Systemic mifepristone blocks reconsolidation of cue-conditioned fear; Propranolol prevents this effect.

Abstract

Reducing reconsolidation of reactivated traumatic memories may offer a novel pharmacological treatment for posttraumatic stress disorder (PTSD). Preclinical research is needed to identify candidate drugs. We evaluated the ability of postreactivation mifepristone (RU38486, a glucocorticoid antagonist), alone and in combination with propranolol (a beta-adrenergic blocker), both given systemically, to reduce cue-conditioned fear in rats. On Day 1, a 30-s tone conditioned stimulus (CS) was paired with an electric shock unconditioned stimulus (US). On Day 2, the CS was presented without the US (reactivation), and the freezing conditioned response (CR) was measured. This was immediately followed by subcutaneous injection of vehicle, mifepristone 30 mg/kg, propranolol 10 mg/kg, or both. On Day 3, the CR was again measured as a test of postreactivation long-term memory (PR-LTM). On Day 10, the CR was again measured to evaluate spontaneous recovery. On Day 11, the US was presented alone (reinstatement). On Day 12, the CR was again measured. A fifth group received mifepristone without the CS presentation (nonreactivation) on Day 2. A sixth group was tested four hours after the Day 2 mifepristone injection to measure postreactivation short-term memory. Postreactivation, but not nonreactivation, mifepristone produced a decrement in the CR that did not undergo spontaneous recovery and underwent only modest reinstatement. Mifepristone did not exert its effect when administered concurrently with propranolol. Postreactivation mifepristone did not impair short-term memory. Systemic mifepristone blocks the reconsolidation of cue-conditioned fear in rats. Concurrent administration of propranolol prevents this effect. Postreactivation mifepristone may be a promising treatment for PTSD, but not necessarily in combination with propranolol.

Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

“…Our results are consistent with several studies investigating reconsolidation blockers either systemically (Debiec and Ledoux, 2004;Blundell et al, 2008;Taubenfeld et al, 2009;Pitman et al, 2011) or intracranially (Nader et al, 2000;Debiec and Ledoux, 2004;Ben Mamou et al, 2006;Jin et al, 2007). Indeed, it is accepted in the literature that the lack of spontaneous recovery, the selectivity to reactivated memories, and the presence of intact short-term memory are criteria that define the reconsolidation process.…”

“…Human work 2.4.1 MGH. On the basis of the animal results reported in previous annual reports and published in Pitman et al (2011), we decided to perform a double-blind, placebo-controlled study of prereactivation mifepristone's ability to reduce psychophysiologic responding during traumatic mental imagery in trauma-exposed human subjects. We analyzed data from 34 completed subjects who received PR mifepristone (n=14), NR mifepristone (n=10), or placebo (n=10), randomized and double-blind.…”

Psychophysiology of Delayed Extinction and Reconsolidation in Humans

“…Reactivation of a trauma memory and subsequent interference with its reconsolidation may offer a feasible and effective treatment strategy. Reconsolidation is governed by neurobiological processes similar to those of consolidation (Lee, Everitt, & Thomas, 2004), and is susceptible to pharmacological blockade (Debiec & Ledoux, 2004;Jin, Lu, Yang, Ma, & Li, 2007;Pitman et al, 2011;Przybyslawski, Roullet, & Sara, 1999;Kindt, Soeter & Vervliet, 2009). Studies exploring the efficacy of behavioral intervention, such as modifications to extinction learning within the reconsolidation window, have produced mixed results regarding interference with fear memory reconsolidation.…”

Learned Avoidance in the Male Syrian Hamster: Investigating the Outcome of a Glucocorticoid Antagonist on Reconsolidation

“…Pitman et al (2011) argue that when a memory is extinguished, it may be recovered through a reexposure to the unconditioned stimulus alone, or with the passage of time. On the other hand, it has been suggested that a memory that has undergone reconsolidation blockage is not recoverable, because the memory is thought to be erased, not extinguished.…”

“…However, it impaired post-retrieval in long-term memory and the amnesia did not display any spontaneous recovery six days after retrieval. Pitman et al (2011) described how administration of certain reconsolidation-blocking drugs shortly after memory reactivation produced memory deficits in subsequent testing.…”