sirolimus and Stress-Disorders--Post-Traumatic

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.

Topics: Adult; Combat Disorders; Combined Modality Therapy; Demography; Double-Blind Method; Drug Monitoring; Humans; Immunosuppressive Agents; Life Change Events; Male; Memory, Episodic; Memory, Long-Term; Mental Recall; Middle Aged; Pilot Projects; Psychiatric Status Rating Scales; Sirolimus; Socioeconomic Factors; Stress Disorders, Post-Traumatic; Treatment Outcome; Veterans

Studies about reconsolidation of conditioned fear memories have shown that pharmacological manipulation at memory reactivation can attenuate or enhance the subsequent expression of the conditioned fear response. Here we examined the effects of a single injection of the mTOR inhibitor rapamycin (Rap) into the infralimbic (IL) and prelimbic (PL) areas [which compose the ventromedial prefrontal cortex (PFC)] on reconsolidation and extinction of a traumatic fear memory. We found opposite effects of Rap infused into the PL and IL on reconsolidation and extinction: intra-PL Rap and systemic Rap impaired reconsolidation and facilitated extinction whereas intra-IL Rap enhanced reconsolidation and impaired extinction. These effects persisted at least 10 days after reactivation. Shock exposure induced anxiety-like behavior and impaired working memory and intra-IL and -PL Rap normalized these effects. Finally, when measured after fear retrieval, shocked rats exhibited reduced and increased phosphorylated p70s6K levels in the IL and basolateral amygdala, respectively. No effect on phosphorylated p70s6K levels was observed in the PL. The study points to the differential roles of the IL and PL in memory reconsolidation and extinction. Moreover, inhibiting mTOR via rapamycin following reactivation of a fear memory may be a novel approach in attenuating enhanced fear memories.

Topics: Animals; Anxiety; Avoidance Learning; Basolateral Nuclear Complex; Conditioning, Psychological; Disease Models, Animal; Electroshock; Extinction, Psychological; Fear; Male; Memory Consolidation; Memory, Short-Term; Nootropic Agents; Phosphorylation; Prefrontal Cortex; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Stress Disorders, Post-Traumatic; TOR Serine-Threonine Kinases

Traumatic, stressful life events are thought to trigger acquired anxiety disorders such as post-traumatic stress disorder (PTSD). Recent data suggests that the mammalian target of rapamycin (mTOR) plays a key role in the formation of traumatic memories. The predator stress paradigm allows us to determine whether mTOR mediates the formation of both context-dependent (associative) and context-independent (non-associative) fear memories. Predator stress involves an acute, unprotected exposure of a rat to a cat which causes long-lasting non-associative fear memories manifested as generalized hyperarousal and increased anxiety-like behavior. Here, we show that rapamycin, an mTOR inhibitor, attenuates predator stress-induced hyperarousal, lasting at least three weeks. In addition, rapamycin blocks a subset of anxiety-like behaviors as measured in the elevated plus maze and hole board. Furthermore, when re-exposed to the predator stress context, rapamycin-treated stressed rats showed increased activity compared to vehicle controls suggesting that rapamycin blocks predator stress-induced associative fear memory. Taken together with past research, our results indicate that mTOR regulation of protein translation is required for the formation of both associative and non-associative fear memories. Overall, these data suggest that mTOR activation may contribute to the development of acquired anxiety disorders such as PTSD.

Topics: Animals; Arousal; Behavior, Animal; Cats; Exploratory Behavior; Fear; Male; Maze Learning; Memory; Rats; Rats, Long-Evans; Reflex, Startle; Sirolimus; Stress Disorders, Post-Traumatic; Stress, Physiological; Stress, Psychological; TOR Serine-Threonine Kinases

Established traumatic memories have a selective vulnerability to pharmacologic interventions following their reactivation that can decrease subsequent memory recall. This vulnerable period following memory reactivation is termed reconsolidation. The pharmacology of traumatic memory reconsolidation has not been fully characterized despite its potential as a therapeutic target for established, acquired anxiety disorders including posttraumatic stress disorder (PTSD). The mammalian target of rapamycin (mTOR) kinase is a critical regulator of mRNA translation and is known to be involved in various forms of synaptic plasticity and memory consolidation. We have examined the role of mTOR in traumatic memory reconsolidation.. Male C57BL/6 mice were injected systemically with the mTOR inhibitor rapamycin (1-40mg/kg), at various time points relative to contextual fear conditioning training or fear memory retrieval, and compared to vehicle or anisomycin-treated groups (N=10-12 in each group).. Inhibition of mTOR via systemic administration of rapamycin blocks reconsolidation of an established fear memory in a lasting manner. This effect is specific to reconsolidation as a series of additional experiments make an effect on memory extinction unlikely.. Systemic rapamycin, in conjunction with therapeutic traumatic memory reactivation, can decrease the emotional strength of an established traumatic memory. This finding not only establishes mTOR regulation of protein translation in the reconsolidation phase of traumatic memory, but also implicates a novel, FDA-approved drug treatment for patients suffering from acquired anxiety disorders such as PTSD and specific phobia.

Topics: Animals; Conditioning, Psychological; Electroshock; Extinction, Psychological; Fear; Immunosuppressive Agents; Male; Mechanistic Target of Rapamycin Complex 1; Memory; Mice; Mice, Inbred C57BL; Multiprotein Complexes; Neural Inhibition; Proteins; Sirolimus; Stress Disorders, Post-Traumatic; TOR Serine-Threonine Kinases; Transcription Factors