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The majority of smokers relapse even after successfully quitting because of the craving to smoking after unexpectedly re-exposed to smoking-related cues. This conditioned craving is mediated by reward memories that are frequently experienced and stubbornly resistant to treatment. Reconsolidation theory posits that well-consolidated memories are destabilized after retrieval, and this process renders memories labile and vulnerable to amnestic intervention. This study tests the retrieval reconsolidation procedure to decrease nicotine craving among people who smoke. In this study, 52 male smokers received a single dose of propranolol (n = 27) or placebo (n = 25) before the reactivation of nicotine-associated memories to impair the reconsolidation process. Craving for smoking and neural activity in response to smoking-related cues served as primary outcomes. Functional magnetic resonance imaging was performed during the memory reconsolidation process. The disruption of reconsolidation by propranolol decreased craving for smoking. Reactivity of the postcentral gyrus in response to smoking-related cues also decreased in the propranolol group after the reconsolidation manipulation. Functional connectivity between the hippocampus and striatum was higher during memory reconsolidation in the propranolol group. Furthermore, the increase in coupling between the hippocampus and striatum positively correlated with the decrease in craving after the reconsolidation manipulation in the propranolol group. Propranolol administration before memory reactivation disrupted the reconsolidation of smoking-related memories in smokers by mediating brain regions that are involved in memory and reward processing. These findings demonstrate the noradrenergic regulation of memory reconsolidation in humans and suggest that adjunct propranolol administration can facilitate the treatment of nicotine dependence. The present study was pre-registered at ClinicalTrials.gov (registration no. ChiCTR1900024412).

Fear memories can be reactivated by a fear-associated conditioned stimulus (CS) or unconditioned stimulus (US) and then undergo reconsolidation. Propranolol administration during CS retrieval-induced reconsolidation can impair fear memory that is specific to the reactivated CS. However, from a practical perspective, the US is often associated with multiple CSs, and each CS can induce a fear response. The present study sought to develop and test a US-based memory retrieval interference procedure with propranolol to disrupt the original fear memory and eliminate all CS-associated fear responses in humans. We recruited 127 young healthy volunteers and conducted three experiments. All of the subjects acquired fear conditioning, after which they received the β-adrenergic receptor antagonist propranolol (40 mg) or placebo (vitamin C) and were exposed to the US or CS to reactivate the original fear memory. Fear responses were measured. Oral propranolol administration 1 h before US retrieval significantly decreased subsequent fear responses and disrupted associations between all CSs and the US. However, propranolol administration before CS retrieval only inhibited the fear memory that was related to the reactivated CS. Moreover, the propranolol-induced inhibition of fear memory reconsolidation that was retrieved by the US had a relatively long-lasting effect (at least 2 weeks) and was also effective for remote fear memory. These findings indicate that the US-based memory retrieval interference procedure with propranolol can permanently decrease the fear response and prevent the return of fear for all CSs in humans. This procedure may open new avenues for treating fear-related disorders.

Smoking is partly attributed to alterations of reward processing. However, findings on the neurobiological mechanisms that underlie smoking-related and smoking-unrelated reward processing in smokers have been inconsistent. Neuroimaging experiments that used functional magnetic resonance imaging (fMRI) and reported brain responses to smoking-related cues and nonsmoking reward-related cues in smokers and healthy controls as coordinates in a standard anatomic reference space were identified by searching the PubMed, Embase, and Web of Science databases up to December 2018. Three meta-analyses were performed using random-effect nonparametric statistics with Seed-based d Mapping software, with brain activity contrast from individual studies as the input. The striatum showed higher activation in response to smoking-related cues compared with neutral cues in 816 smokers from 28 studies and lower activation in response to nonsmoking reward-related cues in 275 smokers compared with 271 healthy control individuals from 13 studies. The relative reactivity of the putamen to smoking-related cues increased in 108 smokers compared with 107 healthy controls from seven studies. Meta-regression showed that smokers with a greater severity of nicotine dependence exhibited less engagement of the striatum in response to both smoking-related cues and nonsmoking reward-related cues. The present results reveal the disruption of reward system function in smokers and provide new insights into diverging theories of addiction. With the escalation of nicotine dependence, nicotine appears to exert dynamic effects on reward processing, based on incentive sensitization theory and reward deficiency syndrome theory.