Propranolol-induced inhibition of unconditioned stimulus-reactivated fear memory prevents the return of fear in humans

Abstract

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.

Blockade of β-Adrenergic Receptors by Propranolol Disrupts Reconsolidation of Drug Memory and Attenuates Heroin Seeking

“…We also demonstrated that the effects of post CS retrieval propranolol on heroin seeking are long lasting, suggesting relatively permanent interference with drug memory. Indeed, preclinical and clinical studies have demonstrated that propranolol has the ability to erase maladaptive memories associated with nicotine, cocaine, heroin or fear ( Fricks-Gleason and Marshall, 2008 ; Zhao et al, 2011 ; Xue et al, 2017b ; Deng et al, 2020 ). Thus, there is compelling evidence suggesting that propranolol might have a therapeutic utility in clinical settings and be an attractive candidate for relapse prevention.…”

The Mechanisms and Boundary Conditions of Drug Memory Reconsolidation

“…Nevertheless, the limitations of targeting CS-induced reconsolidation could be addressed by also targeting US-induced reconsolidation (Luo et al, 2015). Propranolol is capable of disrupting US-induced reconsolidation via beta-adrenergic signaling (Xue et al, 2017a,b;Deng et al, 2020), making this signaling pathway a promising target for the prevention of relapse.…”

Continuous theta-burst stimulation over the right dorsolateral prefrontal cortex disrupts fear memory reconsolidation in humans

“…We used a modified fear acquisition procedure based on our previous studies ( Deng et al., 2020 ; Liu et al., 2014 ; Yue et al., 2018 ). The participants were asked to specify the relationship between different CSs (colored square pictures on the computer screen) and a US (mild electric shock to the wrist).…”