A double blind, placebo-controlled study of the effects of post-retrieval propranolol on reconsolidation of memory for craving and cue reactivity in cocaine dependent humans

Abstract

Rationale/Objectives This study examined the effects of propranolol vs. placebo, administered immediately after a 'retrieval' session of cocaine cue exposure (CCE), on craving and physiological responses occurring 24 hr. later during a subsequent 'test' session of CCE. It was hypothesized that compared to placebo-treated cocaine-dependent (CD) individuals, propranolol-treated CD individuals would evidence attenuated craving and physiological reactivity during the test session. Secondarily, it was expected that group differences identified in the test session would be evident at a 1-week follow-up CCE session. Exploratory analyses of treatment effects on cocaine use were also performed at follow-up. Methods CD participants received either 40 mg propranolol or placebo immediately following a 'retrieval' CCE session. The next day, participants received a 'test' session of CCE that was identical to the 'retrieval' session except no medication was administered. Participants underwent a ‘follow-up’ CCE session 1-week later. Craving and other reactivity measures were obtained at multiple time points during the CCE sessions. Results Propranolol- vs. placebo-treated participants evidenced significantly greater attenuation of craving and cardiovascular reactivity during the test session. Analysis of the follow-up CCE session data did not reveal any group differences. Although there was no evidence of treatment effects on cocaine use during follow-up, this study was insufficiently powered to rigorously evaluate differential cocaine use. Conclusions This double-blind, placebo-controlled laboratory study provides the first evidence that propranolol administration following CCE may modulate memories for learning processes that subserve cocaine craving/cue reactivity in CD humans. Alternative interpretations of the findings were considered and implications of the results for treatment were noted.

β-Arrestin–biased signaling mediates memory reconsolidation

“…In animal studies, propranolol has been shown to inhibit reconsolidation of cocaine-and morphine-conditioned place preference (27,42). Postreactivation propranolol administration also attenuates reconsolidation of memories for craving and cue reactivity in cocaine addicts and abstinent heroin addicts (31,43). Previous studies have shown that Arrb2 −/− mice respond well to cocaine in CPP (44), but not to amphetamineinduced locomotor activity, compared with wild-type mice (45).…”

Cocaine Seeking During Initial Abstinence Is Driven by Noradrenergic and Serotonergic Signaling in Hippocampus in a Sex-Dependent Manner

“…Propranolol as a Potential Therapeutic: Actions at NE and 5-HT Receptors Propranolol reduces cue-induced reinstatement of cocaine seeking and conditioned place preference (CPP) for cocaine in rodents, as well as cue-induced craving in cocaine-dependent humans (Bernardi et al, 2006;Smith and Aston-Jones, 2011;Saladin et al, 2013). Alternatively, systemic propranolol increased dopamine release in NAc, and reduced cocaine selfadministration indicating that propranolol may increase cocaine's reinforcing efficacy (Harris et al, 1996;Perry et al, 2015).…”

“…Among cocainedependent patients, exposure to drug-associated cues or stressors results in increased adrenocorticotrophic hormone (ACTH), cortisol, and hypothalamic-pituitary-adrenal (HPA) axis activity (Sinha et al, 2000(Sinha et al, , 2003. Among abstinent heroin addicts and cocaine-dependent individuals, propranolol is effective in reducing cortisol-, stress-, or cueinduced cravings Zhao et al, 2010;Saladin et al, 2013). Racemic propranolol antagonizes β-ARs and 5-HT receptors, and therefore these effects may be due to the actions of either of these receptors.…”

Noradrenergic Regulation of Fear and Drug-Associated Memory Reconsolidation

“…Thus, modification of reconsolidation-related plasticity allows for memory modification and even memory elimination. Reconsolidation is now being studied extensively as disruption of pathologic, emotional forms of memory could alleviate memory-related disorders, such as posttraumatic stress disorder (PTSD; Brunet et al, 2008) and drug addiction (Saladin et al, 2013;Xue et al, 2012).…”