Targeting unconditioned stimulus-induced memory reactivation to prevent nicotine relapse
Yan-Xue Xue1Jia-Hui Deng1,2Ya-Yun Chen1,2Shi-Chao Sun1,2Ping Wu1Li-Bo Zhang1Li-Qun Zhang1Jie Shi1Lin Lu1,2
摘要：Objective: Memories for substance abuse can be decreased by pharmacological interference after conditioned stimulus-induced memory reactivation（CS-MR）. However, the procedure has limitations for "real world" relapse prevention, since the disruptive effect of the procedure is selective to the reactivated cues and does not generalize to other cues that have not been reactivated. In the present study, we investigated whether pharmacological interference after unconditioned stimulus-induced memory reactivation（US-MR） erase all nicotine-associated memory traces. Methods: In animal studies, rats were trained for pavlovian nicotine-associated memory with conditioned place preferences（CPP） and instrumental nicotine-associated memory with self-administration model. Memory was reactivated by exposure to previous nicotine-associated cues（as CS-MR） or a low dose of nicotine（as US–MR）. In human study, smokers were trained for the association between pictures on the computer screen and smoking tobaccos. Memory reactivation was induced by smoking tobacco. Results: We found that cerebral ventricular microinjections of inhibitors of protein synthesis immediately after but not 9 h after CS-MR or US-MR disrupted subsequent recall of nicotine CPP memory. We also confirmed the phenomenon in instrumental nicotine-associated memory（nicotine self-administration）. Subsequently, we found systemic administration of propranolol, an antagonist of adrenergic β-receptor, immediately after US-MR disrupted subsequent recall of nicotine CPP memory or nicotine self-administration memory. Furthermore, when rats were trained for two types of nicotine-associated memories（i.e. CPP memory and self-administration memory）, systemic administration of propranolol immediately after US-MR disrupted subsequent recall of both of them, while propranolol administration immediately after CS-MR only disrupted subsequent recall of the memory reactivated previously. Lastly, after smokers learned the association between smoking tobaccos and two associated cues, oral administration of propranolol one hour before US-MR also decreased all the smoking-associated memories, including new learned cue memories and existing cue memories in real world. Conclusion: Our findings indicate that pharmacological interferences after US-MR lead to erasure of all nicotine-associated memory traces, and the US-MR-targeting inhibition may be a new strategy for the treatment of nicotine relapse.