Abstract
Pharmacotherapeutic intervention during traumatic memory consolidation has been suggested to alleviate or even prevent the development of posttraumatic stress disorder (PTSD). We recently reported that, in a controlled, prospective animal model, depriving rats of sleep following stress exposure prevents the development of a PTSD-like phenotype. Here, we report that administering the wake-promoting drug modafinil to rats in the aftermath of a stressogenic experience has a similar prophylactic effect, as it significantly reduces the prevalence of PTSD-like phenotype. Moreover, we show that the therapeutic value of modafinil appears to stem from its ability to stimulate a specific circuit within the hypothalamus, which ties together the neuropeptide Y, the orexin system and the HPA axis, to promote adaptive stress responses. The study not only confirms the value of sleep prevention and identifies the mechanism of action of a potential prophylactic treatment after traumatic exposure, but also contributes to understanding mechanisms underlying the shift towards adaptive behavioral response.
Highlights
Recurring memories of a traumatic event are a fundamental feature of posttraumatic stress disorder (PTSD) and underlie many aspects of its clinical manifestation, including intrusive thoughts, physiological hyperarousal, avoidance behavior and emotional numbing.[1]
Our previous studies highlight the importance of an initial bolus of endogenous or DISCUSSION We report that a single dose of modafinil (350 mg kg − 1), injected 30 min after predator-scent stress (PSS) exposure, significantly moderated behavioral patterns that represent stress-induced anxiety, avoidance and hyperarousal in the elevated plus maze (EPM) and acoustic startle response (ASR) paradigms
A similar pattern of behavioral stress responses was observed when rats were sleepdeprived by gentle handling for 6 h following PSS exposure,[7] suggesting that the effects of modafinil were mediated by the post-exposure wakefulness
Summary
Recurring memories of a traumatic event are a fundamental feature of posttraumatic stress disorder (PTSD) and underlie many aspects of its clinical manifestation, including intrusive thoughts, physiological hyperarousal, avoidance behavior and emotional numbing.[1]. Independent of the time of the day, enhances the consolidation of newly acquired memory traces[3,5] through an active reorganization of representations, whereas acute sleep deprivation may disrupt this process and impair retrieval functions.[6] We recently reported that depriving rats of sleep for 6 h following exposure to a stressful, traumatic-like event significantly reduces the prevalence of their PTSD-like behaviors and impairs the formation and consolidation of hippocampusdependent traumatic memories—a mechanism possibly relevant to the development of PTSD.[7] The logical step is to examine, in an established animal model of PTSD, whether pharmacologically disrupting sleep in the aftermath of a stressogenic experience can alleviate or altogether prevent PTSD-related symptoms. We chose to use modafinil [(RS)-2-(diphenylmethylsulfinyl) acetamide]; the mechanism of action of this drug is yet unknown,[12] it has been approved by the FDA for treating excessive daytime sleepiness associated with narcolepsy, shift work sleep disorder and obstructive sleep apnea/hypopnea syndrome
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