/kg, subcutaneous). (B) Effect of the experimental manipulations on the CPP score. Data are mean ± SEM of preference score in seconds (time spent in the morphine-paired chamber minus time spent in the saline-paired chamber) during the CPP tests. Asterisk indicates different from the “no memory retrieval” condition; P < 0.05; n = 9 to 11 rats per experimental condition.

Fig. 2

In rats, retrieval of drug-cue memories 10 min before extinction sessions attenuated heroin-priming–induced reinstatement of drug seeking. (A) Timeline of the experimental procedure. Rats were trained to self-administer intravenous heroin during three 1-hour daily sessions over 10 days. Twenty-four hours later, the rats were divided into two groups and given different memory retrieval-extinction manipulations: 195-min extinction training or 15-min memory retrieval + 180-min extinction training, with 10 min between memory retrieval and extinction training. The rats were then tested for reinstatement of nosepoke responding after noncontingent priming injections of heroin (0.25 mg/kg, subcutaneous). (B and C) Number of responses (mean ± SEM) on the active and inactive nosepoke devices during the extinction sessions and the heroin-priming test. Asterisk indicates different from the “no memory retrieval” condition; P < 0.05; n = 6 to 7 rats per experimental condition.

Fig. 3

In humans, retrieval of drug-cue memories 10 min before extinction sessions caused long-lasting attenuation of cue-induced heroin craving. (A) Timeline of the experimental procedure. Neutral- and heroin-cue–induced drug craving (see supplementary materials) in abstinent heroin addicts was measured with VAS on day 1. Twenty-four hours later, the participants were divided into three groups and given different memory retrieval-extinction manipulations for 2 consecutive days: neutral cue exposure + 10-min delay + 60-min extinction training (in one group), or 5-min heroin-cue exposure (memory retrieval) + 60-min extinction training (in the other two groups—with 10 min or 6 hours between memory retrieval and extinction training). During the extinction sessions, the participants were given four consecutive sessions of repeated exposures to three different heroin-related cues (supplementary material). Measures of subjective craving and sympathetic activation (heart rate and blood pressure) were obtained after the extinction sessions. Cue-induced heroin craving was assessed again on days 4, 34, and 184 by using a procedure identical to that used on day 1. (B) Cue-induced heroin craving (mean ± SEM) on day 1 (baseline), days 4, 34, and 184 (1, 30, and 180 days after the memory retrieval-extinction sessions). Asterisk indicates different from “no memory retrieval” group; P < 0.05; n = 22 human subjects per group for day 1, 4, and 34; n = 16 to 18 human subjects per group for day 184.

Fig. 4

In humans, retrieval of drug-cue memories 10 min before the extinction sessions caused long-lasting attenuation of cue-induced increases in systolic and diastolic blood pressure but not heart rate. The experimental procedure was identical to that described in Fig. 3. (A) Heart rate. (B) Systolic blood pressure. (C) Diastolic blood pressure. Asterisk indicates different from “no memory retrieval” group; P < 0.05, n = 22 human subjects per group for day 1, 4, and 34; n = 16 to 18 human subjects per group for day 184.