RESUMO
Persistent and maladaptive drug-related memories represent a key component in drug addiction. Converging evidence from both preclinical and clinical studies has demonstrated the potential efficacy of the memory reconsolidation updating procedure (MRUP), a non-pharmacological strategy intertwining two distinct memory processes: reconsolidation and extinction-alternatively termed "the memory retrieval-extinction procedure". This procedure presents a promising approach to attenuate, if not erase, entrenched drug memories and prevent relapse. The present review delineates the applications, molecular underpinnings, and operational boundaries of MRUP in the context of various forms of substance dependence. Furthermore, we critically examine the methodological limitations of MRUP, postulating potential refinement to optimize its therapeutic efficacy. In addition, we also look at the potential integration of MRUP and neurostimulation treatments in the domain of substance addiction. Overall, existing studies underscore the significant potential of MRUP, suggesting that interventions predicated on it could herald a promising avenue to enhance clinical outcomes in substance addiction therapy.
RESUMO
BACKGROUND: Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder. An unconditioned stimulus (US)-triggers a memory reconsolidation updating procedure (MRUP) that has been developed and demonstrated its effectiveness in decreasing relapse to cocaine and heroin in preclinical models. However, utilizations of abused drugs as the US to initiate MRUP can be problematic. We therefore designed a translational rat study and human study to evaluate the efficacy of a novel methadone-initiated MRUP. METHODS: In the rodent study, male rats underwent heroin self-administration training for 10 consecutive days, and were randomly assigned to receive saline or methadone at 10 min, 1 h or 6 h before extinction training after 28-day withdrawal. The primary outcome was operant heroin seeking after reinstatement. In the human experimental study, male OUD patients were randomly assigned to get MRUP at 10 min or 6 h after methadone or methadone alone. The primary outcomes included experimental cue-induced heroin craving change, sustained abstinence and retention in the study at post intervention and the 5 monthly follow-up assessments. The secondary outcomes were changes in physiological responses including experimental cue-induced blood pressure and heart rate. FINDINGS: Methadone exposure but not saline exposure at 10 min or 1 h before extinction decreased heroin-induced reinstatement of heroin seeking after 28-day of withdrawal in rats (F (8,80) = 8.26, p < 0.001). In the human study, when the MRUP was performed 10 min, but not 6 h after methadone dosing, the MRUP promoted sustained abstinence from heroin throughout 5 monthly follow-up assessments compared to giving methadone alone without MRUP (Hazard Ratio [95%CI] of 0.43 [0.22, 0.83], p = 0.01). The MRUP at 10 min, but not at 6 h after dosing also decreased experimental cue-induced heroin craving and blood pressure increases during the 6-month study duration (group × months × cue types, F (12, 63·3) = 2.41, p = 0.01). INTERPRETATION: The approach of MRUP within about 1 to 6 h after a methadone dose potently improved several key outcomes of OUD patients during methadone maintenance treatment, and could be a potentially novel treatment to prevent opioid relapse. FUNDING: National Natural Science Foundation of China (NO. U1802283, 81761128036, 82001400, 82001404 and 31671143) and Chinese National Programs for Brain Science and Brain-like Intelligence Technology (NO. 2021ZD0200800).