Effect And Neural Mechanism Of β-Blocker On Reconsolidation Of Alcohol Reward Memory

BackgroundA core symptom of alcohol dependence is a strong craving for alcohol,even if it causes serious negative consequences and still used repeatedly.The core of craving is repeated drinking and alcohol-related cues can form pathological reward memory.The long-term existence of reward memory is the root cause of craving and relapse.Therefore,the extinction of the alcohol related reward memory is important for reducing relapse.Previous studies suggest that drug-associated memory undergoes a process of memory reconsolidation when it was retrieved by drug-associated conditioned stimulus（CS）,and propranolol can interfere with the process of memory retrieval-reconsolidation.Based on the above,we hypothesized that propranolol can interfere with the process of memory reconsolidation retrieved by alcohol-related CS and reduce alcohol craving in alcohol-dependent patients.Meanwhile,we used fMRI to explore the neural mechanism which is related to the effect ofβ-receptor blocker on retrieval-reconsolidation of reward memory.ObjectivesExplore the effect and neural mechanism of beta-blocker in the process of reconsolidation of alcohol reward memory retrieved by conditioned stimulus.MethodsThe study was randomized,double-blind,placebo-controlled trial design and divided into two parts:In the first part,one hundred male alcohol-dependent patients who meet the enrollment criteria are recruited and divided into 5 groups:20 in each group（retrieval/propranolol group,retrieval/placebo group,no retrieval/propranolol group,no retrieval/placebo group,and retrieval/6 hours/propranolol group）.Collect their general demographic data,all subjects conduct alcohol-related learning and give placebo or propranolol 20 mg immediately after retrieval.Blood pressure and heart rate were monitored during learning,retrieval and test process,and the degree of craving was assessed by visual analogue scores;In the second part,included 22 male alcohol-dependent patients and 11 healthy subjects served as the control group whose matched with alcohol dependent group in age and education.22 alcohol-dependent patients were divided into two groups:propranolol group and placebo group.The image data collected by task-state fMRI scanning.SPM12 was used to analyze the BOLD data in fMRI,and to compare the differences in task-state fMRI characteristics between the alcohol-dependent group and the healthy control group,and the alcohol-dependent subjects propranolol group and placebo group.Results1.Behavioral test results:In the testing stage,after performing CS-related learning and retrieval on the subjects,we found that the heart rate,systolic blood pressure,diastolic blood pressure,and craving degree were reduced retrieval/propranolol group with test before,and the differences were statistically significant（P<0.05）.The heart rate,systolic blood pressure,diastolic blood pressure,and craving degree were still increased in other within-four groups.The heart rate difference(F_4,95=25.25,P<0.05),systolic blood pressure（F4,95=22.17,P<0.05）,diastolic blood pressure difference（F4,95=20.44,P<0.05）,craving difference（F4,95=22.08,P<0.05）were statistically significant in between-five groups.2.fMRI results:We found that compared with the healthy control group,the Alcohol-dependent group is bilateral medial frontal gyrus,right inferior frontal gyrus,left lingual gyrus,left fusiform gyrus,bilateral precuneus gyrus,and left superior parietal gyrus and the left posterior cingulate gyrus were more activated when viewing alcohol-related pictures（P<0.05,GRF corrected）;Compared with non-alcoholic pictures,the alcohol-dependent group showed stronger activation of the left fusiform gyrus and left inferior occipital gyrus when viewing alcohol-related pictures（P<0.05,GRF correction）;Compared with the placebo group,the activation of bilateral anterior wedge,left parietal gyrus and left posterior cingulate gyrus in the propranolol group was significantly reduced when viewing alcohol-related pictures（P<0.05,GRF correction）.Conclusions1.β-blocker interfere with the process of reconsolidation of alcohol reward memory retrieved by conditioned stimulus,which may be an effective way to reduce alcohol craving in alcohol-dependent patients.2.fMRI analysis found that alcohol-related cues make bilateral medial frontal gyrus,right inferior frontal gyrus,left lingual gyrus,left fusiform gyrus,bilateral precuneus gyrus,and left superior parietal gyrus,and left posterior cingulate gyrus were increased activation in brain regions associated with reward.3.Propranolol weakened the activation of bilateral anterior wedge,left parietal inferior marginal gyrus and left posterior cingulate gyrus,suggesting that norepinephrine may be involved in the process of retrieval-reconsolidation of alcohol reward memory in these brain regions.