Obsessive-compulsive disorder (OCD) is a mental disease characterized by the obsessions which cause marked distress or anxiety and/or compulsions intended to alleviate this distress. The results of experimental and clinical studies suggest a possible role of GABA B receptors in the pathogenesis of OCD, making it relevant to study the effect of ligands of these receptors on the behavior of rodents. Objectives : Studying the effects of GIZH-290 and baclofen in animal models of OCD. Methods . The effects of GIZH-290 (0.01, 0.1, 1 mg/kg, i.p.) and baclofen (0.1, 1, and 5 mg/kg, i.p.) were studied in the marble burying test and the rotarod test, as well as in the 8-OH-DPAT-induced decrease in spontaneous alternation in mice. Results . Baclofen and GIZH-290 attenuated compulsive-like behavior in mice by reducing the number of buried marbles in the marble burying test at all tested doses. However, the effect of baclofen at a dose of 5 mg/kg was accompanied by a disruption of the animals’ motor coordination in the rotarod test. At the same time, neither baclofen nor GIZH-290 attenuated 8-OH-DPAT-induced (2 mg/kg, i.p.) decrease in spontaneous alternation behavior in mice. On the contrary, baclofen at a dose of 1 mg/kg exacerbated this disruption. Conclusion . Baclofen and GIZH-290 have anticompulsive activity in the marble burying test, but not in the 8-OH-DPAT-induced decrease in spontaneous alternation behavior in mice.

The effect of 5-HT 1A receptor agonist 8-OH-DPAT (intraperitoneal injection in doses of 1, 2, and 4 mg/kg) on spontaneous alternation behavior of mice in Y-maze was studied without and with habituation procedure and food reward. In the first case, 8-OH-DPAT administration led to a decrease in spontaneous alternation and locomotor activity in mice. At the same time, 8-OH-DPAT treatment after habituation and food deprivation increased repeated choices of goal arms without affecting locomotor activity, which was consistent with perseverative behavior. 8-OH-DPAT-induced decrease in spontaneous alternation behavior in Y-maze in mice with habituation and food reward is the most suitable procedure for experimental modeling of the perseverative behavior and studying the anticompulsive activity of new substances.

Сomorbidity of malignant tumors and affective disorders is an urgent problem. It is known that some psychotropic drugs may adversely influence the growth of malignant tumors and metastasis; in the experiment, a connection between neurotransmitters and tumors was established. Earlier, in experiments on mice, the ability of diazepam to stimulate the growth of Ehrlich's ascites carcinoma was demonstrated. The aim of this study was to assess the role of central and peripheral benzodiazepine receptor sites in the stimulating effect of diazepam on Ehrlich's carcinoma. The effects of diazepam (0.03 and 3.0 mg / kg, intragastric) on the development of Ehrlich's ascites carcinoma and an orientation-exploratory response in the "open field" test on male SHK mice were studied. It was found that diazepam at a dose of 0.03 mg / kg, but not at a dose of 3 mg / kg, increases the cellularity of the malignant ascites. At the same time, diazepam in both doses studied causes an increase in the peripheral motor activity of mice, which indicates an increase in anxiety reactions. It was found that flumazenil, but not PK11195, attenuates the stimulating effect of diazepam on Ehrlich's ascites carcinoma and inhibits the pro-anxiogenic effect of a small dose of diazepam. The results obtained allow us to conclude that there is no associative relationship between the pro-tumor effect of diazepam and its effect on anxiety responses, but at the same time, the participation of central mechanisms in the stimulating effect of benzodiazepine on the tumor cannot be ruled out.

Изучены поведенческие и нейрохимические эффекты амитриптилина (10 мг/кг, внутрибрюшинно) и флуоксетина (20 мг/кг, внутрибрюшинно) после однократного и хронического введения в условиях моделирования хронического умеренного стресса у аутбредных мышей ICR (CD-1). После 28 дней воздействия стресса наблюдали усиление депрессивных реакций мышей в тесте «вынужденное плавание» и уменьшение уровней серотонина (5-НТ) и 5-оксииндолуксусной кислоты (5-ОИУК) в гиппокампе, повышение концентрации норадреналина (НА) в гипоталамусе. Однократное и хроническое введение амитриптилина или флуоксетина приводило к уменьшению времени иммобилизации и увеличению плавания мышей в тесте «вынужденное плавание». Антидепрессивный эффект флуоксетина, но не амитриптилина, после однократного введения сочетался с увеличением обмена 5-НТ в гиппокампе. Хроническое введение антидепрессантов приводило к повышению уровней НА в гипоталамусе. Таким образом, антидепрессивный эффект амитриптилина и флуоксетина может быть результатом усиления стресс-зависимых адаптивных механизмов, истощенных хроническим стрессом.

We studied the influence of intraperitoneal injection of ATP-sensitive potassium channels inhibitor glibenclamide in doses of 0.01, 0.1, 1, and 10 mg/kg on the effects of a new pyrazolo[C]pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1Hpyrazolo[ 4,3-C]pyridine-3-on, chloral hydrate; 20 mg/kg, intraperitoneally) in the marble burying and open-field tests in mice. It was found that glibenclamide produced an anxiolytic effect in the open-field test (in a dose of 0.01 mg/kg) and anticompulsive effect in the marble burying test (in doses of 1 and 10 mg/kg). The observed behavioral effects of glibenclamide did not depend on blood glucose level. At the same time, glibenclamide in subeffective (0.01 and 0.1 mg/kg) and effective (1 and 10 mg/kg) doses potentiated the psychotropic effects of GIZh-72 in these tests. It can be assumed that the psychotropic effects of GIZh-72 depend on functional activity of ATP-sensitive potassium channels.

It was shown that finasteride, a 5α-reductase inhibitor (50 mg/kg, intraperitoneally) produced analgesic and antiexudative effects in experimental peritonitis induced by intraperitoneal injection of 1% acetic acid. These results agree with published data on its anti-inflammatory properties and ability to potentiate the analgesic effect of morphine in rodents. New pyrazolo[C] pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1H-pyrazolo[4,3-C]pyridine-3-on, chloral hydrate) injected intraperitoneally in doses of 20-80 mg/kg produced dose-dependent antiexudative effects, but exhibited no analgesic properties.

The behavioral and neurochemical effects of amitriptyline (10 mg/kg, i.p.) and fluoxetine (20 mg/kg, i.p.) after single and chronic administration in the setting of unpredictable mild stress in outbred ICR (CD-1) mice were studied. After a 28-day exposure to stress, we observed an increase in depressive reaction in a forced swim test in mice, as well as reduced hippocampal levels of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) and an increased hypothalamic level of noradrenaline (NA). Single and chronic administration of amitriptyline and fluoxetine shortened the immobility period and increased the time corresponding to active swimming in the forced swim test. The antidepressant-like effect of fluoxetine - but not of amitriptyline - after a single injection coincided with an increase in the 5-HT turnover in the hippocampus. Chronic administration of the antidepressants increased the hypothalamic levels of NA. Thus, the antidepressant-like effect of amitriptyline and fluoxetine may result from an enhancement of the stress-dependent adaptive mechanisms depleted by chronic stress.

Standard water-reinforced drug discrimination model was employed to train Wistar rats to discriminate the intraperitoneal injections of tricyclic antidepressant amitriptyline (5.4 mg/kg) and physiological saline. To examine the role of GABAA receptors in psychotropic action of amitriptyline, the substitution tests were performed with muscimol (0.1-1.0 mg/kg) and pregnenolone (30-50 mg/kg). Similar tests were carried out with amitriptyline interoceptive antagonists bicuculline (1 mg/kg), flumazenil (15 mg/kg), finasteride (5 mg/kg), and indomethacin (7.5 mg/kg). The study showed that interoceptive effects of amitriptyline depend on functional activity of GABAA receptors but not on the neurosteroid site of GABAA receptor complex.

Материалы V съезда фармакологов России «Научные основы поиска и создания новых лекарств» (14-18 мая 2018 года, г. Ярославль)

Изучено влияние внутрибрюшинного введения селективного блокатора митохондриального транслокационного белка 18kD РК11195 (5 мг/кг), ингибитора 3α-гидроксистероидной оксидоредуктазы индометацина (5; 10 мг/кг), ингибитора 5α-редуктазы финастерида (5; 15 мг/кг) и нейростероида прегненолона (20 мг/кг) на ориентировочно-исследовательскую реакцию в тесте «открытое поле» у самцов мышей инбредных линии BALB/c, C57BL/6 и крыс Вистар. Установлено, что введение PK11195 ослабляет ориентировочно-исследовательское поведение в тесте «открытое поле» у мышей обеих линий. Финастерид и индометацин вызывают снижение поведенческой активности у грызунов независимо от вида и типа эмоционально-стрессовой реакции. Прегненолон обладает активирующим действием в тесте «открытое поле», но при этом потенцирует депримирующий эффект финастерида у мышей BALB/c.

There were the cases to observe the development of anxiety following administration of indomethacin. One mechanism suggested of this side drug effect is indomethacin-induced inhibition of the synthesis of the positive modulator GABA receptors allopregnanolon. In test «open field» for the first time has shown anxiety in male of inbred mice Balb/c administrated with 10 mg/kg of indomethacin. It was observed the decrease of indomethacin-induced anxiety 30 minute after treatment with classic anxiolytic diazepam with single dose of 1 mg/kg intraperitoneally. There was complete elimination of the anxiety response.