Animal Model Of Post-traumatic Stress Disorder Research Articles

The Stressed-out Rat

The Stressed-out Rat

Prenatal stress exacerbates the impact of an aversive procedure on the corticosterone response to stress in female rats

Post-traumatic stress disorder (PTSD) is associated with marked alterations in hypothalamic-pituitary adrenal (HPA) function. In rats, prenatal restraint stress (stress applied to pregnant mothers, PRS) is known to impact behavioral and neuroendocrine sensitivity to several kinds of mild stress in adulthood. We have recently shown that PRS also modifies behavioral responses after exposure to an intense footshock in a potential animal model of PTSD. The aim of the present study was to evaluate the long-term effects of an aversive procedure (footshock followed by 3 weekly situational reminders) on the corticosterone response to a novel stress (restraint stress, 140 days after the footshock) in adult female PRS rats. Our data extend previous results showing that PRS leads to a long-lasting increase in plasma corticosterone after restraint stress in adult male rats. Moreover, we demonstrate that 140 days after the intense footshock, female PRS rats have lower corticosterone levels 60 min after restraint stress, suggesting an increase in the negative feedback of the HPA axis. These results indicate that early stress may favor long-lasting modifications of the HPA axis subsequent to exposure to an intense stress in adulthood.

Gender-related qualitative differences in baseline and post-stress anxiety responses are not reflected in the incidence of criterion-based PTSD-like behaviour patterns

Background. Most epidemiological studies report higher prevalence rates of stress-related disorders such as acute stress disorder, post-traumatic stress disorder (PTSD) and major depressive disorder in women than in men. Few animal models of PTSD have taken gender differences into account and have typically used male subjects. In order to explore gender-related PTSD-like stress-responses more thoroughly, we applied an animal model that focuses selectively on individual patterns of behavioural responses. Methods. Prevalence rates of individual behavioural response to a single exposure to predator scent stress (PSS) were assessed by both elevated plus-maze and startle response paradigms. Prevalence rates of extreme behavioural disruption (EBR) on both tests were assessed, correlated to corticosterone levels, and compared to global population response data. In addition, we assessed learning and memory in the Morris water-maze (MWM). Results. There were no significant differences between the behavioural responses related to oestrous cycle phase in terms of global data for the groups or in terms of prevalence rates of EBR. The overall patterns of response of males and females were affected, yet females demonstrated greater levels of baseline anxiety-like behaviour and lower peak levels of post-exposure anxiety-like behaviour than males. However, the prevalence rates of individual subjects who responded with PTSD-like behaviour were equal for female and male subjects. PSS-exposed female subjects demonstrated significantly compromised performance in the MWM compared to males. Conclusions. In this animal model, the results clarified that the assumption that females are more vulnerable is true for the magnitude of the response, but not for the prevalence of pathological response patterns in rat populations.

Exposure to extreme stress impairs contextual odour discrimination in an animal model of PTSD

Post-traumatic stress disorder (PTSD) patients respond to trauma-related danger cues even in objectively safe environments as if they were in the original event, seemingly unable to adequately modulate their responses based on the contextual cues present. In order to model this inability to utilize contextualized memory, in an animal model of PTSD, a novel experimental paradigm of contextual cue processing was developed--the differential contextual odour conditioning (DCOC) paradigm--and tested in trauma-exposed animals and controls. In the DCOC paradigm, animals encountered cinnamon odour in both an aversive environment and a rewarding (safe) environment. Response (freezing) to cinnamon odour was tested in a third, neutral environment to examine the ability of animals to modulate their responses based on the contextual cues. The effect of exposure to traumatic stressors, e.g. predator scent stress (PSS) and underwater trauma (UWT), on contextual cue discrimination was assessed. Rats trained in the DCOC paradigm acquired the ability to modulate their behavioural responses to odour cue based on contextual cues signalling safe vs. dangerous environment. The PSS and UWT stressors abolished the ability to modulate their responses based on contextual cues, both when exposure preceded DCOC training, and when it followed successfully completed training. The DCOC paradigm offers a promising model for studying the neurobiological basis of contextual modulation of response to potential threat in animals, a process that is disrupted by exposure to severe stress/trauma, and thus might be particularly salient for the study of PTSD.

Brief post-stressor treatment with pregabalin in an animal model for PTSD: Short-term anxiolytic effects without long-term anxiogenic effect

Background: The short- and long-term behavioral effects of a brief course of pregabalin, an antiepileptic structural analogue of α-aminobyturic acid with analgesic and anxiolytic effects, were assessed in an animal model of post-traumatic stress disorder (PTSD). Method: Two-hundred thirty-three adult male Sprague–Dawley rats were employed. Behavioral responses to traumatic stress exposure (predator urine scent) were assessed immediately after (1 h) and 30 days after treatment with saline or pregabalin (at doses of 30, 100 and 300 mg/kg) in terms of behavior in the elevated plus maze (EPM) and the acoustic startle response (ASR) paradigms. At day 31 the freezing response to a trauma cue (clean cat litter) was assessed. The same treatment regimen initiated at day 7 was assessed at day 30 and in response to the trauma cue on day 31 in a separate experiment. Results: In the short term, doses of 100 mg/kg and 300 mg/kg of pregabalin effectively attenuated anxiety-like behaviors. In the longer-term, pregabalin did not attenuate the onset of PTSD-like behaviors or the prevalence rates of severe cue-responses, for either the immediate or the delayed treatment regimens. Conclusion: Pregabalin may present an alternative compound for acute anxiolytic treatment after exposure to trauma, but has no long-term protective/preventive effects.

Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder

People who are exposed to horrific, life-threatening experiences are at risk for developing post-traumatic stress disorder (PTSD). Some of the symptoms of PTSD include persistent anxiety, exaggerated startle, cognitive impairments and increased sensitivity to yohimbine, an α2-adrenergic receptor antagonist. We have taken into account the conditions known to induce PTSD, as well as factors responsible for long-term maintenance of the disorder, to develop an animal model of PTSD. Adult male Sprague–Dawley rats were administered a total of 31 days of psychosocial stress, composed of acute and chronic components. The acute component was a 1-h stress session (immobilization during cat exposure), which occurred on Days 1 and 11. The chronic component was that on all 31 days the rats were given unstable housing conditions. We found that psychosocially stressed rats had reduced growth rate, reduced thymus weight, increased adrenal gland weight, increased anxiety, an exaggerated startle response, cognitive impairments, greater cardiovascular and corticosterone reactivity to an acute stressor and heightened responsivity to yohimbine. This work demonstrates the effectiveness of acute inescapable episodes of predator exposure administered in conjunction with daily social instability as an animal model of PTSD.

Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD

Although the impaired extinction of traumatic memory is one of the hallmark symptoms of posttraumatic stress disorder (PTSD), the underlying mechanisms of impaired extinction are unclear and effective pharmacological interventions have not yet been developed. Single prolonged stress (SPS) has been proposed as an animal model of PTSD, since rats subjected to SPS (SPS rats) show enhanced negative feedback of the HPA axis and increased contextual fear, which are characteristics similar to those observed in patients with PTSD. In this study, using SPS rats, we examined (a) the ability of SPS to impair fear extinction, (b) whether D-cycloserine (DCS) can alleviate impaired fear extinction in SPS rats, and (c) the effect of SPS and/or DCS on the levels of N-methyl-D-aspartate (NMDA) receptor subunit mRNAs in the rat hippocampus during extinction training. SPS rats exhibited impaired fear extinction in the contextual fear test, which was alleviated by the repeated administration of DCS. The effect of enhanced extinction, induced by the administration of DCS to SPS rats, was maintained for one week following extinction training. SPS induced significant upregulation of the levels of NMDA receptor subunit mRNAs before and during the period of extinction training, while repeated administration of DCS eliminated the enhanced mRNA levels of NMDARs. Behavioral analyses indicated that SPS is an appropriate animal model of PTSD and that DCS may be effective in the treatment of PTSD. These findings suggest that DCS, irrespective of its mechanistic involvement in the enhancement of fear extinction, may help to reverse hippocampal plasticity, and thus reverse the NMDA compensatory alterations.

Induction of c-Fos expression in the brain of the animal model of posttraumatic stress disorder (PTSD)

Animals using a single prolonged stress (SPS) paradigm (a number of different stressors in one prolonged session followed by a 1-week ‘no stress’ interval) show enhanced glucocorticoid negative feedback, which is PTSD-specific neuroendocrine abnormality, and are suggested to be an animal model of PTSD. To elucidate the neuronal mechanisms implicated in this negative feedback, we compared the distribution of Fos-like immunoreactivity in the brain of the SPS animals with the results in the animals which received acute neurogenic stress.

Post-traumatic stress behavioural responses in inbred mouse strains: can genetic predisposition explain phenotypic vulnerability?

Clinical studies of twin pairs and families of post-traumatic stress disorder (PTSD) patients raise questions as to possible genetic predisposition to PTSD. Studies using isogenic animal populations exposed to a stress paradigm could elucidate the relative contributions of genotype and environment to endophenotypic expression. The prevalence of individuals displaying severely compromised behavioural responses to predator scent stress (PSS) was assessed in six inbred strains of mice in an animal model of PTSD that classifies individuals into groups according to the degree of their behavioural response. The choice of strains was based on the frequent use of these mice in transgenic research. The prevalence of extreme behavioural response in the elevated plus maze and the acoustic startle response paradigms, performed in sequence, was assessed at baseline and 7 d after PSS exposure between and within strains, and compared to differences in circulating corticosterone levels. Narrow-sense trait heritability was determined by comparing the between-strain variance to the total variance. Although strain-specific differences in anxiety-like behaviours were demonstrated, the results revealed a significant degree of individual variability in response patterns within each of the inbred strains, yielding a baseline heritability factor for anxiety-like behaviours of 30%, but only 10% for response to stress exposure. Baseline anxiety-like behaviours were found not to be predictive of post-exposure behavioural responses. The response of the individual to stress is multifactorial and environmental factors play a predominant role in characterizing the individual response to stress exposure, although there are significant genetic underpinnings.

P.2.17 Perinatal nicotine exposure increases sensitivity to reinforcing effect of nicotine and has long-term effect on behavior

Research on post-traumatic stress disorder (PTSD) is faced with the challenge of understanding how a traumatic experience produces long-lasting detrimental effects on behavior and brain functioning, and more globally, how stress exacerbates somatic disorders, including cardiovascular disease. Moreover, the design of translational research needs to link animal models of PTSD to clinically relevant risk factors which address why only a subset of traumatized individuals develop persistent psychopathology. In this review, we have summarized our psychosocial stress rodent model of PTSD which is based on well-described PTSD-inducing risk factors, including a life-threatening experience, a sense of horror and uncontrollability, and insufficient social support. Specifically, our animal model of PTSD integrates acute episodes of inescapable exposure of immobilized rats to a predator with chronic daily social instability. This stress regimen produces PTSD-like effects in rats at behavioral, cognitive, physiological, pharmacological and epigenetic levels of analysis. We have discussed a recent extension of our animal model of PTSD in which stress exacerbated coronary pathology following an ischemic event, assessed in vitro. In addition, we have reviewed our research investigating pharmacological and non-pharmacological therapeutic strategies which may have value in clinical approaches toward the treatment of traumatized people. Overall, our translational approach bridges the gap between human and animal PTSD research to create a framework with which to enhance our understanding of the biological basis of trauma-induced pathology and to assess therapeutic approaches in the treatment of psychopathology.

Prazosin administered prior to inescapable stressor blocks subsequent exaggeration of acoustic startle response in rats

Exposure to traumatic stress can result in a number of pathophysiological conditions, including post-traumatic stress disorder (PTSD). PTSD is characterized by a number of persistently heightened physiological and behavioral indicators, including increased sensory arousal and increased startle response. Similar effects can be seen in an animal model of PTSD in which stress results from restraint and inescapable tailshocks to rats. The present study used this animal model to investigate the effects of prazosin, an α 1 adrenoceptor antagonist, on stress-induced elevation of acoustic startle response (ASR). To investigate this, male Sprague–Dawley rats were injected with 0.5 mg/kg of prazosin 30 min before restraint and inescapable tail shock on three consecutive days. ASR testing was performed 1, 4, 7 and 10 days post-stress and compared to baseline and control values. Results show a significant reduction of ASR hyperarousal in the group treated with prazosin prior to stress compared to vehicle treated stressed animals and controls. Pre-stress treatment with lower levels of prazosin (0.25, 0.1 and 0.05 mg/kg) showed similar results. These findings further implicate an α 1 adrenoceptor role in the pathophysiological response to traumatic stress and suggest a potential preventative role for prazosin.

Stress vulnerabilities in an animal model of post-traumatic stress disorder

We have studied the effects of inescapable electric foot shocks (ISs) on rats by using a subsequent avoidance/escape task performed in a shuttle box as an animal model of post-traumatic stress disorder (PTSD). In this study, the behavioral differences and the effects of chronic stress exposure prior to IS were examined among male rats of the Wistar, Fischer 344, and Lewis strains. In concordance with our previous report on the Wistar rats, we observed the characteristic features of PTSD in all three rat strains tested, that is, the hyperactive and hypoactive bidirectional behavioral changes that are associated with hypervigilant and hyperarousal behavior, and the numbing and avoidant behavior, respectively. The induction of hypoactive behaviors after IS was most exaggerated in the Fischer and Lewis strains. Although the count of hyperactive behaviors was maximal in the Fischer strain both at basal levels without IS and after IS, the increase in the rate of hyperactive behaviors by IS was the most prominent in the Lewis strain. In addition, preloaded chronic variable stress (CVS) enhanced the degree of hyperactive behavioral changes in the Wistar strain. Thus, we consider that the present study further validates the use of shuttle box paradigm as an animal model of PTSD by demonstrating the vulnerability due to genetic background and environmental preloaded stress.

The effects of chronic valproate and diazepam in a mouse model of posttraumatic stress disorder

To better understand neurochemical and psychopharmacological aspects of post-traumatic stress disorder (PTSD), it is necessary establish an animal model of PTSD in which behavioral changes persist for a long time after the initial traumatization. The present study aimed to characterize long-term behavioral alterations in male ICR mice as an animal model of PTSD consisting of a 2-day foot shock (0.8 mA, 10 s) followed by 3 weekly situational reminders (SR), and to evaluate the effects of repeated administration of valproate and diazepam on behavioral deficits of this animal model. The results showed that the aversive procedure induced several long-term behavioral deficiencies: increased freezing behavior and anxiety level, reduced time spent in an aversive like context. Repeated treatment with valproate (100–400 mg/kg, i.p.) induced a dose-dependent reduction of these behavioral changes. In contrast, diazepam at a low dose (0.25 mg/kg) but not at a high dose (4 mg/kg) reduced the behavioral deficiencies. These results demonstrate that exposure to intense foot shock associated with repeated situational reminders elicits long-term disturbances that last about 4 weeks after the foot shock exposure. These behavioral deficits can be ameliorated by repeated administration of valproate or diazepam at some special dose ranges.

Importance of early environment in the development of post-traumatic stress disorder-like behaviors

A number of clinical studies in which early adversities were defined retrospectively, demonstrated that early adverse experiences increased the morbidity rate of post-traumatic stress disorder (PTSD) in later life. However, no prospective studies have yet been conducted to elucidate whether early adversity affects the risk or severity of PTSD. Thus, we examined whether early adversity would strengthen the severity of PTSD symptoms in later life by using neonatal isolation (NI) and single prolonged stress (SPS) as an animal model of PTSD. We measured anxiety-like behavior in the elevated plus maze (EPM), contextual freezing in the contextual fear (CF) test, and analgesia in the flinch-jump and hot-plate tests in four groups of adult rats (sham, NI, SPS, and NI + SPS). NI significantly enhanced the SPS-induced decrease in the percentage of open arm time and open arm entries in the EPM, enhanced the SPS-induced increase in contextual freezing, and strengthened SPS-induced analgesia, without any changes in locomotor activity in the open field locomotor test. In addition, we examined the effect of environmental enrichment (EE). Repeated exposure to EE ameliorated the NI-induced enhancement of contextual freezing, but not anxiety-like behavior or analgesia, in response to SPS. The results of the present study demonstrated that while early adversity strengthened PTSD-like symptoms, EE alleviated the enhanced contextual freezing by NI and SPS. These findings suggest that early adversity may worsen dysfunction of the amygdala and hippocampus in PTSD, and an early intervention may alleviate the early adversity-mediated enhancement of hippocampal dysfunction in PTSD.

The Contribution of an Animal Model Toward Uncovering Biological Risk Factors for PTSD

Clinical studies of posttraumatic stress disorder (PTSD) have elicited proposed risk factors for developing PTSD in the aftermath of stress exposure. Generally, these risk factors have arisen from retrospective analysis of premorbid characteristics of study populations. A valid animal model of PTSD can complement clinical studies and help to elucidate issues, such as the contribution of proposed risk factors, in ways which are not practicable in the clinical arena. Important qualities of animal models include the possibility to conduct controlled prospective studies, easy access to postmortem brains, and the availability of genetically manipulated subjects, which can be tailored to specific needs. When these qualities are further complemented by an approach which defines phenomenologic criteria to address the variance in individual response pattern and magnitude, enabling the animal subjects to be classified into definable groups for focused study, the model acquires added validity. This article presents an overview of a series of studies in such an animal model which examine the contribution of two proposed risk factors and the value of two early postexposure pharmacological manipulations on the prevalence rates of subjects displaying an extreme magnitude of behavioral response to a predator stress paradigm.

Anisomycin, a Protein Synthesis Inhibitor, Disrupts Traumatic Memory Consolidation and Attenuates Posttraumatic Stress Response in Rats

Paradoxical changes in memory represent a troublesome characteristic of posttraumatic stress disorder (PTSD). Exceptionally vivid intrusive memories of some aspects of the trauma are mingled with patchy amnesia regarding other important aspects. Molecular studies of the memory process suggest that the conversion from labile short-term memory into long-term fixed traces involves protein synthesis. This study assessed the effects of administration of anisomycin, a protein synthesis inhibitor, after initial exposure, after exposure to a cue associated with triggering experience, and after reexposure to the triggering trauma in an animal model of PTSD. Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in rats that were exposed to predator stress, with and without microinjection of anisomycin. Microinjection of anisomycin before and after stress exposure reduced anxiety-like and avoidant behavior, reduced the mean startle amplitude, and reversed the stress-induced habituation deficit 7 days later. The persistent anxiety-like behaviors that were seen after stress exposure do not appear to be sensitive to anisomycin after reexposure to a cue associated with the event or after reexposure to the index experience. Disruption of the process of traumatic memory consolidation may be useful for mitigating PTSD symptoms.

Blunted HPA Axis Response to Stress Influences Susceptibility to Posttraumatic Stress Response in Rats

Posttraumatic stress disorder (PTSD) is associated with low levels of circulating cortisol, and recent studies suggest that cortisol administration may reduce PTSD symptoms. This study investigated the role of cortisol in the manifestation of anxiety- and fear-like symptoms in an animal model of PTSD. Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in three strains of rats exposed to predator stress, with and without prior corticosterone treatment. Extreme behavioral changes in both paradigms implied an extreme behavioral response (EBR), representing PTSD-like symptoms. Lewis rats exhibited greater baseline anxiety-like behaviors and greater stress-induced increases in anxiety-like behaviors than Fischer F344 or Sprague-Dawley rats, with only minor corticosterone increases following stress. Prevalence of EBR was 50% among Lewis rats compared with 10% of Fischer F344 and 25% of Sprague-Dawley rats. Administering corticosterone 1 hour before stress exposure reduced the prevalence of EBR from 50% to 8% in the Lewis rats. These results suggest that a blunted HPA response to stress may play a causal role in this model of PTSD and that this susceptibility may be prevented by administration of cortisol before stress exposure.

Nitric oxide as inflammatory mediator in post-traumatic stress disorder (PTSD): evidence from an animal model.

Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that may develop after experiencing or witnessing a traumatic event. Recent clinical evidence has suggested the involvement of neurodegenerative pathology in the illness, particularly with brain imaging studies revealing a marked reduction in hippocampal volume. Of greater significance is that these anatomical changes appear to be positively correlated with the degree of cognitive deficit noted in these patients. Stress-induced increases in plasma cortisol have been implicated in this apparent atrophy. Although not definitive, clinical studies have observed a marked suppression of plasma cortisol in PTSD. The basis for hippocampal neurodegeneration and cognitive decline therefore remains unclear. Stress and glucocorticoids increase glutamate release, which is recognized as an important mediator of glucocorticoid-induced neurotoxicity. Recent preclinical studies have also noted that glutamate and nitric oxide (NO) play a causal role in anxiety-related behaviors. Because of the prominent role of NO in neuronal toxicity, cellular memory processes, and as a neuromodulator, nitrergic pathways may have an important role in stress-related hippocampal degenerative pathology and cognitive deficits seen in patients with PTSD. This paper reviews the preclinical evidence for involvement of the NO-pathway in PTSD, and emphasizes studies that have addressed these issues using time-dependent sensitization - a putative animal model of PTSD.

Long-term behavioural alterations in female rats after a single intense footshock followed by situational reminders

Post-traumatic stress disorder (PTSD) affects a vulnerable sub-population of individuals exposed to a traumatic event. This psychopathology induces long-lasting hypothalamo-pituitary-adrenal (HPA) axis hypoactivity, hyperarousal and avoidance of trauma-like situation. PTSD also manifests a high co-morbidity with anxiety disorders. The aim of the present study was to characterise long-term biobehavioural alterations in female rats in an animal model of PTSD consisting in an intense footshock (2 mA, 10s) followed by three weekly situational reminders. This procedure induced several long-term alterations: increased anxiety behaviour, reduced time spent in an 'aversive-like' context, altered social behaviour and blunted corticosterone response to stress. These results demonstrate that exposure to an intense footshock associated with repeated situational reminders elicited long-term disturbances which lasted more than 1 month after the footshock administration. Our findings suggest that this paradigm could provide a useful animal model of PTSD.

Effect of paroxetine on a model of posttraumatic stress disorder in rats

To better understand neurochemical and psychopharmacological aspects of post-traumatic stress disorder (PTSD), it is necessary to establish an animal model of PTSD in which behavioral changes persist after the initial traumatization. We administered inescapable electric foot-shock (IS) to male Wistar rats in a shuttle-box with the gate closed. With or without paroxetine (PRX; belonging to selective serotonin reuptake inhibitors) treatment for 2 weeks after IS, we performed an avoidance/escape task session in the shuttle-box using signal lights as non-specific anxiogenic stimulants. Locomotor activity decreased before the task session and avoidance behavior increased during the session. Two weeks of PRX administration reduced hypervigilant behavior during the task session. We considered these behavioral changes as representative of numbing/avoidance and hypervigilance, referred to as bi-directional changes in PTSD.