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

Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94143-0464, USA.
Anesthesiology (Impact Factor: 5.88). 03/2009; 110(3):487-95. 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.

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Available from: Michael Fanselow, Sep 26, 2015
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    • "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]. "
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    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.
    Medical science monitor: international medical journal of experimental and clinical research 03/2014; 20:499-512. DOI:10.12659/MSM.890589 · 1.43 Impact Factor
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    • "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 resistant [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]. "
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    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.
    Journal of Alzheimer's disease: JAD 01/2010; 22 Suppl 3:43-8. DOI:10.3233/JAD-2010-100822 · 4.15 Impact Factor
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