Interfering with the reconsolidation of traumatic memory: Sirolimus as a novel agent for treating veterans with posttraumatic stress disorder
ABSTRACT Development of novel treatment approaches for combat-related posttraumatic stress disorder (PTSD) is critical, given the increasing prevalence of PTSD in veterans returning from war zone deployment. Established preclinical research using protein synthesis inhibitors (such as sirolimus) to interfere with fear memory reconsolidation provides a compelling rationale for investigation in humans.
This double-blind, placebo-controlled translational pilot study examined the effects of pairing reactivation of a trauma memory with a single administration of sirolimus on the frequency and intensity of PTSD symptoms in male combat veterans.
Primary analyses found no significant differences between treatment groups on any of the clinical or physiologic outcome measures. In an exploratory analysis of a subsample of post-Vietnam-era veterans who had more recent combat trauma, PTSD symptom scores fell significantly more in these veterans than in controls.
The post-Vietnam-era veteran findings suggest that further investigation of this pairing of sirolimus with traumatic memory reactivation may be warranted. Theoretically, interference with the reconsolidation of fear memories could ameliorate military-related psychological trauma symptoms. Future research should focus on veterans of more recent eras whose traumatic memories may be less entrenched and more amenable to pharmacologic modification within this procedure.
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ABSTRACT: Many psychiatric disorders are characterized by intrusive, distracting, and disturbing memories that either perpetuate the illness or hinder successful treatment. For example, posttraumatic stress disorder (PTSD) involves such strong reemergence of memories associated with a traumatic event that the individual feels like the event is happening again. Furthermore, drug addiction is characterized by compulsive use and repeated relapse that is often driven by internal memories of drug use and/or by exposure to external stimuli that were associated with drug use. Therefore, identifying pharmacological methods to weaken the strength of maladaptive memories is a major goal of research efforts aimed at finding new treatments for these disorders. The primary mechanism by which memories could be pharmacologically disrupted or altered is through manipulation of memory reconsolidation. Reconsolidation occurs when an established memory is remembered or reactivated, reentering a labile state before again being consolidated into long-term memory storage. Memories are subject to disruption during this labile state. In this chapter we will discuss the preclinical and clinical studies identifying potential pharmacological methods for disrupting the integrity of maladaptive memory to treat mental illness.Handbook of experimental pharmacology 01/2015; 228:381-415. DOI:10.1007/978-3-319-16522-6_13
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ABSTRACT: The experience of fear is closely linked to the survival of species. Fear can be conceptualized as a brain state that orchestrates defense reactions to threats. To avoid harm, an organism must be equipped with neural circuits that allow learning, detecting, and rapidly responding to threats. Past experience with threat can transform neutral stimuli present at the time of experience into learned threat-related stimuli via associative learning. Pavlovian threat conditioning is the central experimental paradigm to study associative learning. Once learned, these stimulus-response associations are not always expressed depending on context or new experiences with the conditioned stimuli. Neural circuits mediating threat learning have the inherent plasticity to adapt to changing environmental threats. Encounters devoid of danger pave the way for extinction or reconsolidation to occur. Extinction and reconsolidation can both lead to changes in the expression of threat-induced defense responses, but differ in stability and have a different neural basis. This review presents the behavioral models and the system-level neural mechanisms in animals and humans of threat learning and modulation. For further resources related to this article, please visit the WIREs website. The authors have declared no conflicts of interest for this article. © 2015 Wiley Periodicals, Inc.Wiley interdisciplinary reviews. Cognitive science 06/2015; DOI:10.1002/wcs.1353 · 0.79 Impact Factor