Effect of Selective Inhibition of Reactivated Nicotine-Associated Memories With Propranolol on Nicotine Craving.
A relapse into nicotine addiction during abstinence often occurs after the reactivation of nicotine reward memories, either by acute exposure to nicotine (a smoking episode) or by smoking-associated conditioned stimuli (CS). Preclinical studies suggest that drug reward memories can undergo memory reconsolidation after being reactivated, during which they can be weakened or erased by pharmacological or behavioral manipulations. However, translational clinical studies using CS-induced memory retrieval-reconsolidation procedures to decrease drug craving reported inconsistent results.



To develop and test an unconditioned stimulus (UCS)-induced retrieval-reconsolidation procedure to decrease nicotine craving among people who smoke.



A translational rat study and human study in an academic outpatient medical center among 96 male smokers (aged 18- 45 years) to determine the association of propranolol administration within the time window of memory reconsolidation (after retrieval of the nicotine-associated memories by nicotine UCS exposure) with relapse to nicotine-conditioned place preference (CPP) and operant nicotine seeking in rats, and measures of preference to nicotine-associated CS and nicotine craving among people who smoke.



The study rats were injected noncontingently with the UCS (nicotine 0.15 mg/kg, subcutaneous) in their home cage, and the human study participants administered a dose of propranolol (40 mg, per os; Zhongnuo Pharma).



Nicotine CPP and operant nicotine seeking in rats, and preference and craving ratings for newly learned and preexisting real-life nicotine-associated CS among people who smoke.



Sixty-nine male smokers completed the experiment and were included for statistical analysis: 24 in the group that received placebo plus 1 hour plus UCS, 23 who received propranolol plus 1 hour plus UCS, and 22 who received UCS plus 6 hours plus propranolol. In rat relapse models, propranolol injections administered immediately after nicotine UCS-induced memory retrieval inhibited subsequent nicotine CPP and operant nicotine seeking after short (CPP, d = 1.72, 95% CI, 0.63-2.77; operant seeking, d = 1.61, 95% CI, 0.59-2.60) or prolonged abstinence (CPP, d = 1.46, 95% CI, 0.42-2.47; operant seeking: d = 1.69, 95% CI, 0.66-2.69), as well as nicotine priming-induced reinstatement of nicotine CPP (d = 1.28, 95% CI, 0.27-2.26) and operant nicotine seeking (d = 1.61, 95% CI, 0.59-2.60) after extinction. Among the smokers, oral propranolol administered prior to nicotine UCS-induced memory retrieval decreased subsequent nicotine preference induced by newly learned nicotine CS (CS1, Cohen d = 0.61, 95% CI, 0.02-1.19 and CS2, d = 0.69, 95% CI, 0.10-1.28, respectively), preexisting nicotine CS (d = 0.57, 95% CI, -0.02 to 1.15), and nicotine priming (CS1, d = 0.82, 95% CI, 0.22-1.41 and CS2, d = 0.78, 95% CI, 0.18-1.37, respectively; preexisting nicotine CS, d = 0.92, 95% CI, 0.31-1.52), as well as nicotine craving induced by the preexisting nicotine CS (d = 0.64, 95% CI, 0.05-1.22), and nicotine priming (d = 1.15, 95% CI, 0.52-1.76).



In rat-to-human translational study, a novel UCS-induced memory retrieval-reconsolidation interference procedure inhibited nicotine craving induced by exposure to diverse nicotine-associated CS and nicotine itself. This procedure should be studied further in clinical trials.
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Yan-Xue
YX
Xue
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China2Peking University Sixth Hospital (Institute of Mental Health), Peking University, Beijing, China.
Jia-Hui
JH
Deng
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China2Peking University Sixth Hospital (Institute of Mental Health), Peking University, Beijing, China.
Ya-Yun
YY
Chen
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Li-Bo
LB
Zhang
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Ping
P
Wu
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Geng-Di
GD
Huang
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China2Peking University Sixth Hospital (Institute of Mental Health), Peking University, Beijing, China.
Yi-Xiao
YX
Luo
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Yan-Ping
YP
Bao
Peking University Sixth Hospital (Institute of Mental Health), Peking University, Beijing, China.
Yu-Mei
YM
Wang
Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland.
Yavin
Y
Shaham
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Jie
J
Shi
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China2Peking University Sixth Hospital (Institute of Mental Health), Peking University, Beijing, China3National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing, China5Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
Lin
L
Lu
D000293:Adolescent; D000328:Adult; D000818:Animals; D001245:Association Learning / Q000187:drug effects*; D003214:Conditioning, Classical / Q000187:drug effects; D066249:Craving / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D000069077:Memory Consolidation / Q000187:drug effects; D011939:Mental Recall / Q000187:drug effects*; D008875:Middle Aged; D009538:Nicotine; D011433:Propranolol / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D016540:Smoking Cessation / Q000379:methods* / Q000523:psychology*; D014029:Tobacco Use Disorder / Q000523:psychology* / Q000534:rehabilitation*; D057170:Translational Research, Biomedical; D055815:Young Adult
D009538:Nicotine; D011433:Propranolol