Diagnostic technique for posttraumatic stress disorder modelled in laboratory animals

FIELD: medicine.

SUBSTANCE: laboratory animals are exposed to "recalling" stress. The diagnostics is based on blood parametres in the hormone samples taken in the pre set time with the blood samples drawn in 30 and 60 minutes after the stress. Each sample is analysed for corticosterone concentration. And if in the 60-minute sample, it is lower than in the 30-minute sample, posttraumatic stress disorder in an animal unit is diagnosed.

EFFECT: method requires introduction of an exogenous hormone, thereby enabling to observe an indicator via the level of endogenic glucocorticoids, and to diagnose specific disorders of fast regulation of hypophysial-adrenocortical systems.

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The invention relates to experimental medicine and can be used to diagnose hormonal symptoms of post-traumatic stress disorder (PTSD) in models in laboratory animals.

Over the next analogues accepted: how to detect violations of rapid glucocorticoid feedback in models of PTSD in rats [1], and the method then we switched to dexamethasone test in laboratory conditions [2] and clinical practice [3, 4]. Method [1] is aimed at diagnosis of sensitization mechanisms for rapid feedback specific to PTSD, to substantiate the adequacy of the (legitimacy) experimental models of this disorder in rats. Method [1] based on the fact that in post-traumatic pathology presenting a brief "reminiscent of" traumatic episode (restless) is a characteristic rapid inhibition of the activity of the pituitary-adrenocortical system (GUS). Taking into account this phenomenon and developed hormone tests, including sampling blood to determine the level of adrenocorticotropic hormone (ACTH) in the early stages after the start of restless (5-30 min), which allows us to characterize the activation phase GUS and identify its inclusion pathological inhibition. The feature of the method [1] injection of the glucocorticoid hormone cortisol (i.e. exogenous "load") by analogy with the known load test - d is camerazoom test. According to the method [1], exogenous "load" is produced immediately before restress using non-synthetic, natural glucocorticoid (cortisol). It is assumed that the exogenous input hormone should increase the braking action of endogenous glucocorticoids, i.e. to provoke the inclusion of pathological quick feedback. It should be noted that additional exogenous load cortisol and use as a primary option, the level of ACTH makes way [1] inconvenient for use in experimental work on animals, for whom the main glucocorticoid is cortisol, and in the clinic in person. This is because the analysis of the level of ACTH is available only to specialized laboratories, endocrine profile, and analysis of the level of the main glucocorticoid - cortisol, which is a more public figure, is not applicable due to the presence of exogenous cortisol, which also binds the labeled anticorodal along with endogenous. This advantage has a classic then we switched to dexamethasone test [2, 3, 4], which introduced exogenous synthetic hormone (dexamethasone), and consequently in the quality measure is used to analyse the level of cortisol, which does not require special capabilities and makes the test easy for a wide applied what I like in clinics, and laboratories. On the other hand, the use of classical then we switched to dexamethasone test and its modifications for diagnostic characteristic of PTSD disorders hormonal regulation is not very interesting, because it does not include activating factor GUS (restless or exogenous neurohormone of corticoliberin), and the time in the test too big (at least 6-12 hours). Need a new way to diagnose hormonal disorders in PTSD, combining all the advantages of the method [1] with the ease of use characteristic then we switched to dexamethasone test.

Task - specific diagnosis of disorders of fast regulation GUS.

The essence of the proposed method for the diagnosis of post-traumatic stress disorder, characterized was bred "like" effects and diagnostics on hormonal parameters in blood samples at specified times after exposure and include the selection of hormonal blood samples were taken after 30 and 60 min after exposure, determination of the level of the main glucocorticoid (corticosterone) and diagnosis by comparing levels in samples of 30 minutes and 60 minutes

In the drawings 1 and 2 presents the results of comparative tests of the proposed method and the method-analogue of [1], where

1, 5 - Characteristics of the dynamics of corticosterone in the blood samples of control animals.

2 - Characterization of the dynamics of the level is corticosterone in the blood samples of animals with experimental PTSD, not receiving a "load" exogenous hormone.

3 - Characterization of the dynamics of corticosterone in the blood samples of animals with experimental PTSD who received the "burden" of exogenous hormone (according to the similar [1]).

4 - Characterization of the dynamics of corticosterone in the blood samples of animals with experimental depression.

The proposed method is that individuals previously suffered severe traumatic stress, expose "reminiscent" of the episode and after 30 and 60 min after the start produce sampling blood with subsequent determination of corticosterone. If individuals PTSD corticosterone in the 60th min lower than in the 30th minute, triggers rapid inhibition of GUS activity, which is a distinctive feature of PTSD and can be used as a diagnostic criterion.

Example. In experiments on adult male Wistar rats was investigated method for the detection of pathological inclusions rapid glucocorticoid feedback specific to PTSD. A comparative analysis with the known method [1], as well as with other experimental pathology endogenous depression, which described the pathology is not typical.

For the induction of experimental analogue PTSD in rats was used to model the stress-restress" or gramasevaka sensitizatio [1, str]. Rats were subjected to severe combined stress, consisting of a 2-hour immobilization, 20-min forced swimming and after a 15-minute break is essential to stress until he lost consciousness. For the purposes of reproduction etiological features of PTSD showed "reminding" episode (remainder). reminder) of these rats (restless, which consisted of 30-min immobilization stress), to which the rats were subjected to 6 days (on day 7) after traumatic stress. As a result, the rats were formed sustainable alarming condition characterized by symptoms of PTSD and amenable to effective pharmacological correction by the introduction of antidepressant-anxiolytic of paxil. For the induction of different forms of anxiety-depressive States used the paradigm of "learned helplessness". Rats were subjected to the inevitable uncontrolled skin irritation, resulting in them developing sustainable depressivnopodobnoe state.

Test fast feedback using two methods (analogue and claimed) was performed 6 days after the heavy aversive stress model PTSD, or "learned helplessness". According to the similar, just before landing rats that survived 6 days ago heavy aversive (traumatic) stress, immobilization pencil case DL is restress them intraperitoneally injected cortisol (Gedeon Richter, Hungary) 30 µg/100 g/0.1 ml of saline. In another series, according to the claimed method, an injection of the hormone is not produced. In the two control series of experiments used a group of intact rats, previously heavy stress is not exposed, one of which was introduced exogenous hormone, and the other is not. All series of hormonal blood samples were taken after 3, 10, 30 and 60 min, and as the main indicator used condition end link GUS, which was estimated based on the determination of the content of corticosterone in plasma using a radioimmunoassay method.

Figure 1. Dynamics of the level of the glucocorticoid hormone corticosterone, illustrating the inclusion of pathological quick feedback during the development of experimental PTSD. It is obvious that the additional load of exogenous hormone (series "PTSD-G") is not necessary to detect the effect, because the results are similar to those obtained in experiments without load ("PTSD") - reduction of hormone levels to 60 min at 43% and 47% of the 30-minute values, respectively. In the control group (without post-traumatic pathology) abnormal inhibition was not observed regardless, introduced them exogenous hormone (series "control-G") or not ("control").

Figure 2. Dynamics of the level glucocorticoides the hormone corticosterone, illustrating the absence of pathological rapid inhibition in experimental depression.

The main advantage of the proposed method lies in the fact that he, unlike [1], is not a load, i.e. does not include the injection of exogenous glucocorticoid hormone cortisol. Taking into account the need for appropriate time shifts this makes it possible as an option to use ACTH and glucocorticoid hormones, content analysis which is more accessible for most medical institutions and laboratories. This set of essential features of the proposed method opens up broad prospects for its use as a criterion for the diagnosis of PTSD.

The technical result of the claimed method is that it allows to detect the characteristic of PTSD disorders hormonal regulation not less effective than the known method [1], but it has several significant advantages over the latter: does not require the introduction of exogenous hormones, relieving the experimenter from additional manipulations; allows you to use as an indicator of the level of endogenous glucocorticoids, which analysis much easier and more affordable than the level of ACTH in the known method [1].

Purpose - in experimental studies n the laboratory animals, as well as for implementation in clinical practice as a diagnostic criterion that facilitates differential diagnosis of PTSD from other forms of anxiety and depressive disorders.

Sources of information

[1] Liberzon I., Krstov M. and Young, E. Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology. 1997. Vol.22, No.6, pp.443-453. description of the prototype - str-447.

[2] Zhukov D.A. - Zhukov D.A. The dexamethasone suppression test in genetically different rats exposed to inescapable and escapable electric shocks. Psychoneuroendocrinology. 1993. 18(7):467-74.

[3] Muller YL, Ostroumov MO - Nuller Yu. L., Ostroumova M.N. Resistance to inhibiting effect of dexamethasone in patients with endogenous depression. Acta Psychiat. Scand. 1980, vol.61, p.169-177.

[4] Carroll Century. The dexamethasone suppression test for melanchcolia. Brit. J. Psychiat. 1982. vol.140, p.292-304.

Method for the diagnosis of posttraumatic stress disorder in models in laboratory animals, including strassenwesen "reminding" the impact and diagnosis on blood parameters in hormonal samples taken at the specified time, wherein
blood samples taken after 30 and 60 min after exposure,
in each sample determine the level of corticosterone,
and when its level in the sample 60 min lower than in the sample 30 min, diagnosed with post-traumatic stress disorder in individuals.


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