Neural substrates of propranolol-induced impairments in the reconsolidation of nicotine-associated memories in smokers

Xiao Lin,Lin Lu,Yanxue Xue,Lin Liu,Jiahui Deng,Jie Shi,Jianyu Que,Hongqiang Sun,Jiajia Liu,Le Shi,Ping Wu,Kai Yuan,Qiandong Wang,Peng Li,Yanping Bao,Wei Yan

doi:10.1038/s41398-021-01566-6

Abstract

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).

Highlights

Nicotine addiction is a chronic relapsing disorder and one of the leading causes of preventable death worldwide [1]
Brain regions that are involved in reward memory exhibited propranolol-induced changes in activation after memory retrieval
These findings indicate that pre-retrieval propranolol administration blocked the re-stabilization of smoking-related cues

Summary

Introduction

Nicotine addiction is a chronic relapsing disorder and one of the leading causes of preventable death worldwide [1]. Repeated contiguous pairings between smoking-related cues and nicotine reinforcement lead to the cues acquiring the ability to elicit a host of conditioned responses (e.g., subjective craving) [3,4,5]. As the state of addiction develops, the processing of smoking-related cues becomes controlled by automatic stimulus–response associations via the abnormal activation of mesocorticolimbic circuitry. Associative learning and memory processes are contributory causal factors in the establishment and maintenance of nicotine-reinforced smoking. If the maladaptive memories for this learning can be disrupted, their contribution to the maintenance of smoking behavior can be reduced or eliminated, thereby decreasing the risk of relapse in smokers attempting to quit [6, 7]

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Results

Conclusion