The effects of chronic (17 days) intranasal administration of low (50 IU/kg) and intermediate (8000 IU/kg) doses of human interferon-α (IA) on behavioral indicators of anxiety and depression and the monoaminergic system of the brain were studied in rats. Control rats received the same volume of intranasal physiological saline. IA was found to have any ambiguous effects on anxiety levels. Thus, anxiety in the open field test increased after administration of both doses of IA and decreased in the light-dark test and elevated plus maze test after small doses of IA. In the forced swimming test, administration of both doses of IA was followed by an increase in the duration of immobility (a behavioral symptom of depression). Administration of the intermediate (but not the small) dose of IA was followed by increases in the contents of dopamine and its metabolites in the olfactory bulb and decreases in the nucleus accumbens; the noradrenaline content decreased in the prefrontal cortex. It is suggested that these neurochemical changes in the brain may underlie the behavioral symptoms of depression induced by intranasal administration of intermediate doses of IA. Depression-like behavioral symptoms occurring after administration of small doses of IA were evidently not linked with changes in brain monoaminergic systems but could be due to other mechanisms.

Objective. We studied the effect of glutamate antibodies by intranasal administration on the development of stress reactions and aspartate, glycine and taurine content in the brain structures of rats with different initial behavioral activity (active and passive). Methods. Stress caused by placing the animals in the living cell with water (21°С) covered with a grid for 30 min. Glutamate antibodies in a dose of 250 mg/kg in a volume of 10 mkl were administered intranasally to the experimental group of rats immediately after the stress. After 1 h after stress exposure and antibodies administration in all rats was investigated motor activity in the test of the «open field». Amino acids aspartate, glycine and taurine in the brain structures (hippocampus and hypothalamus) were determined by HPLC with fluorescence detection. Results. Combined water-immersion stress caused significant changes in the behavioral activity of rats in the «open field», but a more pronounced decline in the total index were observed in the behaviorally passive group of rats. The stress was accompanied by a change in the content of neurotransmitter amino acids (glycine and taurine) in the hippocampus. The most significant changes in the levels of glycine (decrease) and taurine (an increase) was observed in the hippocampus behaviorally active rats. Glutamate antibodies at a dose of 250 mg/kg administered intranasally immediately after stress exposure prevents the development of behavioral stress reactions and contributed to an increase in the hippocampus the content of glycine and taurine, related to stress-limiting systems. Conclusions. The glutamate antibodies under stress act as endogenous bioregulators and prevent the development of stress reactions.

We studied the effect of thrombosis of retina vessels on the development of glutamate excitotoxicity in chinchilla rabbits. Thrombosis was induced by administration of Bengal rose dye at a dose of 40 mg/kg into the auricular vein of the animals followed by focal lighting with white light. Lighting was performed for 10 min on average at the temporal vascular arcade in the location of the angulation of vessels over the border of the disk of the optic nerve using a binocular ophtalmoscope and a condensing +14.0 D lens. We found that experimental thrombosis induced the accumulation of glutamate, aspartate, glycine, and GABA, as well as oxidative stress, which was associated with decreased activity of superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase.

We studied changes in the levels of inhibitory and excitatory neurotransmitters in female rat brain structures during different phases of the estrous cycle in health and after creation of a cobalt epileptogenic focus at stage I of epileptogenic system development. The most pronounced shifts were found in the contralateral cortex, where the levels of GABA and glycine decreased significantly during the diestrus-2 phase (corresponding to menstruation), which attests to a convulsive threshold decrease during this period.

It is known that neuroglutam (at 26 mg/kg) potentiates stereotypy that is induced by the agonist of postsynaptic dopamine receptors apomorphine (1 mg/kg), and suppresses catalepsy that is induced by the blocker of postsynaptic dopamine receptors haloperidol (1 mg/kg), which points to its stimulatory influence on dopaminergic neurotransmission. Neuroglutam (26 mg/kg) does not affect the contents of noradrenaline and dopamine (DA) in homogenates of rat brain structures; however, it increases the concentration of the metabolites of dopamine 3,4-dioxyphenylacetic acid (DOPAC) in the frontal cortex and homovanillic acid (HVA) in the hippocampus, which points to its positive influence on the rate of DA utilization, and, in addition, an increase in indices that characterize the rate of DA turnover, viz., DOPAC/DA and HVA/DA in the striatum. We used the method of radioligand binding in vitro with [G- 3 H]-sulpiride to show that neuroglutam (10 −10 –10 −4 M) does not directly interact with dopamine D 2 receptors; however, during subchronic administration (5 days; a single daily dose of 26 mg/kg) neuroglutam promotes an increase in the density of D2 receptors in the prefrontal cortex, which points to its ability to modulate the expression of these receptors. The data from neurochemical and radioligand analysis suggest that both presynaptic (intensification of metabolic DA turnover) and postsynaptic (DA receptors) mechanisms of dopaminergic neurotransmission are involved in the neuropsychotropic action of neuroglutam. Neuroglutam did not influence the strength of hyperkinesia that was induced by the metabolic precursor of serotonin 5-hydroxytryptophan on the content of serotonin and its metabolites in rat-brain structures and did not alter the receptor binding of [G- 3 H]-ketanserin (an antagonist of 5-HT 2A receptors) in the prefrontal cortex both under in vitro conditions and during subchronic administration ex vivo, which points to the absence of direct participation of the serotonergic system in the pharmacological action of the studied drug.

We studied the effects of irradiation with protons at doses of 1 and 2 Gy in the Bragg Peak with an energy of 170 MeV on learning, recall of skills, and concentration of monoamines and their metabolites in the prefrontal cortex, nucleus accumbens, hypothalamus, striatum, and hippocampus of rats. In the T-maze, we performed discriminant learning with food reinforcement. Rats were trained for 5 days; from the second to fifth days, we found a considerable level of learning as compared to the first day. After training, on the sixth day, we found a trend to a decrease in the efficacy of test performance, which achieved significant differences on the seventh day of testing. Irradiation by protons at doses of 1 and 2 Gy in the Bragg peak did not influence the elaboration and recall of the passive avoidance reflex. This treatment causes a decrease in the concentration of catecholamines in the prefrontal cortex and 3-MT, a metabolite of dopamine, in the striatum. On the basis of disturbances of neurochemical indices in the corresponding brain structures, it is possible to logically explain the observed disturbances in behavior.

We investigated the levels of monoamines and their metabolites in certain brain structures of rats at 30 and 90 days after exposure to carbon ions ( 12 C) with an energy of 500 MeV/nucleon. The linear energy transfer and radiation dose were 10.6 keV/µm and 1 Gy, respectively. The concentrations of substances were measured in five structures of the brain, including the prefrontal cortex, nucleus accumbens, hypothalamus, hippocampus, and striatum. On day 30 after the exposure, the most pronounced changes in the concentration of monoamines and their metabolites were observed in the nucleus accumbens; the smallest changes were found in the hippocampus and striatum. After 90 days, significant changes were still present in the nucleus accumbens. At the same time, these changes became less evident in other structures. A comparison of our results with the data of similar previous experiments (24 hours after exposure) showed that the most pronounced effect was observed soon after radiation exposure. The induced damage diminished at a later period. Based on the results of our study, we made the hypothesis that the change in the metabolism of monoamines may be compensated if the linear-energy transfer values were relatively low (10.6 keV/μm). At higher values of linear-energy transfer, compensatory and regenerative processes did not occur; the effect increased with time. An increased susceptibility of the nucleus accumbens was found at all the time points after the exposure, which may indicate an important role of this brain structure in the radiation-induced impairment of cognitive functions and emotional and motivational states.

Изучали влияние облучения протонами в дозах 1 и 2 Гр в пике Брэгга с энергией 170 МэВ на процессы обучения, воспроизведения навыков и концентрацию моноаминов и их метаболитов в префронтальной коре, прилежащем ядре (nucleus accumbens), гипоталамусе, стриатуме и гиппокампе крыс. В Т-образном лабиринте проводили дискриминантное обучение с пищевым подкреплением. Крыс обучали пять дней, из которых со второго до пятого дня животные выявили значимый уровень обучения по сравнению с первым днем. После облучения, на шестой день наметилась тенденция к снижению эффективности выполнения теста, достигшая значимых различий на седьмой день тестирования. Облучение протонами в дозах 1 и 2 Гр в пике Брэгга не повлияло на выработку и воспроизведение рефлекса пассивного избегания. То же самое воздействие вызывает уменьшение концентрации катехоламинов в префронтальной коре и концентрации 3-МТ – метаболита дофамина в стриатуме. На основании обнаруженных нарушений нейрохимических показателей в соответствующих структурах мозга можно достаточно логично объяснить наблюдаемые нарушения поведения.

Установлено, что нейроглутам (26 мг/кг) потенцирует стереотипию, вызванную агонистом постсинаптических дофаминовых рецепторов апоморфином (1 мг/кг) и подавляет каталепсию, вызванную блокатором постсинаптических дофаминовых рецепторов галоперидолом (1 мг/кг), что свидетельствует о его стимулирующем влиянии на дофаминергическую нейропередачу. Нейроглутам (26 мг/кг) не влияет на содержание норадреналина и дофамина (ДА) в гомогенатах структур мозга крыс, однако увеличивает концентрацию метаболитов дофамина 3,4-диоксифенилуксусной кислоты (ДОФУК) во фрональной коре и гомованилиновой кислоты (ГВК) в гиппокампе, что говорит о его положительном влиянии на скорость утилизации ДА, кроме того, увеличивает показатели, характеризующие скорость кругооборота ДА - ДОФУК/ДА и ГВК/ДА в стриатуме. Методом радиолигандного связывания in vitro с использованием [G-3H]-сульпирида показано, что нейроглутам (10-10 10-4 М) не проявляет прямого взаимодействия с дофаминовыми Д2-рецепторами, однако при субхроническом системном введении (5 дней – ежедневно однократно в дозе 26 мг/кг) нейроглутам способствовует повышению плотности Д2-рецепторов в префронтальной коре, что указывает на его способность модулировать экспрессию указанных рецепторов. Данные нейрохимического и радиолиандного анализа свидетельствуют об участии в нейропсихотропном действии нейроглутама как пресинаптических (интенсификация метаболического оборота ДА), так и постсинаптических (ДА-рецепторы) механизмов дофаминергической нейропередачи. Нейроглутам не влиял на выраженность гиперкинеза, вызванного метаболическим предшественником серотонина 5-гидрокситриптофаном, на содержание серотонина и его метаболитов в структурах мозга крыс, не изменял рецепторного связывания [G-3H]-кетансерина (антагониста 5-HT2A-рецепторов) в префронтальной коре мозга как в условиях in vitro, так и при субхроническом введении в условиях ex vivo, что указывает на отсутствие прямого участия серотонинергической системы в фармакологическом действии изучаемого средства.

Изучались поведение и нейрохимические изменения, вызванные моделированием болезни Альцгеймера (БА) путем билатерального введения (по 7.5 нмоль) в желудочки мозга крыс. Через 5.5 нед у крыс с выраженным симптомокомплексом, характерным для БА, наблюдалось развитие когнитивных и психоэмоциональных нарушений в тестах пространственного обучения по Моррису и вынужденного плавания по Порсолту. Определение содержания моноаминов и их метаболитов в структурах мозга крыс проводили методом ВЭЖХ с ЭХД на следующий день после завершения тестов. Установлено, что в дорсальном стриатуме крыс с БА отмечалось снижение содержания метаболитов дофамина (ДА): ГВК (гомованилиновая кислота), ДОФУК (3,4 диоксифенилуксусная кислота), 3-МТ (3-метилтирамин) и уменьшение величины комплексных показателей, характеризующих скорость утилизации ДА – ДОФУК/ДА и ГВК/ДА, тогда как концентрация самого ДА в этой структуре не изменялась. В прилежащем ядре (ПЯ, вентральный стриатум) наблюдалось снижение оборота внеклеточного ДА, регистрируемое по уменьшению показателя ГВК/ДА. В этой же структуре регистрировалось замедление оборота серотонина (5-ОТ) по показателю 5-ОИУК (5-оксииндолуксусная кислота)/5-ОТ при увеличении уровня самого 5-ОТ. В гипоталамусе выявлено достоверное снижение содержания ДА и его метаболитов 3-МТ, ГВК, а также оборота 5-ОТ. При исследовании эффектов на параметры аминацидергической нейропередачи отмечалось статистически достоверное увеличение содержания глутамата в стриатуме. Результаты работы свидетельствуют об участии дофамин- (тубероинфундибулярной, мезолимбической, нигростриарной), серотонин- и глутаматергической (в стриатуме) нейротрансмиттерных систем мозга в патофизиологических механизмах развития когнитивных и психоэмоциональных нарушений, возникающих при БА, моделируемой введением .

We studied behavioral and neurochemical alterations that were induced by modeling of Alzheimer’s disease (AD) using bilateral intracerebroventricular administration of Aβ25–35 at a dose of 7.5 nmol in each ventricle. After 5.5 weeks, cognitive and psychoemotional alterations in the Morris spatial learning and Porsolt’s forced-swim tests were observed in rats with strong symptoms that are typical of AD. Measurement of the contents of monoamines and their metabolites in rat-brain structures was performed using the HPLC with the ECD method 1 day after the end of the tests. In the dorsal striatum, we found a decrease in the contents of metabolites of dopamine (DA), including homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 3-methyltyramine (3-MT), and a decrease in the indices of DA utilization, including DOPAC/DA and HVA/DA, whereas the DA content was stable in this structure. In the nucleus accumbens (NA, ventral striatum), we found a decreased level of the HVA/DA ratio, which reflects the lower turnover of extracellular DA. We also found a lower turnover of serotonin (5-HT), which was seen as a decrease in the 5-hydroxyindolacetic acid (5-HIAA)/5-HT ratio, whereas the 5-HT content was elevated. In the hypothalamus, we revealed a significant decrease in the DA level and the levels of its metabolites, including 3-MT and HVA, and 5-HT turnover. We found that Aβ25–35 influenced the indices of amino-acidergic neurotransmission, which was reflected by the higher glutamate content in the striatum. Our data show that cerebral neurotransmitter systems, such as the tuberoinfundibular, mesolimbic, and nigrostrial dopaminergic and the striatal serotonergic and glutamatergic systems, are involved in pathophysiological mechanisms of the development of cognitive and psychoemotional impairments that occur in AD, as modeled by administration of Aβ25–35.

Изучено влияние пептидного анксиолитика селанка (0.3 мг/кг) на поведенческие параметры синдрома отмены алкоголя в опытах in vivo и нейрохимические показатели серотонинергической системы в структурах мозга в опытах ex vivo у беспородных крыс со сформировавшимся предпочтением к 10% раствору этанола. Установлено, что селанк при однократном введении купирует тревожную реакцию в тесте “приподнятый крестообразный лабиринт” через 48 ч после отмены этанола, увеличивая время нахождения в открытых рукавах и число выходов в открытые рукава. С использованием метода ВЭЖХ показано, что селанк препятствует повышению уровня серотонина во фронтальной коре, гипоталамусе и миндалине, что может быть связано с уменьшением синтеза серотонина. Полученные данные свидетельствуют об анксиолитической активности селанка в условиях алкогольной абстиненции, что позволяет расширить сферу его использования в клинической практике.

Study appraisal and Synthesis methods: After examination of the abstracts collected from those database searches, the full version of relevant clinical trials were examined and the data of interest were extracted. According to the Cochrane bias assessment, the risk of bias was also inspected. The efficacy outcomes were the mean changed scores of ADHD rating scales, the overall response rate, and the overall remission rates. The overall discontinuation rate and the discontinuation rate due to adverse events were determined as measures of acceptability and tolerability, respectively. Relative risks (RRs), and weighted mean differences (WMDs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs) were estimated by using a random effect model. Results: A total of 146 subjects in four RCTs that compared bupropion with methylphenidate in the treatment of ADHD were included. There was not a significant heterogeneity in each efficacious outcome. The pooled mean changed scores of the Iowa-Conners Abbreviated Parent and Teacher Questionnaires (ICQ) and Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) for parents and teachers in child and adolescent ADHD in bupropionand methylphenidate-treated groups were not significantly different [SMD (95%CI) of −0.41 (−0.92, 0.11), I2 = 10% and SMD (95%CI) of −0.10 (−0.57, 0.38), I2 = 0%]. Additionally, the pooled mean changed score, measured by the ADHD-RS-IV and the adult ADHD rating scale (AARS), in adult ADHD between the two groups was also not significantly different [SMD (95%CI) of −0.38 (−0.81, 0.06), I2 = 0%]. The pooled response rate for adult ADHD between the two groups was not significantly different [RR (95%CI) of 1.36 (0.84, 2.21), I2 = 0%]. Unfortunately, the pooled response rate for the child and adolescent group was not calculated since only one study reported this response rate. Conclusions: Based on limited data from this systematic review, bupropion is as effective as methylphenidate for ADHD patients. Additionally, tolerability and acceptability are also comparable. However, these findings should be considered as the very preliminary results. To confirm this evidence, further studies in this area should be conducted.

У крыс линии WAG/Rij первые пик – волновые разряды (ПВР) начинают появляться в возрасте 2–3 мес. и полностью проявляются к 5–6 мес. Наличие ПВР в ЭЭГ является основным показателем абсансной эпилепсии. Развернутая абсансная эпилепсия у 5–6 месячных крыс линии WAG/Rij сопровождается уменьшением концентрации дофамина и его метаболитов в мезо-кортико-лимбической и нигро-стриатной дофаминергических системах мозга, что приводит к экспрессии симптомов депрессивноподобного поведения. У 36-дневных крыс линии WAG/Rij не проявляются ПВР, не выявляется дефицит дофамина в структурах мозга и не проявляются симптомы депрессивноподобного поведения. В настоящей работе были исследованы особенности поведения и концентрация моноаминов, а также их метаболитов в 5 структурах мозга (префронтальная кора, прилежащее ядро, гипоталамус, стриатум, гиппокамп) у двухмесячных крыс линии WAG/Rij по сравнению с крысами Wistar аналогичного возраста. Уменьшение концентрации дофамина и его метаболитов у двухмесячных крыс линии WAG/Rij выявлено только в префронтальной коре, что указывает на быструю реакцию префронтальной коры или на ее высокую чувствительность. Предполагается, что быстрая реакция префронтальной коры является фундаментальным свойством этой структуры мозга. Уменьшение концентрации дофамина и его метаболитов в префронтальной коре у двухмесячных крыс линии WAG/Rij сочеталось с особенностями поведения, которые можно рассматривать как состояние так называемой “предпатологии” (повышенная тревожность и стресс-реактивность), предшествующей развитию депрессивноподобного поведения, характерного для 5–6 месячных крыс этой линии.

Отмечено, что после экспериментальных воздействий (длительное фракционированное -облучение, антиортостатическая гиподинамия, а также одновременное действие этих факторов), моделирующих в наземном эксперименте влияние факторов космического полета, у животных (крыс) достаточно быстро восстанавливалась двигательная и ориентировочно-исследовательская активность при тестировании их в “открытом поле”. При исследовании динамики дискриминантного обучения крыс экспериментальных групп существенных различий с контролем не выявлено. Установлено, что незначительное влияние данных воздействий на когнитивную деятельность животных соответствует слабо выраженным изменениям концентрации моноаминов в структурах мозга, отвечающих за когнитивные и эмоционально-мотивационные функции.

Experiments on the model of bilateral photothrombosis in prefrontal cortex showed that antibodies to glutamate one-time administered intranasally 1h after ischemic damage to the brain cortex lead to decrease of neurodegenerative influence of excitatory neurotransmitter after photothrombosis. It was showed the change of the level of dopamine, serotonin and their metabolites in hippocampus and prefrontal cortex.

Experimental treatment (long-term fractionated γ-irradiation, antiorthostatic hypodynamia, and the combination of these factors) simulating the effect of space flight in ground-based experiments rapidly restored the motor and orienting-investigative activity of animals (rats) in "open-field" tests. The study of the dynamics of discriminant learning of rats of experimental groups did not show significant differences from the control animals. It was found that the minor effect of these factors on the cognitive performance of animals correlated with slight changes in the concentration ofmonoamines in the brain structures responsible for the cognitive, emotional, and motivational functions.

We studied the in vivo effects of the peptide anxiolytic selank (0.3 mg/kg) on the behavioral parameters of the syndrome of alcohol withdrawal and the neurochemical indices of the serotonergic system in the brain structures in ex vivo experiments in outbred rats with a preference for a 10% solution of ethanol. We found that a single administration of selank eliminates the anxious response in the elevated plus maze at 48 h after the withdrawal of ethanol and increases the time spent in the open arms and the number of entries into the open arms. Using HPLC, we showed that selank prevents an increase in the serotonin level in the frontal cortex, hypothalamus, and amygdala, which may be related to a decrease in the synthesis of serotonin. The data we obtained indicate that selank has anxiolytic activity under conditions of alcohol abstinence, which suggests that the sphere of its use in clinical practice may be widened.