[Effect of intranasally administered glutamate antibodies on the content of excitatory and inhibitory amino acids in the rat`s hippocampus and hypothalamus at the combined stress exposure].

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°Ð¡) 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 field¼. 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 field¼, 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.

[The influence of glutamate antibodies on the level of neurotransmitter monoamines in brain structures of rats with ischemic damage of prefrontal cortex].

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.

[Concentrations of monoamines in the brain structures and features of behavior in the two-month old WAG/Rij rats].

The first spike-wave discharges (SWDs) in WAG/Rij rats begin to appear at age of 2-3 months and are fully manifested by 5-6 months. Occurrence of SWDs in the EEG is the main indicator of absence epilepsy. Extensive absence epilepsy in 5-6 months-old WAG/Rij rats is accompanied by decreases in dopamine and its metabolites concentrations in the meso-cortico-limbic and nigro-striatal dopaminergic brain systems, resulting in the expression of depression-like behavioral symptoms. In 36 day-old WAG/Rij rats, SWDs are not manifested, deficiency of dopamine is not revealed, and symptoms of depression-like behavior are not expressed. In this study, behavior and monoamines and their metabolites concentrations were investigated in 5 brain structures (prefrontal cortex, nucleus accumbens, hypothalamus, striatum, hippocampus) in 2 month-old WAG/Rij rats in comparison with Wistar rats of the same age. Reduction of the dopamine and its metabolites concentration in 2 month-old WAG/Rij rats was found only in the prefrontal cortex, indicating rapid response of the prefrontal cortex or its high sensitivity. Rapid response of the prefrontal cortex is supposed to be a.fundamental property of this brain structure. Decreases in the dopamine and its metabolites concentration in the prefrontal cortex in 2 month-old WAG/Rij rats were associated with features of behavior which can be regarded as a state of so called pre-pathology (increased anxiety and stress reactivity) preceding the development of depression-like behavior typical for 5-6-months old rats of this strain.

[Effect of space flight factors simulated in ground-based experiments on the behavior, discriminant learning, and exchange of monoamines in different brain structures of rats].

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.

Effects of antiglutamate antibodies on the development of stress response and neurotransmitter content in the hippocampus and hypothalamus of rats with different behavioral activity.

We studied the effects of intranasal administration of antiglutamate antibodies on the development of stress response and level of neurotransmitter amino acids and monoamines in brain structures of rats with different initial behavioral activity. The stress exposure was followed by significant changes in behavioral activity and concentration of neurotransmitters in rat hippocampus and hypothalamus. The changes in the level of neurotransmitter amino acids and monoamines were more pronounced in the hippocampus. Antiglutamate antibodies administered intranasally in a single dose of 250 µg/kg immediately after stress exposure prevented the development of the stress response and normalized the level of neurotransmitters in the brain structures of rats. The effect of antibodies was the most pronounced in behaviorally active rats.

Immunological parameters of the blood and monoamine content in the brain of rats during long-term overcrowding.

Blood immunological parameters (cytokine profile and interferon status) and the level of monoamines and their metabolites in various brain structures (amygdala, hippocampus, septum, and hypothalamus) were studied in rats kept under standard conditions or in overpopulated cages. Long-term overcrowding was associated with reduced expression of IL-4 gene, increased transcription of IL-17, and decreased production of IFN-γ, which attested to impaired humoral and cell-mediated immunity and disturbances in IFN-γ synthesis at the post-transcriptional level. Under these conditions, the levels of norepinephrine and dopamine decreased in the septum, but increased in the hypothalamus. The amount of dopamine metabolite dihydroxyphenylacetic acid decreased in both these structures, and the index of dopamine metabolism (dihydroxyphenylacetic acid/dopamine ratio, DOPAC/dopamine) decreased only in the hypothalamus. Overcrowding was not followed by changes in the parameters of noradrenergic and dopaminergic systems in the amygdala and hippocampus and serotoninergic system in all study structures.

[Neurotensin NT (8- 13) dipeptide analog dilept increases the pain threshold and decreases the severity of morphine withdrawal syndrome in rats].

The pain threshold effects of a neurotensin NT (8 - 13) dipeptide analog (dilept), morphine, and their combination have been studied using the tail flick test in rats. The animals of another experimental group were administered with morphine in increasing doses (10 - 20 mg/kg, i.p.) for 5 days in order to induce the state of dependence. The physical dependence on morphine was evaluated in the open-field test by monitoring 16 specific behavioral signs of withdrawal syndrome (WS) induced by the opioid receptor antagonist naloxone, after which the WS total index was calculated. It was established, that dilept (1.6 mg/kg, i.p.) produced a mild analgesic effect via increasing the pain threshold by 34% (p < 0.01), did not effect on the morphine analgesic effect, and decreased the expression of morphine WS by 29.1 and 37.5% (p < 0.01) after a single or subchronic administration, respectively. These behavioral effects of dilept were accompanied by normalization of dopamine and serotonin turnover in the hypothalamus, frontal cortex, and striatum of experimental animals.

[Effects of exposure to high-energy protons on rat's behavior and underlying neurochemical mechanisms].

Effects of 1.5 and 3 Gy from high-energy protons (165 MeV) on rat's motor and oriented trying activities, rate of the Y-labyrinth learning with electric pain stimulation, and levels of monoamines and their metabolites in different brain structures were studied. The experimental results showed that irradiation with these proton doses caused considerable inhibition of the motor and oriented trying activities, and strengthening of passive defense reactions in the open field test; however, no significant change was induced in the learning rate or monoamines turnover. Apparently, emotional and motivational systems were affected to a greater degree than cognitive functions.

[Behavioral and neurochemical aspects of the antidepressive action of GSB-106 dipeptide BDNF fragment].

The behavioral and neurochemical effects of synthetic dipeptide fragment GSB-106 of BDNF, administered in a single dose of 0.1 mg/kg (i.p.), have been studied in comparison to amitriptyline (10 mg/kg, i.p.) on the Nomura depressive state model employing forced-rotating-wheel swim test (FST) in Wistar rats. Amitriptyline is known to increase both the number of wheel turns and the index of correlation between the number of turns in the first and last 5-min intervals of observation. It is established that GSB-6 produces a pronounced antidepressant effect comparable to that of amitriptyline, while not influencing the content of monoamines in brain structures of intact (non-depressive) rats. HPLC study showed that GSB-106 increased the complex parameters of dopamine metabolism (DOPAC/DA and HVA/DA) in nucleus accumbens and striatum of rats undergoing FST as compared to the same indices in intact animals. A decrease in the norepinephrine (NE) content by 50% was detected in striatum and hippocampus of rats with depression model. GSB-106 to significantly increased the number of wheel turnings and prevent the elevation of DA and its metabolite DOPAC levels in hypothalamus. A decrease in 5-HIAA (serotonin metabolite) content was also detected in frontal cortex and hypothalamus.

Effect of combined administration of afobazole and 5-HT2b/2c receptor antagonist SB-200646A on neurochemical profile of brain structures in C57Bl/6 and BALB/c mice.

The effects of combined administration of afobazole and 5-HT(2b/2c)receptor antagonist SB-200646A on the content of monoamines and their metabolites in brain structures of C57Bl/6 and BALB/c mice were studied by the methods of HPLC with electrochemical detection. Combined administration of afobazole and SB-200646A increased the content of epinephrine in the striatum of BALB/c mice (to 230% of the control) and in the hippocampus of both mouse strains. The content of dihydroxyphenylacetic and homovanillic acids and parameters of dopamine metabolism in these structures were reduced. The content of dopamine in the hypothalamus and amygdala was elevated in C57Bl/6, but not in BALB/c mice. These findings attest to the involvement of monoamine systems of the brain in the mechanism of afobazole action and suggest that the enhanced anxiolytic effect of afobazole combination with SB-200646A can be interpreted as a positive modulation of the effect of anxiolytic determined by blockade of 5-HT(2)serotonin receptors.

Effects of neurotensin dipeptide analog dilept on dopamine metabolism and synthesis in the nucleus accumbens of Wistar rats.

We studied the effects of neurotensin dipeptide analog Dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) on dopamine metabolism and synthesis in the nucleus accumbens of Wistar rats. Dilept increased the levels of dopamine and its metabolites (homovanillic acid and dioxyphenylalanine) and stimulated dopamine turnover in this structure. Dilept accelerated dopamine synthesis under conditions of pulsed activity blockade in dopaminergic neuron by injection of γ-butyrolactone combined with inhibition of aromatic acid decarboxylase with 3-hydroxybenzylhydrazine. The spectrum of pharmacological activities of Dilept towards the dopaminergic system of the nucleus accumbens was similar to that of atypical neuroleptics and neurotensin (endogenous antipsychotic).

Modeling of presymptomatic and symptomatic stages of parkinsonism in mice.

A degradation of the nigrostriatal dopaminergic (DA-ergic) system is the key component of pathogenesis of Parkinson's disease (PD). Initial clinical symptoms appear 20-30 years after the onset of neurodegeneration, at a 70% DA depletion in the striatum and a 50% loss of nigral DA-ergic neurons. Low efficacy of the therapy might be improved if preclinical diagnostics and preventive therapy are developed. The development of appropriate experimental models should precede clinical trials. This multidisciplinary study first managed to model in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) all together the following stages of parkinsonism: (a) the early presymptomatic stage manifested by a subthreshold degeneration of axons and DA depletion in the striatum without loss of nigral cell bodies; (b) the advanced presymptomatic stage manifested by a subthreshold degeneration of striatal axons and DA depletion and by a subthreshold loss of nigral cell bodies; (c) the advanced presymptomatic stage characterized by threshold depletion of striatal DA and a loss of DA-ergic axons and nigral cell bodies resulting in motor dysfunction. The degeneration of axons proceeds and prevails that of cell bodies suggesting higher sensitivity to MPTP of the former. Compensatory processes were developed in parallel to neurodegeneration that was manifested by the increase of the DA content in individual nigral cell bodies and DA turnover in the striatum. The developed models might be exploited for: (a) an examination of pathogenetic mechanisms not only in the nigrostriatal system but also in other brain regions and in the periphery; (b) a study of the compensatory mechanisms under DA deficiency; (c) a search of precursors of motor disorders and peripheral biomarkers in presymptomatic parkinsonism; (d) the development of preventive therapy aiming to slow down the neurodegeneration and strengthen compensatory processes. Thus, the models of the early and advanced presymptomaic stages and of the early symptomatic stage of parkinsonism were developed in mice with MPTP.

Changes in the levels of inhibitory and excitatory amino acids in the brain structures of female rats with cobalt epileptogenic focus during different phases of the estrous cycle.

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.

[Possible role of serotonin 5-HT2 receptors in mechanism of afobazole anxiolytic action: neurochemical study of inter-line differences in mice].

Effects of separate and combined introduction of afobazole and SB-200646A (highly selective 5-HT2B/2C receptor antagonist) on the content of monoamines and their metabolites in brain structures of mice of C57/Bl/6 and BALB/C lines have been studied using neurochemical methods and high-performance liquid chromatography (HPLC). Afobazole (5 mg/kg, i.p.) significantly increased dopamine (DA) level in hypothalamus and amygdala of C57/Bl/6 mice, while no changes of DA content were observed in BALB/C mice. At the same time, the concentrations of DA metabolites dioxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the same structures as well as in striatum were decreased compared to control. Afobazole also led to a decrease in the content of 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA/5-HT index in frontal cortex and amygdala of C57/Bl/6 mice; analogous decrease in the latter parameter was observed in striatum of BALB/C mice. The introduction of SB-200646A (10 mg/kg, i.p.) almost did not influence the neurochemical indices of the content and metabolism of monoamines, except for an increase in the HVA content in amygdala and the DOPAC and 5-HIAA concentrations in striatum of C57/Bl/6 mice. The joint introduction of afobazole and SB-200646A led to an increase in the content of norepinephrine (NE) in striatum of BALB/C mice and in hippocamp of mice of both lines. The data obtained may be indicative of the involvement of NE- and DA-ergic neurotransmitter systems in the mechanisms of afobazole action. Enhanced anxiolytic effect of the joint introduction of afobazole and SB-200646A can be interpreted as a positive modulation of the anxiolytic drug action related to the blocking of 5-HT2-type serortonin receptors. The results also reveal inter-line differences of neurochemical responses induced by combination of afobazole and selective antagonist of serotonin.

[Neurochemical study of effects of the new anxiolytic drugs afobazol and ladasten on the synthesis and metabolism of monoamines and their metabolites in the brain structures of Wistar rat on the model of monoamine synthesis blockade induced by aromatic amino acid decarboxylase inhibitor NSD-1015].

Results of a neurochemical study of the effects of the new anxiolytic drugs afobazole and ladasten on the synthesis and metabolism of monoamines and their metabolites determined by HPLC on the model of monoamine synthesis blockade induced by NSD-1015 (aromatic L-amino acid decarboxylase) in the brain structures of Wistar rats are reported. A decrease in the levels of DOPAC in hypothalamus and HVA in striatum after afobazole injection may be evidence of an inhibitory action of this drug on the activity of monoamine oxidase (MAO-A), which is the main enzyme involved in dopamine biodegradation. Afobazole was also found to increase the content of serotonin (5-HT) as well as its precursor (5-OTP) and its main metabolite (5-HIAA) in hypothalamus by up to 50, 60 and 50%, respectively, which confirms a hypothesis that this anxiolytic drug can modulate the activity of tryptophan hydroxylase (5-OTP synthesis enzyme). In contrast to afobazole, ladasten demonstrated the ability to increase the level of L-DOPA (a dopamine precursor) in virtually all functional structures of the brain (except for hippocamp), which may support the hypothesis suggestion concerning a predominant action of this drug on the activity of tyrosine hydroxylase. Ladasten exhibited selectivity with respect to the dopaminergic system and affected only parameters of the dopamine metabolism, in particular, by increasing the HVA content in nucleus accumbens and decreasing it in the hypothalamus. The drug also affected the dopamine turnover parameters, producing an increase in both HVA/dopamine ratio in nucleus accumbens and DOPAC/dopamine ratio in hippocamp.

[Effects of amitriptyline, fluoxetine, and tianeptine on the content of monoamines and their metabolites in Wistar rat brain structures].

The effects of antidepressant drugs belonging to different pharmacological groups--amitriptyline, fluoxetine (prozac), and tianeptine (coaxyl)--on the content of monoamines and their metabolites in Wistar rat brain structures (frontal cortex, hypothalamus, nucleus accumbens, striatum, and hippocamp) has been studied using HPLC with electrochemical detection. Tricyclic antidepressant amitriptyline (10 mg/kg) was found to produce a moderate increase in the DOPAC/dopamine turnover index in nucleus accumbens, but did not influence the levels of serotonin (5-HT), dopamine, and its metabolites (5-HIAA, DOPAC, and HVA) in other brain structures studied (frontal cortex, hypothalamus, striatum, hippocamp). Fluoxetine (Prozac) (20 mg/kg) decreased both the 5-HIAA content and the 5-HIAA/5-HT (5-HT turnover index) in all brain structures of Wistar rats. In contrast, the effects of Prozac on the level of catecholamines and their metabolites in various brain regions was more complex. Tianeptine (Coaxyl) was demonstrated to increase both the 5-HIAA content and the 5-HIAA/5-HT ratio in all the structures studied (except for nucleus accumbens), in good agreement with the hypothesis concerning a two-phase mode of tianeptine action with enhanced 5-HT secretion in the synaptic gap in the first stage of pharmacological response.

[Effect of dipeptide neurotensin analog dilept on extracellular concentrations of glutamate, GABA and HVA in N. accumbens of rat brain].

The influence of dilept (GZR-123, N-caproyl-L-prolyl-L-tyrosine methyl ester)--a dipeptide analog of neurotensin (NT)--on extracellular concentration of glutamate, gamma-aminobutyric acid (GABA) and homovanillic acid (HVA) in n. accumbens of Wistar rats has been studied. By means of microdialysis, it was shown that dilept increases the concentrations of glutamate and GABA and decreases the HVA content in n. accumbens. These effects of dilept are similar to those produced by NT introduced into n. accumbens. Thus, dilept can be considered as a systemically active dipeptide analog of NT, which is capable of modulating the dysbalance of glutamate-, GABA-, and dopaminergic systems of n. accumbens. These neurochemical data taken together with previously established behavioral effects of dilept suggest that this dipeptide is a potential antipsychotic drug.

Increased concentrations of serotonin and 5-hydroxyindoleacetic acid in blood plasma from patients with pulmonary hypertension due to mitral valve disease.

Serotonin content in the plasma and platelets and 5-hydroxyindoleacetic acid concentration in the plasma were shown to increase in patients with pulmonary arterial hypertension due to mitral valve disease. A positive correlation was found between the severity of pulmonary arterial hypertension and concentrations of serotonin (r=0.48) and 5-hydroxyindoleacetic acid in the plasma (r=0.9).

[The state of sympathetic-adrenal system in patients with chronic cardiac insufficiency].

Activation of sympato-adrenal system plays an important role in the development of chronic cardiac failure (CCF). However, its relation to morpho-functional state of myocardium in CCF patients is virtually unknown. HPLC with electrochemical detection was used to determine plasma noradrenalin, adrenalin, and their precursors, 3,4-dioxyphenylalanine (DOPA) and dopamine, in patients with different morpho-functional changes in myocardium. The study demonstrated enhanced activity of sympato-adrenal system in patients with CCF. It showed for the first time that activity of sympato-adrenal system in CCF patients depends on the morpho-functional status of myocardium.

[Effect of phenibut on the content of monoamines, their metabolites, and neurotransmitter amino acids in rat brain structures].

Effects of the nootropic drug phenibut, which is a structural analog of gamma-aminobutyric acid (GABA), on the content of monoamines, their metabolites, and neurotransmitter amino acids in brain structures have been studied on Wistar rats. It is established that a single administration of phenibut in a dose of 25 mg/kg (i.p.) produces a statistically significant increase in the content of dopamine metabolite (3,4-dioxyphenylacetic acid) and the retarding amino acid taurine in striatum. At the same time, phenibut did not significantly influence the levels of GABA, serotonin, and dopamine in various brain structures and produce a moderate decrease in the level of norepinephrine in the hippocampus.