Analysis of Antidepressant-like Effects and Action Mechanisms of GSB-106, a Small Molecule, Affecting the TrkB Signaling

Induction of BDNF-TrkB signaling is associated with the action mechanisms of conventional and fast-acting antidepressants. GSB-106, developed as a small dimeric dipeptide mimetic of BDNF, was previously shown to produce antidepressant-like effects in the mouse Porsolt test, tail suspension test, Nomura water wheel test, in the chronic social defeat stress model and in the inflammation-induced model of depression. In the present study, we evaluated the effect of chronic per os administration of GSB-106 to Balb/c mice under unpredictable chronic mild stress (UCMS). It was observed for the first time that long term GSB-106 treatment (1 mg/kg, 26 days) during ongoing UCMS procedure ameliorated the depressive-like behaviors in mice as indicated by the Porsolt test. In addition, chronic per os administration of GSB-106 resulted in an increase in BDNF levels, which were found to be decreased in the prefrontal cortex and hippocampus of mice after UCMS. Furthermore, prolonged GSB-106 treatment was accompanied by an increase in the content of pTrkB706/707 in the prefrontal cortex and by a pronounced increase in the level of pTrkB816 in both studied brain structures of mice subjected to UCMS procedure. In summary, the present data show that chronic GSB-106 treatment produces an antidepressant-like effect in the unpredictable chronic mild stress model, which is likely to be associated with the regulation of the BDNF-TrkB signaling.

Experimental modeling of behavioral disorders accompanying hashimoto’s thyroiditis by means of specific immunoglobulins

Among the manifestations of Hashimotos autoimmune thyroiditis, there are various psychoneurological disorders. For more than a century, it has been known about psycho-neurological disorders associated with hypothyroidism, but along with that, there are also mental disorders in patients with thyropathies in euthyroid state. In 1966, Hashimotos encephalopathy was described, the pathogenesis and clear differential diagnostic criteria of which have not yet been determined. This article describes an experimental study in laboratory mice with intracisternal stereotaxic injection of IgG isolated from patients with autoimmune thyroiditis and comorbid depression or schizophrenia. A control group included animals receiving polyclonal IgG from healthy donors. Then behavioral tests were carried out, which revealed the characteristics and changes in behavior in the operated animals. Thus, animals that received immunoglobulins from patients with autoimmune thyroiditis and depression were less active in relation to the development of risk behavior. Porsolts tests on the 4th and 15th days after surgery showed that, regardless of the kind of the injected solutions, there was a change in the temporal relationships between the behavior patterns. In mice received IgG from patients with autoimmune thyroiditis and schizophrenia during the delayed Porsolt test, the ratio of the forms of motor activity shifted towards passive swimming. The mice received IgG from healthy donors did not demonstrate this change.

IMPACT OF EARLY LIFE STRESS ON ANTI-DEPRESSANT SENSITIVITY

Long-term consequences of impaired perinatal development are very significant. They appear during the neonatal period and in the first years of life, and persist during ontogenesis. There is little data on the impact of any prenatal factors on the sensitivity of a sexually mature organism to medications. The aim of the study is to assess the impact of early life stress on the development of individual antidepressant sensitivity. Materials and Methods. The authors conducted the experiments on sexually mature outbred male rats. To simulate the early life stress, a standard protocol was used. From the 2nd to 15th days of the postnatal period the pup rats were separated from their mother for 3 hours and kept in an incubator. The open-field test, Porsolt test and Sucrose consumption test were used to determine rat’s anxiety level as well as motor, orientation and exploratory activity at puberty. Then, for 14 days, the rats were intragastrically administered with a fluoxetine solution (10 mg/kg/daily), followed by their full examination. Statistical analysis of results was performed using the Mann-Whitney U-test to compare unrelated groups and Wilcoxon's test to compare related groups. Results. Fluoxetine did not have a pronounced antidepressant effect in animals that survived the early life stress. Such animals demonstrated passive floating during the Porsolt test, without any changes in immobility time. When testing in an open field, a sharp increase in the number of freezing behavior was observed, which was an indicator of an increased anxiety level in animals. Conclusion. The results obtained indicate that the long-term effects of neonatal stress may be associated with a change in antidepressant sensitivity or an increase in development of unwanted adverse reactions. Keywords: early life stress, depression, antidepressants, fluoxetine, rats. Отдаленные последствия нарушения перинатального развития весьма значительны и не только проявляются в период новорожденности и в первые годы жизни, но и сохраняются в период онтогенеза. Данные о влиянии каких-либо пренатальных факторов на чувствительность половозрелого организма к действию лекарственных веществ в доступной литературе представлены незначительно. Цель исследования – оценить роль стресса раннего периода жизни в формировании индивидуальной чувствительности к действию антидепрессантов. Материалы и методы. Эксперименты проведены на половозрелых беспородных крысах-самцах. Для моделирования стресса раннего периода жизни использовали стандартный протокол, подразумевающий отделение детенышей от матери со 2-го по 15-й дни постнатального периода на 3 ч в условиях инкубатора. В половозрелом возрасте проводили оценку уровня тревожности, двигательной и ориентировочно-исследовательской активности крыс в условиях теста открытого поля, теста Порсолта и теста «Потребление раствора сахарозы». Затем в течение 14 дней крысам внутрижелудочно вводили раствор флуоксетина (10 мг/кг/сут), после чего обследование повторяли в том же объеме. Статистический анализ результатов исследования проводили с использованием U-критерия Манна–Уитни для сравнения несвязанных групп и критерия Вилкоксона для сравнения связанных групп. Результаты. У животных, переживших стресс раннего периода жизни, флуоксетин не оказывал выраженного антидепрессантного действия. У данных животных в тесте Порсолта преобладало пассивное плавание, без изменения длительности иммобильности. При тестировании в открытом поле наблюдалось резкое повышение числа актов фризинга, что является показателем повышенного уровня тревожности у животных. Выводы. Полученные результаты свидетельствуют о том, что отдаленные последствия неонатального стресса могут быть связанны с изменением чувствительности к действию антидепрессантов или повышением риска развития нежелательных побочных реакций. Ключевые слова: стресс раннего периода жизни, депрессия, антидепрессанты, флуоксетин, крысы.

EFFECTS OF GLYPROLINES ON THE BEHAVIOR OF RATSIN THE PORSOLTTEST AND EXPERIMENTALLYINDUCED SOCIALS

In this work we studied the effect of glyprolines on the behavior of rats under conditions of experimental social stress. White male rats 6-8 months of age were used in the experiment. Throughout the experiment all animals were kept in standard-barrier conditions. The effect of glyprolines on the behavior of white male rats was studied on the model of social stress, implying that the animals are kept in conditions of a constant sensory contact. Glyprolines (Selank, Pro-Gly-Pro, Pro-Gly-Pro-Leu) were injected to the animals Intraperitoneally at a dose of 100 μg/kg/day within 20 days. Porsolt test was employed to carry out behavioral analysis in the animals. The outcomes revealed that regardless of the type of behavior (aggressive and submissive) in all the animals depression and anxiety disorders were developed, whereas Selank, Pro-Gly-Pro, Pro-Gly-Pro-Leu facilitated their alleviation. Thus, our experiment has demonstrated a psychomodulatory effect of the glyprolines.

Complex effect of caffeine and dioxidine on behavioral responses in mice in Porsolt test

Relevance. In light of the popularization of the use of caffeine-containing products, the question of the combined use of caffeine with substances exhibiting a toxic effect remains open. The doses of caffeine, which have a pronounced antidepressant effect, are also insufficiently studied. The aim of the study was to study the effect of repeated administration of caffeine and dioxidine on the behavioral responses of mice in the Porsolt test. Materials and methods. The experiment was carried out on 36 outbred male mice, divided into 6 groups. Experimental groups for 15 days of the study received caffeine at a dose of 40 mg/kg (first) or 100 mg/kg (second), dioxidine at a dose of 200 mg/kg (third), together with caffeine 40 mg/kg or 100 mg/kg, and dioxidine (fourth and fifth groups, respectively). The animals of the control group were injected with saline. To study the behavior, the Porsolt test was carried out, evaluating the following indicators on the 1st, 8th and 15th days of the experiment: the total time of immobilization, active swimming, climb, the number of grooming and shaking off acts. Results . The administration of caffeine at a dose of 40 mg/kg caused an increase in the time of active swimming and a decrease in the duration of immobilization on the 8th and 15th days. When caffeine was used at a dose of 100 mg/kg, an increase in the time of active swimming was noted with a single exposure, with an experiment duration of 8-15 days, an increase in the duration of immobilization was observed. Dioxidine caused a significant decrease in the time of active swimming and an increase in the duration of immobilization during all days of the experiment. The combined use of caffeine (40 mg/kg and 100 mg/kg) and dioxidine on the 1st day led to a decrease in immobilization and the time of active swimming. In both groups, 100 % animal mortality was observed by the 15th day. Conclusion. The results of the study indicate the presence of an antidepressant effect in caffeine at a dose of 40 mg/kg on the 8th and 15th days of the experiment and the absence of this effect in caffeine at a dose of 100 mg/kg with a duration of administration of 8-15 days. The use of dioxidine led to the absence of antidepressant activity and the presence of the opposite effect. The combined administration of caffeine (40 mg/kg and 100 mg/kg) and dioxidine led to 100 % mortality in the experimental groups by the 15th day of the experiment

Effects of a Single and Course Application of Remote Ischemic Preconditioning on the Physical Performance of Laboratory Animals

Previous publications reported the use of remote ischemic preconditioning (rIPC) as a non-drug method for increasing physical performance. However, the reported data are of a contradictory nature. Aim: to evaluate the potential of rIPC for increasing the physical performance of laboratory animals. The study was performed on 72 white outbred male rats. An assessment of the physical performance was carried out using a modified Porsolt test. The hind limbs of non-anesthetized animals were subjected to preconditioning. The results of a single and course (during 5 days) application of rIPC was evaluated. A single use of rIPC increased the average swimming time in the experimental group by 38.5%. The course application of rIPC did not lead to significant changes in the indicators of physical performance in any of the animal groups.

The effect of early and late pharmacological correction with GABA derivatives of psychoemotional state of offspring of rats with experimental preeclampsia

Introduction: Preeclampsia is a serious complication of pregnancy, which increases the risk of anxiety disorders and depression in children at different stages of ontogenesis. Materials and methods: The psychoemotional state of 70-day-old offspring of rats with experimental preeclampsia (EP) was studied after pharmacological correction from the 40th to 70th day of offspring life with GABA derivatives – succicard (22 mg/kg), salifen (7.5 mg/kg), phenibut (25 mg/kg) and comparison drug pantogam (50 mg) – in the Open field test, the Elevated plus maze test, and the Marble burying test. The above mentioned tests, together with the Porsolt test, were performed at the age of 18 months. At the second step, the offspring received succicard (44 mg/kg), salifen (15 mg/kg), phenibut (50 mg/kg) and pantogam (100 mg) from the 24th to 25th month of life. After that, the animals were tested. Results and discussion: The EP progeny had an increased level of anxiety and depression, as well as obsessive-compulsive disorder. Early GABA derivatives exposure limited anxiety and depression in the animals aged 70 days and 18 months, with salifen limiting compulsive behavior. Late GABA derivatives “treatment” exerted anti-compulsive and antidepressant effects, with phenibut having a greater degree of anxiolytic activity. Succicard, salifen and phenibut were comparable or superior to pantogam in terms of effectiveness. Conclusion: EP has a negative effect on the psychoemotional state of offspring. Early and late pharmacological correction with derivatives of GABA, such as succicard, salifen and phenibut, reduced anxiety, manifestations of obsessive-compulsive disorder, and depression in offspring of the rats with EP pregnancy.

Antidepressant-like activity of the dipeptide mimetic of brain-derived neurotrophic factor GSB-106 in Porsolt test after intraperitoneal sub-chronically and chronically treatment in mice

The present work was to study the GSB-106 effect on the immobility behavior of mice Balb/c in the Porsolt test. GSB-106 was administered sub-chronically and chronically intraperitoneal in dose 1 mg/kg. GSB-106 administration significantly decreased immobility time in mice by 1.2 times after 4 days, by 1.3 times after 14 days and 1.2 times after 21 days’ injections. Thus, the dependence of the GSB-106 effect-time administration in the Porsolt test was not established.

Stimulation of Vagus By Phenylephrine Increases the Efficiency and Safety of Antidepressants and Anti-Epileptics

Background: Earlier, we discovered the possibility of potentiation of the therapeutic effects of small (threshold) doses of CNS agents by phenylephrine and adrenaline, while eliminating their side effects. However, the question of the possibility of potentiation by phenylephrine and other CNS potentiators of high therapeutic doses of CNS agents remained unstudied. This study is devoted to the research of this problem. Objective: The aim of the study was to investigate the effect of the threshold dose of phenylephrine on the antidepressant effect of amitriptyline and the anticonvulsant effect of diazepam, as well as their side sedation in high doses. Method: The experiments were carried out on the animated models of depression (Porsolt test) and epilepsy (clonic pentylenetetrazole (PTZ)-induced seizures), resistant to antidepressants and antiepileptics even at high therapeutic doses. Side sedative effect of substances was evaluated in the "open field" test. Results: We established that the stimulation of gastric vagal afferents with phenylephrine, when administered orally at threshold doses, potentiates the anticonvulsant effect of diazepam and the antidepressant effect of amitriptyline in high therapeutic doses to the maximum level that is impossible in their application by themselves, and at the same time eliminates their side sedation. Conclusion: A synergistic effect of phenylephrine and CNS drugs on the peripheral and central links of the vagal stress-protective reflex is discussed. It is assumed that the potentiation of therapeutic effect by phenylephrine and the elimination of side effects of the CNS agents occurs as a result of strengthening the vagal stress-protective reflex, eliminating the drug stress.

THE SULPIRIDE CORRECTION OF BEHAVIORAL DISORDERS IN ALCOHOLIZED WHITE MALE RATS WITH DIFFERENT DEGREES OF DEPRESSION

Целью исследования является оценка коррекции поведенческих нарушений, вызванных двухнедельной алкоголизацией у самцов белых крыс, путем блокирования сульпиридом ауторецепторов дофамина с учетом индивидуально-типологических особенностей животных. Методика. Эксперимент был выполнен на 40 половозрелых крысах-самцах массой 180-220 г. Уровень тревожности крыс определяли в приподнятом крестообразном лабиринте по общему времени пребывания животного на открытом пространстве лабиринта за 5 мин тестирования и числу повторных выходов на него. Двигательную и исследовательскую активность, а также число актов груминга животных оценивали в тесте открытого поля в течение 5 мин. Уровень депрессивности животных устанавливали с помощью теста Порсолта с подсчетом количества и общей продолжительности периодов полной иммобильности (неподвижности) животного. По количеству фекальных болюсов судили об эмоциональности животных. После исходного (контрольного) тестирования в батарее вышеуказанных тестов животные были разделены на три подгруппы согласно выраженности депрессивности в тесте Порсолта. Алкоголизацию проводили в течение 14 сут путем внутрибрюшинного введения раствора этанола в виде 10% раствора из расчета 2 г/кг веса животного, после чего животные проходили повторное тестирование в поведенческих тестах. Сульпирид («Eglonyl», Sanofi Winthrop Industrie, France) вводили в течение 14 сут в дозе 10 мг/кг, внутрибрюшинно, после чего животные снова проходили тестирование. Результаты. Двухнедельная алкоголизация приводит к увеличению тревожности и депрессивности самцов с исходно низким и средним уровнем депрессивности, на что указывает сокращение пребывания животных данных подгрупп на открытом пространстве приподнятого крестообразного лабиринта (p<0,01), уменьшение числа повторных выходов на него (p<0,05) и значительное увеличение общего времени неподвижности в тесте Порсолта (p<0,01). Последующее введение сульпирида корректирует анксиогенный и депрессогенный эффекты алкоголизации у самцов этих подгрупп. Исходно высокодепрессивные животные не проявили чувствительности к 14-дневному введению этанола и последующему блокированию D2/D3-рецепторов дофамина в приподнятом крестообразном лабиринте и тесте Порсолта. Введение этанола в течение 14 дней угнетает исследовательскую активность (p<0,01) самцов в открытом поле независимо от исходного уровня их депрессивности и двигательную (p<0,01) у низкодепрессивных животных. Последующее введение сульпирида не привело к компенсации эффекта алкоголизации на показатели поведенческой активности в открытом поле. У низкодепрессивных самцов на фоне двухнедельной алкоголизации развивается депрессивноподобное состояние, характеризующееся выраженным поведенческим дефицитом в открытом поле. Двухнедельная алкоголизация приводит к значительному (в 2-3,5 раз, p<0,01) росту эмоциональности независимо от исходного уровня депрессивности крыс, что полностью корректируется последующим введением сульпирида у высокодепрессивных самцов, и к частичному снижению проявлений эмоциональности у низко- и среднедепрессивных животных. Заключение. Полученные результаты свидетельствуют о возможности коррекции тревожных и депрессивных нарушений, возникших на фоне двухнедельной алкоголизации, сульпиридом с учетом индивидуально-типологических особенностей организма. The aim of the study was to evaluate correction of behavioral disorders with sulpiride, a dopamine autoreceptor inhibitor, in alcoholized rats taking into account individual typological features of the animals. Methods. Experiments were performed on sexually mature male rats weighing 180-220 g. The level of anxiety was determined in the elevated plus-maze by the total time of stay in and number of exits from the open space of the maze during 5 minutes of testing. Locomotor and exploratory activity and grooming behavior were assessed in the open field for 5 minutes. The severity of animal depression was determined using the standard Porsolt test by the number and total duration of immobility periods. The emotional state of animals was evaluated by the number of fecal boluses. After the initial (control) tests, the rats were divided into three subgroups based on the severity of depression as determined in the Porsolt test. Alcoholism was modeled by intraperitoneal injections of 10% ethanol (2 g/kg body weight) for 14 days. Then the animal behavior was re-tested. Sulpiride (Eglonyl, Sanofi Winthrop Industrie, France) was administered for 14 days at a dose of 10 mg/kg, intraperitoneally; then the animals were tested again. Results. Two-week alcoholization resulted in increased anxiety and depression of rats with low and medium depression degree at baseline. These disorders were evident from shortened stay of these animals in the open space of elevated plus-maze, reduced number of repeated exits from the open space, and a significant increase in the total time of immobility in the Porsolt test. The subsequent sulpiride treatment corrected the anxiogenic and depressogenic effects of alcoholism in male rats of these subgroups. Originally high-depressive animals did not show a sensitivity to the 14 day-administration of ethanol and subsequent inhibition of D2/D3-dopamine receptors in the elevated plus-maze and Porsolt test. Administration of ethanol for 14 days suppressed both the exploratory activity of rats in the open field regardless of their baseline degree of depression, and the locomotor activity of low-depressive animals. The subsequent sulpiride treatment did not abolish the effect of alcohol on the behavioral activity in the open field. Low-depressive alcoholized males developed a depression-like condition characterized by a marked behavioral deficit in the open field. The two-week alcoholization resulted in a significant (2-3.5 times) increase in the emotionality irrespective of the baseline degree of depression. This disorder was fully corrected by the sulpiride treatment in high-depressive rats and partially reduced the signs of emotionality in low- and medium-depressive animals. Conclusion. The study showed a possibility for correction of anxiety and depressive disorders induced by two weeks of modeled alcohol abuse with sulpiride depending on individual typological features of animals.