Implications For Posttraumatic Stress Disorder Research Articles

A Novel Animal Behavioral Model For Assessing Arousal and Anxiety States: Implications for Post-Traumatic Stress Disorder

Background: Post-traumatic stress disorder (PTSD) is a highly prevalent disorder with widespread impact on health co-morbidities, including cardiovascular disease (CVD). There is a pressing need to understand its underlying mechanisms. This study builds upon our previous published clinical and pre-clinical findings assessing cardiovascular and autonomic responses to stress. Using a recently developed behavioral model and lab-developed software for integrated behavioral and cardio-autonomic analysis, we sought to assess the impact of chronic unpredictable threat reminders on arousal and anxiety behavior as well as cardiovascular and autonomic function in pair-housed mice. Methods: Male and female C57bl/6J mice underwent Pavlovian auditory fear conditioning (n=10-16/group) and were returned to the home cage, equipped with speaker and top-down camera with infrared capabilities. Using a customized software to remotely deliver the conditioned stimulus (CS), pair-housed mice received 6 tones (30sec. 6kHz) throughout the light-dark (LD) cycle over a 24hr period (3 light, 3 dark), repeated for 14 days. The first CS during each LD cycle was recorded and freezing behavior was manually scored. Videos were used to train DeepLabCutTM (DLC) for automated behavioral analysis. On day 15, to evaluate whether evoked freezing is context-dependent, mice were placed into a novel context and CS-dependent freezing was measured. Mice then underwent elevated plus maze (EPM), uncued startle reactivity testing, and fear-potentiated startle (FPS) to assess locomotor, anxiety, and hyperarousal and heightened vigilant behaviors. Results: Following 14 days of chronic unpredictable conditioned threat reminders, fear-conditioned male and female mice exhibited strong CS-evoked freezing in the home cage. Circadian evaluation revealed enhanced freezing in the light versus the dark phase ( males, p<0.01; females, p<0.01). DLC analysis successfully and accurately quantified freezing of group-housed mice. Over 14 days, CS-dependent freezing declined, though this was context-dependent as freezing was significantly higher in a novel context on day 15 ( males, p<0.01; females, p=0.02). While chronic threat reminders did not affect behavior in the EPM, males, but not females, displayed hyperarousal in both uncued (startle to 120dB, males, p<0.01, females, p=0.62) and cued (FPS, males, p=0.04, females, p=0.60) startle testing, though neither males nor females had increased background anxiety during FPS ( males, p=0.77, females, p=0.77). Conclusions: Here we demonstrate, using lab-developed software, environment- and circadian-dependent conditioned freezing in the home cage of group-housed mice. These results further demonstrate that the delivery of chronic intermittent unpredictable conditioned threat reminders leads to an enhanced startle phenotype, that may be sex-dependent. Future studies are needed to assess direct measures of autonomic function in this model, which could provide novel insights into and potentially revealing new therapeutic and preventive strategies for mitigating PTSD-related autonomic dysfunction. (CDMRP) PR210574. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Predator Odor Stressor, 2,3,5-Trimethyl-3-Thiazoline (TMT): Assessment of Stress Reactive Behaviors During an Animal Model of Traumatic Stress in Rats.

Animal models utilizing predator odor stress are important in understanding implications for post-traumatic stress disorder. 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) has been used to measure stress reactive behaviors during TMT exposure, indicative of stress coping behaviors. In addition, long-term consequences of stress including contextual-induced stress memory, anxiety-like and hyperarousal behaviors, and subsequent increases in alcohol self-administration can also be examined after TMT exposure. In this article, we describe the TMT exposure protocol used in our lab and how we measure different stress-reactive behaviors that rats engage in during the TMT exposure. Rats are placed in Plexiglass chambers that contain white bedding on the bottom of the chamber and a metal basket in the top right corner containing a filter paper that 10 µl of TMT is pipetted onto. During the 10 min exposure, rats can move around the chamber freely. Exposures are recorded by a video camera for later analysis. During TMT exposure, rats engage in a variety of stress-reactive behaviors, including digging and immobility behavior. These are two distinctly different types of stress-induced behavioral coping strategies to measure individual differences in stress responsivity. To examine individual differences, we group rats into TMT-subgroups based on time spent engaging in digging or immobility behavior. We calculate a digging/immobility ratio score in which we divide the total time spent digging by the total time spent immobile. A cut-off strategy is used such that rats with a criterion ratio score <1.0 are classified as TMT-1 (i.e., low digging/high immobility; greater passive coping) and rats with a ratio score >1.0 are classified as TMT-2 (i.e., high digging/low immobility; greater active coping). Here, we provide a detailed description of the TMT exposure protocol and step-by-step process in evaluation of stress-reactive behaviors. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Predator odor stressor exposure using TMT Basic Protocol 2: Description of stress-reactive behaviors during TMT exposure and formation of TMT-subgroups.

Involvement of cannabinoid receptors and neuroinflammation in early sepsis: Implications for posttraumatic stress disorder

Sepsis is associated with several comorbidities in survivors, such as posttraumatic stress disorder (PTSD). This study investigated whether rats that survive sepsis develop the generalization of fear memory as a model of PTSD. Responses to interventions that target the endothelin-1 (ET-1)/cannabinoid system and glial activation in the initial stages of sepsis were evaluated. As a control, we evaluated hyperalgesia before fear conditioning. Sepsis was induced by cecal ligation and puncture (CLP) in Wistar rats. CLP-induced sepsis with one or three punctures resulted in fear generalization in the survivors 13 and 20 days after the CLP procedure, a process that was not associated with hyperalgesia. Septic animals were intracerebroventricularly treated with vehicle, the endothelin receptor A (ETA) antagonist BQ123, the cannabinoid CB1 and CB2 receptor antagonists AM251 and AM630, respectively, and the glial blocker minocycline 4 h after CLP. The blockade of either CB1 or ETA receptors increased the survival rate, but only the former reversed fear memory generalization. The endothelinergic system blockade is important for improving survival but not for fear memory. Treatment with the CB2 receptor antagonist or minocycline also reversed the generalization of fear memory but did not increase the survival rate that was associated with CLP. Minocycline treatment also reduced tumor necrosis factor-α levels in the hippocampus suggesting that neuroinflammation is important for the generalization of fear memory induced by CLP. The influence of CLP on the generalization of fear memory was not related to Arc protein expression, a regulator of synaptic plasticity, in the dorsal hippocampus.

Global Neuropeptidome Profiling in Response to Predator Stress in Rat: Implications for Post-Traumatic Stress Disorder.

Traumatic stress triggers or exacerbates multiple psychiatric illnesses, including post-traumatic stress disorder (PTSD). Nevertheless, the neurophysiological mechanisms underlying stress-induced pathology remain unclear, in part due to the limited understanding of neuronal signaling molecules, such as neuropeptides, in this process. Here, we developed mass spectrometry (MS)-based qualitative and quantitative analytical strategies to profile neuropeptides in rats exposed to predator odor (an ethologically relevant analogue of trauma-like stress) versus control subjects (no odor) to determine peptidomic alterations induced by trauma. In total, 628 unique neuropeptides were identified across 5 fear-circuitry-related brain regions. Brain-region-specific changes of several neuropeptide families, including granin, ProSAAS, opioids, cholecystokinin, and tachykinin, were also observed in the stressed group. Neuropeptides from the same protein precursor were found to vary across different brain regions, indicating the site-specific effects of predator stress. This study reveals for the first time the interaction between neuropeptides and traumatic stress, providing insights into the molecular mechanisms of stress-induced psychopathology and suggesting putative novel therapeutic strategies for disorders such as PTSD.

Emotional Memory Processing during REM Sleep with Implications for Post-Traumatic Stress Disorder.

REM sleep is important for the processing of emotional memories, including fear memories. Rhythmic interactions, especially in the theta band, between the medial prefrontal cortex (mPFC) and limbic structures are thought to play an important role, but the ways in which memory processing occurs at a mechanistic and circuits level are largely unknown. To investigate how rhythmic interactions lead to fear extinction during REM sleep, we used a biophysically based model that included the infralimbic cortex (IL), a part of the mPFC with a critical role in suppressing fear memories. Theta frequency (4-12 Hz) inputs to a given cell assembly in IL, representing an emotional memory, resulted in the strengthening of connections from the IL to the amygdala and the weakening of connections from the amygdala to the IL, resulting in the suppression of the activity of fear expression cells for the associated memory. Lower frequency (4 Hz) theta inputs effected these changes over a wider range of input strengths. In contrast, inputs at other frequencies were ineffective at causing these synaptic changes and did not suppress fear memories. Under post-traumatic stress disorder (PTSD) REM sleep conditions, rhythmic activity dissipated, and 4 Hz theta inputs to IL were ineffective, but higher-frequency (10 Hz) theta inputs to IL induced changes similar to those seen with 4 Hz inputs under normal REM sleep conditions, resulting in the suppression of fear expression cells. These results suggest why PTSD patients may repeatedly experience the same emotionally charged dreams and suggest potential neuromodulatory therapies for the amelioration of PTSD symptoms.SIGNIFICANCE STATEMENT Rhythmic interactions in the theta band between the mPFC and limbic structures are thought to play an important role in processing emotional memories, including fear memories, during REM sleep. The infralimbic cortex (IL) in the mPFC is thought to play a critical role in suppressing fear memories. We show that theta inputs to the IL, unlike other frequency inputs, are effective in producing synaptic changes that suppress the activity of fear expression cells associated with a given memory. Under PTSD REM sleep conditions, lower-frequency (4 Hz) theta inputs to the IL do not suppress the activity of fear expression cells associated with the given memory but, surprisingly, 10 Hz inputs do. These results suggest potential neuromodulatory therapies for PTSD.

P.0801 Stress exposure differentially regulates Methyl-CpG binding protein 2 peripheral expression according to gender: implications for post-traumatic stress disorder

P.0801 Stress exposure differentially regulates Methyl-CpG binding protein 2 peripheral expression according to gender: implications for post-traumatic stress disorder

How Processing of Sensory Information From the Internal and External Worlds Shape the Perception and Engagement With the World in the Aftermath of Trauma: Implications for PTSD.

Post-traumatic stress disorder (PTSD) is triggered by an individual experiencing or witnessing a traumatic event, often precipitating persistent flashbacks and severe anxiety that are associated with a fearful and hypervigilant presentation. Approximately 14–30% of traumatized individuals present with the dissociative subtype of PTSD, which is often associated with repeated or childhood trauma. This presentation includes symptoms of depersonalization and derealization, where individuals may feel as if the world or self is “dream-like” and not real and/or describe “out-of-body” experiences. Here, we review putative neural alterations that may underlie how sensations are experienced among traumatized individuals with PTSD and its dissociative subtype, including those from the outside world (e.g., touch, auditory, and visual sensations) and the internal world of the body (e.g., visceral sensations, physical sensations associated with feeling states). We postulate that alterations in the neural pathways important for the processing of sensations originating in the outer and inner worlds may have cascading effects on the performance of higher-order cognitive functions, including emotion regulation, social cognition, and goal-oriented action, thereby shaping the perception of and engagement with the world. Finally, we introduce a theoretical neurobiological framework to account for altered sensory processing among traumatized individuals with and without the dissociative subtype of PTSD.

On the role of social position on extreme stress appraisal: Implications for post-traumatic stress disorder

IntroductionRecently, several studies have implicated the social context during a traumatic experience in susceptibility to, and severity of, post-traumatic stress disorder (PTSD). Although the precise mechanisms through which the social context affects the development of PTSD are unknown, it has been suggested that the neuropeptides oxytocin and β-endorphin may play a key role in this dynamic through their effects on both the locus coeruleus and the mesocortical and mesolimbic dopamine systems.ObjectivesThis experiment aims to identify in how far a formal social position, endowed by a recognised authority, modulates the stress response in cadets at the Czech military academy during a highly stressful training exercise.MethodsAs part of survival training, 40 cadets partake in a simulation of an avalanche. Although the maximum duration of the experience (being buried under snow) is 15 minutes, most cadets do not last longer than a few minutes with a significant portion requesting termination after a matter of seconds. During the experience, participants are fitted with a heart-rate and heart-rate variability monitor and tested before and after for pain resilience (a common proxy measure for β-endorphin). Participants are randomly allocated to have their individual scores or the average of their collective scores (in small groups of 5) incorporated in their final evaluation of the exercise.ResultsNot all data has been collected yet.ConclusionsWe expect to see a difference in resilience (measured in duration) between the two groups which is mirrored in the afore mentioned biomarkers.

Ventral Tegmental Area Dysfunction and Disruption of Dopaminergic Homeostasis: Implications for Post-traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition characterized by intrusive recollections of the traumatic event, avoidance behaviors, hyper-arousal to event-related cues, cognitive disruption, and mood dysregulation. Accumulating preclinical and clinical evidence implicates dysfunction of the ventral tegmental area (VTA) dopaminergic system in PTSD pathogenesis. This article reviews recent advances in our knowledge of the relationship between dopaminergic dyshomeostasis and PTSD, including the contributions of specific dopaminergic gene variants to disease susceptibility, alterations in VTA dopamine neuron activity, dysregulation of dopaminergic transmission, and potential pharmacological and psychological interventions for PTSD targeting the dopaminergic system. An in-depth understanding of PTSD etiology is crucial for the development of innovative risk assessment, diagnostic, and treatment strategies following traumatic events.

Investigating cultural differences in the effects of expressive suppression when processing traumatic distressing material

While suppression is associated with detrimental post-traumatic psychological adjustment, research has not considered the effect of culture on this relationship. This study investigated cultural differences in the effects of expressive suppression, whilst watching a traumatic film, on subjective distress, psychophysiological responses and intrusive memory. Australians of European heritage or East Asian Australian participants (n = 82) were randomly assigned to either a suppression group (instructed to suppress their emotions during the film) or a control group (no instructions regarding emotion management). Electrodermal activity, heart rate and heart rate variability (root mean square of the successive differences; RMSSD) were measured pre-, during and post-film. Participants reported the number of film-related intrusions in the 5 min and 7 days post-viewing. While the European Australian group did not differ significantly on RMSSD, the East Asian suppression group scored significantly higher on RMSSD during the film than the East Asian control group. Second, those in the suppression groups, regardless of cultural background, reported significantly fewer intrusions immediately post-film than controls. Third, we found that for the European Australian group, change in heart rate interacted with group (control versus suppression) when predicting weekly intrusions. However, for the East Asian group change in heart rate did not interact with group when predicting weekly intrusions. The findings are discussed in the context of current research on culture and emotion regulation and implications for post-traumatic stress disorder.

Post-traumatic stress disorder and dementia in veterans: A scoping literature review.

Emerging research has found an association between post-traumatic stress disorder (PTSD) and dementia in veterans, yet little is known about the nature of this association and how it is conceptualized in the literature. The purpose of this scoping review is to understand how the relationship between PTSD and dementia in veterans is recognized and described in the peer-reviewed literature. A scoping review was conducted using Arksey and O'Malley's (International Journal of Social Research Methodology, 8, 19, 2005) framework. Articles are included if participants were veterans with a focus on PTSD and dementia. A total of six databases (CINAHL, MEDLINE, EMBASE, PsycINFO, HealthSTAR, and PubMed) were searched along with the reference lists of eligible sources in September 2018. Thematic analysis was used to summarize the data. Thirty-six studies were included in this review. Three main themes emerged from the literature: (i) symptomatic expression of PTSD and dementia; (ii) aetiology underlying the relationship between PTSD and dementia; and (iii) implications of PTSD and dementia on healthcare providers, treatment, and resources. This study highlights the ongoing need to understand mechanisms underlying the association between PTSD and dementia, the need for definition of PTSD symptoms, and to sensitize healthcare providers to the presence of PTSD when caring for veterans with dementia.

Decreased Nociceptin Receptors Are Related to Resilience and Recovery in College Women Who Have Experienced Sexual Violence: Therapeutic Implications for Posttraumatic Stress Disorder

BackgroundPosttraumatic stress disorder (PTSD) is a stress disorder that develops in only some individuals following a traumatic event. Data suggest that a substantial fraction of women recover after sexual violence. Thus, the investigation of stress and antistress neuropeptides in this sample has the potential to inform the neurochemistry of resilience following trauma. Nociceptin is an antistress neuropeptide in the brain that promotes resilience in animal models of PTSD. Methods[11C]NOP-1A positron emission tomography was used to measure the in vivo binding to nociceptin receptors in 18 college women who had experienced sexual violence irrespective of whether they met DSM-5 diagnostic criteria for PTSD. [11C]NOP-1A data from 18 healthy control subjects were also included to provide a contrast with the sexual violence group. [11C]NOP-1A total distribution volume (VT) in the regions of interest were measured with kinetic analysis using the arterial input function. The relationships between regional VT and Clinician-Administered PTSD Scale for DSM-5 total symptom and subscale severity were examined using correlational analyses. ResultsNo differences in [11C]NOP-1A VT were noted between the sexual violence and control groups. VT in the midbrain and cerebellum were positively correlated with PTSD total symptom severity in the past month before positron emission tomography. Intrusion/re-experiencing and avoidance subscale symptoms drove this relationship. Stratification of subjects by a DSM-5 PTSD diagnosis and contrasting their VT with that in control subjects showed no group differences. ConclusionsDecreased midbrain and cerebellum nociceptin receptors are associated with less severe PTSD symptoms. Medications that target nociceptin should be explored to prevent and treat PTSD.

Serotonin 2A receptors are a stress response system: implications for post-traumatic stress disorder

Serotonin, one of the first neurotransmitters to be identified, is an evolutionarily old molecule that is highly conserved across the animal kingdom, and widely used throughout the brain. Despite this, ascribing a specific set of functions to brain serotonin and its receptors has been difficult and controversial. The 2A subtype of serotonin receptors (5-HT2A receptor) is the major excitatory serotonin receptor in the brain and has been linked to the effects of drugs that produce profound sensory and cognitive changes. Numerous studies have shown that this receptor is upregulated by a broad variety of stressors, and have related 5-HT2A receptor function to associative learning. This review proposes that stress, particularly stress related to danger and existential threats, increases the expression and function of 5-HT2A receptors. It is argued that this is a neurobiological adaptation to promote learning and avoidance of danger in the future. Upregulation of 5-HT2A receptors during stressful events forms associations that tune the brain to environmental cues that signal danger. It is speculated that life-threatening situations may activate this system and contribute to the symptoms associated with post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine, which activates 5-HT2A receptors, has been successful in the treatment of PTSD and has recently achieved status as a breakthrough therapy. An argument is presented that 3,4-methylenedioxymethamphetamine may paradoxically act through these same 5-HT2A receptors to ameliorate the symptoms of PTSD. The central thematic contention is that a key role of serotonin may be to function as a stress detection and response system.

The Role of the Amygdala and the Ventromedial Prefrontal Cortex in Emotional Regulation: Implications for Post-traumatic Stress Disorder.

The importance of the amygdala as a salience detector and in emotional learning is now well accepted. The mechanisms that regulate and inhibit the amygdala, however, are less well understood. This review provides evidence from imaging and lesion studies to support the role of the ventromedial prefrontal cortex (vmPFC) as a moderator and inhibitor of the amygdala. The dual inhibition model centres on the broadly defined ventromedial prefrontal cortex (vmPFC) and the distinct role of two of its subcomponents, the rostral anterior cingulate cortex and orbitofrontal cortex. The dual inhibition model posits that these two regions, along with their associated inhibitory pathways, must interact for adequate inhibitory control of the amygdala and emotional regulation. Following a description of the model's experimental support, it is then proposed as a neuropsychological mechanism for post-traumatic stress disorder (PTSD). Flashbacks, as a defining feature of PTSD, are described in terms of a subcortical orienting network. Finally, there is a discussion of how a neuropsychological understanding of post-traumatic stress disorder (PTSD) might inform a clinician's approach to treatment and how the dual inhibition model might have a more general application to understanding emotional dysregulation.

Mindfulness and Fear Extinction: A Brief Review of Its Current Neuropsychological Literature and Possible Implications for Posttraumatic Stress Disorder.

Research in the neuroscience of mindfulness has grown rapidly in recent years. This includes empirical investigations into structural and functional changes in several brain regions-particularly, the hippocampus, the prefrontal cortex, and the amygdala-in association with the practice of mindfulness. Of interest to the current paper is that such brain regions are also implicated in empirical research focusing on fear extinction. While fear extinction has, therefore, been suggested as one of the possible mechanisms to underlie the positive effects of mindfulness, the conceptual links and research implications have lacked specific focus and detailed discussion in the literature. The purpose of this paper is, therefore, two-fold. First, this paper briefly reviews the extant literature on the neuropsychological mechanisms underlying mindfulness-particularly that, which has been found to be similarly implied in fear extinction-and hence, suggests future research directions based on its current state in the literature. Second, this paper explores the implications of this for fear-based psychopathologies, specifically for posttraumatic stress disorder (PTSD). Discussion from this paper suggests the idea of fear extinction as an underlying mechanism of mindfulness to be one that is still preliminary, yet promising; in turn, elucidating the need for further methodologically rigorous study to specifically determine fear extinction as a result of mindfulness, as well as to incorporate neuroimaging techniques in supporting the existing literature that have found preliminary support of mindfulness for PTSD.

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD.

Posttraumatic stress disorder (PTSD) is characterized by hyperarousal and recurrent stressful memories after an emotionally traumatic event. Extensive research has been conducted to identify the neurobiological determinants that underlie the pathophysiology of PTSD. In this review, we examine evidence regarding the molecular and cellular pathophysiology of PTSD focusing on two primary brain regions: the vmPFC and the amygdala. This discussion includes a review of the molecular alterations related to PTSD, focusing mainly on changes to glucocorticoid receptor signaling. We also examine postmortem gene expression studies that have been conducted to date and the molecular changes that have been observed in peripheral blood studies of PTSD patients. Causal, mechanistic evidence is difficult to obtain in human studies, so we also review preclinical models of PTSD. Integration of peripheral blood and postmortem studies with preclinical models of PTSD has begun to reveal the molecular changes occurring in patients with PTSD. These findings indicate that the pathophysiology of PTSD includes disruption of glucocorticoid signaling and inflammatory systems and occurs at the level of altered gene expression. We will assess the impact of these findings on the future of PTSD molecular research.

From “bystander to witness”: The art of mourning and the Veterans’ Art Movement

Numerous veterans have observed that one does not heal from war, but rather one learns to surrender to the complicated losses that wartime experiences bring. Veterans have pushed back against stereotyped images of themselves as heroes, victims, or perpetrators. Many have challenged the implications of posttraumatic stress disorder (PTSD) as a diagnosis, as well as the effectiveness of evidence-based treatment procedures for PTSD. Work emerging from the Veterans’ Art Movement by a poet, a photographer, and a “Combat Paper” maker will be discussed in relation to the tasks of mourning, reparation, and formation of postwar narratives. The work of these veterans offers useful insights into the psychosocial implications of unresolvable traumatic loss, as well as detailed strategies for the creation of therapeutic mourning spaces. Through a variety of artistic practices, veterans have created opportunities to transform themselves and their communities from mere bystanders to attuned witnesses of the dire consequences of war. Their work calls our attention to the therapeutic actions of aesthetic representation and art-making in the communalization of war trauma. Additionally, they expand our understanding of art practices for the identification of postwar losses and the working-through of moral injury.

Sleep Disruption, Safety Learning, and Fear Extinction in Humans: Implications for Posttraumatic Stress Disorder.

Fear learning is critical in the development and maintenance of posttraumatic stress disorder (PTSD) symptoms, and safety learning and extinction are necessary for recovery. Studies in animal models suggest that sleep disruption, and REM sleep fragmentation in particular, interfere with safety learning and extinction processes, and recently, studies are extending these findings to humans. A discussion of the human literature is presented here, which largely consists of experimental studies in healthy human control subjects. A theoretical model for the relationship between fear learning, sleep disruption, and impaired safety learning and extinction is proposed, which provides an explanatory framework for sleep disruption and its relationship to PTSD. Overall, findings suggest that sleep disruption plays a role in the development and maintenance of PTSD symptoms, and thus presents an important modifiable target in PTSD treatment.

Role of the endogenous cannabinoid system in fear circuitry: Translational findings and clinical implications for post-traumatic stress disorder

s / Drug and Alcohol Dependence 146 (2015) e34–e117 e61 Human pharmacology of mephedrone: A dose-finding pilot study Esther Papaseit1,3, Clara Perez-Mana1,3, Mitona Pujadas1, Francina Fonseca2, Marta Torrens2,3, Rafael De La Torre1,4, Magi Farre1,3 1 Human Pharmacology and Neurosciences, Hospital del Mar Medical Research Institute-IMIM, Barcelona, Spain 2 Drug Addiction Unit, Hospital del Mar-INAD, Barcelona, Spain 3 Universidad Autonoma de Barcelona-UAB, Barcelona, Spain 4 Universidad Pompeu Fabra-UPF, Barcelona, Spain Aims: Mephedrone is a synthetic cathinone included in the “Novel Psychoactive Substances” group. European epidemiological data showed a high prevalence of use. There are not experimental data in humans of the pharmacological effects of mephedrone. Objective was to obtain preliminary data on the effects of mephedrone and doses for future investigations. Methods: Nine healthy male, recreational users of psychostimulants, participated as outpatients in three different experimental sessions, inwhichoneof the substanceswasadministeredeachday. They receivedsingleoraldosesofmephedrone (n=3,50mg,100mg and placebo; n=3, 150mg, 200mg and placebo; n=3, 150mg, 200mg and MDMA 100mg). Drugs were administered doubleblind, and randomised (lower doses were allocated before higher doses for safety reasons in case of 150mg and 200mg). Study variables included: vital signs (blood pressure, heart rate, temperature, pupil diameter), subjective effects (visual analog scales-VAS, ARCI49 item short form, VESSPA questionnaire), and blood and urine samples for pharmacokinetics. Results: Mephedrone produced effects at 150 and 200mg, with dose-related increases of blood pressure, heart rate and pupil diameter (but not temperature).Mephedrone producedmore intense effects than MDMA. Mephedrone induced pleasurable effects (ARCI-MBG, VAS “good effects”, VAS “liking”), and mild changes in perceptions but not hallucinations. Conclusions:Mephedroneproducesdose-relatedeffects invital parameters and pleasurable subjective effects. Its pharmacologic profile is similar to MDMA and other psychostimulants. Financial support: Supported by grants from Instituto de Salud Carlos III (ISCIII, FIS-FEDER, FIS PI11/0196), ISCIII-Red de Trastornos Adictivos (RTA RD12/0028/0009). Clara Perez-Mana is a Rio Hortega fellowship (ISCIII, CM12/00085). Esther Papaseit is a Jordi Gras (PSMAR, 2013) and a Rio Hortega fellowship (ISCIII, CM12/00016, 2014). http://dx.doi.org/10.1016/j.drugalcdep.2014.09.534 Role of the endogenous cannabinoid system in fear circuitry: Translational findings and clinical implications for post-traumatic stress disorder Santiago Papini1,2, D.A. Hien1,2, Y. Neria2, F. Levin2 1 City College, New York, NY, United States 2 New York State Psychiatric Institute, New York, NY,

Relationship between Fear Conditionability and Aversive Memories: Evidence from a Novel Conditioned-Intrusion Paradigm

Intrusive memories – a hallmark symptom of posttraumatic stress disorder (PTSD) – are often triggered by stimuli possessing similarity with cues that predicted or accompanied the traumatic event. According to learning theories, intrusive memories can be seen as a conditioned response to trauma reminders. However, direct laboratory evidence for the link between fear conditionability and intrusive memories is missing. Furthermore, fear conditioning studies have predominantly relied on standardized aversive stimuli (e.g. electric stimulation) that bear little resemblance to typical traumatic events. To investigate the general relationship between fear conditionability and aversive memories, we tested 66 mentally healthy females in a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with neutral sounds as conditioned stimuli and short violent film clips as unconditioned stimuli. Subsequent aversive memories were assessed through a memory triggering task (within 30 minutes, in the laboratory) and ambulatory assessment (involuntary aversive memories in the 2 days following the experiment). Skin conductance responses and subjective ratings demonstrated successful differential conditioning indicating that naturalistic aversive film stimuli can be used in a fear conditioning experiment. Furthermore, aversive memories were elicited in response to the conditioned stimuli during the memory triggering task and also occurred in the 2 days following the experiment. Importantly, participants who displayed higher conditionability showed more aversive memories during the memory triggering task and during ambulatory assessment. This suggests that fear conditioning constitutes an important source of persistent aversive memories. Implications for PTSD and its treatment are discussed.