Isoflurane Suppresses Stress-enhanced Fear Learning in a Rodent Model of Post–Traumatic Stress Disorder

Article · March 2009with41 Reads
DOI: 10.1097/ALN.0b013e3181974f3e · Source: PubMed
Abstract
A minority of patients who experience awareness and/or pain during surgery subsequently develop post-traumatic stress disorder. In a rodent model of post-traumatic stress disorder, stress-enhanced fear learning (SEFL), rats are preexposed to a stressor of 15 foot shocks. Subsequent exposure to a single foot shock produces an enhanced fear response. This effect is akin to sensitized reactions shown by some post-traumatic stress disorder patients to cues previously associated with the traumatic event. The authors studied the effect of isoflurane and nitrous oxide on SEFL. Rats were exposed to the inhaled anesthetic during or after a 15-foot shock stressor. Then, rats were given a single foot shock in a different environment. Their fear response was quantified in response to the 15-foot shock and single-foot shock environments. SEFL longevity was tested by placing a 90-day period between the 15 foot shocks and the single foot shock. In addition, the intensity of the foot shock was increased to evaluate treatment effectiveness. Increasing isoflurane concentrations decreased SEFL when given during, but not after, the stressor. At 0.40 minimum alveolar concentration (MAC), isoflurane given during the stressor blocked SEFL 90 days later. A threefold increase in the stressor intensity increased the isoflurane concentration required to block SEFL to no more than 0.67 MAC. As with isoflurane, nitrous oxide suppressed SEFL at a similar MAC fraction. These results suggest that sufficient concentrations (perhaps 0.67 MAC or less) of an inhaled anesthetic may prevent SEFL.
    • However, according to the criteria of PTSD animal models, the predator stress model, although it exhibits reduced open arm activity and reduced risk assessment behavior in the EPM test, does not show bidirectional behaviors characteristic to PTSD patients, such as numbing and pain sensitivity [37]. Similarly, in the single prolonged stress model, which consisted of restraint for 2 h, followed by forced swimming for 20 min and subsequent ether anesthesia, although the stressed animals exhibited behaviors and endocrinal feathers similar to PTSD patients, it is inappropriate for constructive validity of the effect of ether and it is not easy to mimic the re-experience [38]. There are also some reports about the modified single prolonged stress (SPS) model, which accompanied by foot shock of different intensities [39,40].
    [Show abstract] [Hide abstract] ABSTRACT: Background People who experience traumatic events have an increased risk of post-traumatic stress disorder (PTSD). However, PTSD-related pathological changes in the hippocampus and prefrontal cortex remain poorly understood. Material/Methods We investigated the effect of a PTSD-like animal model induced by severe stress. The experimental rats received 20 inescapable electric foot shocks in an enclosed box for a total of 6 times in 3 days. The physiological state (body weight and plasma corticosterone concentrations), emotion, cognitive behavior, brain morphology, apoptosis, and balance of gamma-aminobutyric acid (GABA) and glutamate in the hippocampus and prefrontal cortex were observed. Cell damages were examined with histological staining (HE, Nissl, and silver impregnation), while apoptosis was analyzed with flow cytometry using an Annexin V and propidium iodide (PI) binding and terminal deoxynucleotidyl transferase mediated-dUTP nick end labeling (TUNEL) method. Results In comparison with the sham litter-mates, the stressed rats showed decreased body weight, inhibition of hypothalamic-pituitary-adrenal (HPA) axis activation, increase in freezing response to trauma reminder, hypoactivity and anxiety-like behaviors in elevated plus maze and open field test, poor learning in Morris water maze, and shortened latency in hot-plate test. There were significant damages in the hippocampus but not in the prefrontal cortex. Imbalance between glutamate and GABA was more evident in the hippocampus than in the prefrontal cortex. Conclusions These results suggest that neuronal apoptosis in the hippocampus after severe traumatic stress is related to the imbalance between glutamate and GABA. Such modifications may resemble the profound changes observed in PTSD patients.
    Article · Mar 2014
    • A single acute administration of allopregnanolone, however, may not have a strong enough influence on the fear circuitry to counteract the effects of trauma. SEFL is a long-lasting behavioral effect that has been observed as long as 90 days after the initial trauma (Rau 2009). Thus, the trauma seems to be permanently altering the fear learning circuit and it is likely that a transient boost in allopregnanolone was not able to mitigate the effects of trauma.
    [Show abstract] [Hide abstract] ABSTRACT: Pharmacological Resistance of Stress Enhanced Fear Learning in an Animal Model of Post-Traumatic Stress Disorder Virginia Long, Wendy Fujioka, Dorsa Amir and Michael Fanselow University of California, Los Angeles USA 1. Introduction In anxiety disorders such as PTSD, normal fear responding and learning, which is adaptive and helps us survive, is altered in such way that fear becomes maladaptive, interfering with an organism’s ability to alter and adapt behavior in situationally appropriate ways. Maladaptive fear learning is thought to underlie the behavioral symptoms of anxiety disorders such as PTSD (Charney, 2004; Rosen & Schulkin, 1998) when fear and fear responses dominate behavior even in benign circumstances. The fear learning circuit normally participates in adaptive learning and response to danger, however after trauma some individuals show symptoms of PTSD such as: abnormal response to milder stressors, increased vigilance and startle response (American Psychiatric Association., 2000). Stress enhanced fear learning (SEFL) models some specific aspects of PTSD. Using this model we can examine the consequences of trauma--how acute stress or a traumatic event permanently alters the way fear is learned and how these permanent changes in the fear learning circuitry produce maladaptive responses and maladaptive fear learning. Post-traumatic stress disorder (PTSD) is an anxiety disorder that is debilitating and profoundly affects the lives of men and women worldwide. The Diagnostic and Statistical Manual of Mental Disorders (DSM) criterion for a diagnosis of PTSD requires exposure or experience of a traumatic or life-threatening event (American Psychiatric Association., 2000). Trauma may be caused by combat, violence (such as assault, rape, robbery), severe accidents, disasters (natural or man-made). Any one of these traumatic events will be experienced by one-third of the population (Brunello et al., 2001). While the majority of people will not develop PTSD, it is estimated that 10 to 20% of people who experience an acute traumatic event will develop the disorder (Brunello et al., 2001). Symptoms of PTSD include re-experiencing of the trauma, avoidance, and hyper-arousal. Re-experiencing of the trauma can manifest as vivid and emotionally intense memories of the event in flashbacks, nightmares, or ruminations that give the patient a feeling of re-living the trauma. Avoidance of situations, people, or places that remind patients of the trauma is another aspect of the disorder. Increased physiological and psychological arousal, including enhanced startle response and hyper-vigilance also contribute and are indicative of the maladaptive fear learning associated with PTSD. PTSD is thought to be much more prevalent than the estimated 7.8%. Furthermore, many cases of PTSD may be unreported and thus undiagnosed (Brunello et al., 2001). www.intechopen.com
    Full-text · Chapter · Aug 2011 · Journal of Alzheimer's disease: JAD
    • Indeed, it has been found that prior strong fear conditioning can enhance subsequent weak fear conditioning, even when the weak conditioning occurs following extinction of the strong conditioning (Rau, DeCola, & Fanselow, 2005 ). In addition, this fear learning potentiation phenomenon , which is also observable with auditory fear conditioning , is better identified when the weak conditioning takes place in a context different (new learning) from the initial strong conditioning (Rau, Oh, Laster, Eger, & Fanselow, 2009; Rau et al., 2005). Together, these observations indicate that if, following fear extinction , exposure to a sub-conditioning procedure leads to conditioned fear whatever the training conditions, the initial environment with the initial tone CS or a new environment with a new tone CS (new learning), this effect would correspond to fear learning sensitization (i.e., a decrease of shock sensitivity threshold) rather than fear return.
    [Show abstract] [Hide abstract] ABSTRACT: Post-extinction exposure of rats to a sub-conditioning procedure can evoke conditioned fear, which may correspond to fear return and/or fear learning potentiation. The aim of the present study was to clarify this issue and examine the effects of tetanic stimulation of the hippocampus (HPC) and medial prefrontal cortex (mPFC), two brain regions implicated in post-extinction modulation of conditioned fear. Rats were initially submitted to five tone-shock pairings with either a 0.7-mA or 0.1-mA shock. Tone-evoked freezing was observed only with the higher shock intensity, indicating that the 0.1-mA shock corresponded to a sub-conditioning procedure. All conditioned rats underwent fear extinction with 20 tone-alone trials. When retrained with the sub-conditioning procedure, they displayed again tone-evoked freezing, except when the initial tone was unpaired or a new tone was paired with the 0.1-mA shock, demonstrating fear return rather than fear learning potentiation. We also found that HPC and mPFC tetanic stimulations, applied 24h after the sub-conditioning procedure, similarly reduced this fear return. However, mPFC inactivation abolished temporary HPC tetanus effect, whereas HPC inactivation did not interfere with mPFC tetanus effect. These data confirm our previous findings and reveal the nature of HPC-mPFC interactions in post-extinction modulation of conditioned fear.
    Article · Mar 2011
    • Iguanas were hand-captured and anesthetized with a mixture of isoflurane and air. Isoflurane does not appear to cause retrograde amnesia in vertebrates [21,22]; thus, it seems unlikely that this process affected the iguanas' memory of their initial capture. The surgical site was prepared using aseptic techniques, and the data logger (∼ 15 g; ≤ 1% of male body weight) inserted into the coelomic cavity through a 4–5 cm paramedian incision initiated just caudal to the xiphoid process.
    [Show abstract] [Hide abstract] ABSTRACT: Island tameness is a widely documented phenomenon in which island species, particularly those that have evolved with no or few natural predators, show a greatly reduced behavioral response when faced with unfamiliar predators. This insufficient anti-predator response has led to widespread population declines among many island species exposed to novel predators, and has become a serious conservation problem. Despite its prevalence, the underlying physiology of island tameness is not known. Here we report that although Galápagos marine iguanas (Amblyrhynchus cristatus) initiated flight from an evolutionarily recent and unfamiliar potential predator (humans), they failed to show the cardiovascular stress response that facilitates successful escape, even after a prior capture experience. In contrast, when approached by a native predator (the Galápagos hawk; Buteo galapagoensis), marine iguanas show markedly increased heart rate independent of initiating escape movement. The secretion of catecholamines appears to be central to the initiation of escape behavior: naïve animals remotely injected with epinephrine immediately increased flight initiation distance, whereas those injected with corticosterone did not. Our results provide the first evidence that muted escape behavior in predator-naïve species is indicative of both a cognitive deficit in recognizing potential predators and a catecholamine deficit in response. Understanding how the response to predators differs in predator-naïve species could enable the design of maximally effective techniques for inducing an anti-predator response in these vulnerable species.
    Article · Mar 2010
    • In normal young adult mice, repetitive exposure to isoflurane does not produce persistent cognitive deficits but in transgenic mice with amyloid precursor protein mutations , isoflurane increases the rate of mortality during and after anesthesia; increases the emergence time after anesthesia; decreases the responsiveness to the sensorial stimulation; and produces a long lasting reduction of exploratory behavior [26] (Table 1). The amnesic effects of isoflurane are mediated, at least in part, throughout enhancement of GABA neurotransmission , since the knockout mice for the a4 subunit of the GABA type A receptor are much more re- sistant [27] . Other effects of isoflurane such as depression of breathing and righting response appear to be related to changes in other proteins such as regulatory G signalling protein [28].
    [Show abstract] [Hide abstract] ABSTRACT: Recent clinical studies have suggested that there is an increased risk of Alzheimer's disease (AD) in patients undergoing surgical interventions, but it is unknown whether this effect is related to anesthesia, cardiovascular complications of surgery, or associated conditions such as hypothermia. In addition, many patients, especially the elderly, present persistent post-operative cognitive deterioration after anesthesia, without clear complications during surgery. Experimental studies in animals may be helpful to dissect the pathogenic role of the different factors involved in surgery. Here, we review studies on the effects of anesthesia on neuronal function performed in tissue culture and in experimental animals. Several studies have shown that a small inhalation of anesthetics induces activation of caspases and cell toxicity on glioma and pheochromocitoma cells in culture, which is prevented by treatment with the metal chelating agent clioquinol. Exposure of old rodents to anesthesia produced memory deficits and increased levels of amyloid-β (Aβ) peptide and phosphorylated tau in brain. The effects of long term or short term repetitive exposure to small molecular weight anesthetics are more severe in transgenic AβPPswe than in wild type mice. In the former, low molecular weight increased the number of TUNEL(+) apoptotic cells and the ratio of pro-apoptotic proteins in hippocampus; reduced astroglial and increased microglial responses; increased Aβ aggregates and high molecular weight peptides; abnormal chaperone responses and reduced autophagy. In conclusion, anesthetic gases induce changes which may reproduce AD pathology in mice with mutations which produced AD. It would be interesting to know whether anesthetics are risky for subjects with special genetic risk factors.
    Full-text · Article · Jan 2010
    • Iguanas were hand-captured and anesthetized with a mixture of isoflurane and air. Isoflurane does not appear to cause retrograde amnesia in vertebrates [21,22]; thus, it seems unlikely that this process affected the iguanas' memory of their initial capture. The surgical site was prepared using aseptic techniques, and the data logger (∼ 15 g; ≤ 1% of male body weight) inserted into the coelomic cavity through a 4–5 cm paramedian incision initiated just caudal to the xiphoid process.
    [Show abstract] [Hide abstract] ABSTRACT: Island tameness is a widely documented phenomenon in which island species, particularly those that have been isolated for much of their evolutionary history, show a greatly reduced behavioral response to novel predators. This insufficient escape response has led to widespread population declines among many island species exposed to novel predators, and has become a serious conservation problem. Despite its prevalence, the cause of island tameness is not known. We compared the physiological stress response of the classically tame Galapagos marine iguana (Amblyrhynchus cristatus) when approached by a novel potential predator (human) with that elicited by a native predator (the Galapagos hawk: Buteo galapagoensis). Although iguanas initiated flight from an evolutionarily novel potential predator, they showed no evidence of the cardiovascular stress response that facilitates successful escape. In contrast, when approached by a native predator, marine iguanas displayed the typical highly conserved vertebrate stress response and markedly increased heart rate prior to initiating escape, which is indicative of epinephrine release upon visual contact with a native predator. Our findings suggest that escape behavior in predator-naive species may be constrained by an inappropriate physiological stress response. This altered physiological response could explain why many island species have difficulty adapting to novel predators.
    Full-text · Article · Journal of Alzheimer's disease: JAD
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