Abstract—Here we studied the effects of anti-epileptic substance GIZh-298 and the drug of comparison sodium valproate (NaV) on the contents of excitatory and inhibitory amino acids in the frontal cortex, hypothalamus, striatum, and hippocampus of the mouse brain in a model of generalized tonic-clonic seizures induced by maximal electroshock (MES). The levels of excitatory amino acids such as aspartate in the hypothalamus and glutamate in the hippocampus were decreased by 20.8 and 16.7

Abstract—The study of the status of norepinephrine-, dopamine- and serotonergic neurotransmitter systems of BALB/C mice brain structures on 15 and 64 days of postnatal development (PD) in the model of autistic disturbances induced by injection of sodium valproate (SV, 400 mg/kg , s/c) to pregnant females was carried out using the HPLC/ED method. The level of both catechol- and indolamines in the brain structures of control mice at the age of 15 days was significantly lower than in adult animals at the age of 64 days. Prenatal administration of SV caused a decrease in all parameters of monoaminergic neurotransmission in the striatum of offspring at the age of 15 days but had no effect in other brain structures studied. Subsequently, the level of dopamine increased and by the 64th day of PD did not differ from the parameters of the control group. The parameters of the serotonergic system changed in a similar pattern, with the content of serotonin and the serotonin metabolite 5-OIAA in the striatum increasing gradually and reaching maximum values by the 64th day of PD. Our data allows to assume that the administration of SV to pregnant females affects the activity of the dopamine and serotonergic systems of the brain of the offspring causing a decrease in their activity in the striatum by the 15th day of PD followed by restoration to control values by the 64th day, which we previously observed in male pups. Thus, the patterns of dynamic changes in the neurochemical profile do not differ between males and females.

The aim of the present work was to study the dynamics of neurotransmitter amino acids after acute Noopept (a dipeptide analogue of piracetam used in clinical practice as a nootropic agent) administration in intact and long-term ethanol (ETOH) exposed rats. Albino male rats were given 10% (vol/vol) ETOH solution as the only source of fluid 24 h / 7 days per week (n = 5). Also we used intact rats of the same age which had no access to ethanol (n = 5). The excitatory and inhibitory amino acids in the extracellular space of the dorsal hippocampus region in freely moving intact and ETOH-exposed rats during prolonged alcohol deprivation were measured using the intracerebral microdialysis method followed by HPLC/ED. There were no significant differences in the level of neurotransmitter amino acids between ETOH-exposed and intact animals. For the first time, in vivo experiments the effect of Noopept (1.5 mg/kg, i.p.) on the level of excitatory amino acids (an increase in ASP by 2.38 times and GLU by 2.28 times) along with an increase in the level of the inhibitory amino acid GLI by 3.13 times only in intact rats was shown. Thus, in ETOH-exposed rats under the adaptive rearrangements in prolonged ethanol withdrawal, the neurochemical mechanisms of the hippocampus seem to be characterized by insensitivity to an acute Noopept administration. Animal neurochemical studies of changes in the mediator amino acids due to the long-term effect of alcohol on the CNS may be of practical importance for the development of optimal strategies and pharmacotherapy.

Abstract—The aim of the present work was to study the dynamics of neurotransmitter amino acids after acute Noopept (a dipeptide analogue of piracetam used in clinical practice as a nootropic agent) administration in intact and long-term ethanol (ETOH) exposed rats. Albino male rats were given 10

Increasing evidence suggests that the gut microbiota, through the “microbiota–gut–brain axis”, can regulate anxiety, mood, and cognitive abilities such as memory and learning processes. Consistently with this, treatments altering the gut microbiota, such as antibiotics and probiotics, may influence brain function and impact behavior. The mechanisms that underlie the interplay between the intestinal microbiota and the brain have been intensively studied. We aimed to investigate the effects of two probiotic lactobacilli strains, Lacticaseibacillus rhamnosus 12L and Lactiplantibacillus plantarum 8PA3, on behavioral disorders in mice induced by a two-week parenteral treatment with broad-spectrum antibiotics. On completion of the treatment, the mice were subjected to behavioral tests, including the open field test (OFT), novel object recognition test (ORT), and T-maze test. Antibiotic-treated mice demonstrated anxiety-related behavior, decreased cognition, and retarded exploratory activity that were ameliorated by the administration of probiotics. As was determined by high-performance liquid chromatography (HPLC), both tested strains produced serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), as well as dopamine, which was further metabolized into norepinephrine by L. plantarum 8PA3 and epinephrine by L. rhamnosus 12L. Moreover, these lactobacilli were found to harbor catecholamines and 3,4-dihydroxyphenylacetic acid (DOPAC) in their biomass when grown on MRS broth. Additionally, L. plantarum 8PA3 and L. rhamnosus 12L were able to impact oxidative stress via H2O2 production and antioxidant activity, as determined in this study by the ferrous oxidation–xylenol orange (FOX) assay and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay, respectively. The results obtained in this study support the role of probiotics as a promising therapeutic for neurological disorders. However, more investigations are required to confirm the clinical significance of this finding.

We investigated the effects of combined exposure to hypogravity and ionizing radiations on neurochemical processes in key structures of the rat's brain leading to long dated changes in behavior. The authoring procedure consisted of a synchronous combination of chronic tail-suspension, gamma- irradiation and irradiation by 12С ions in an effort to extrapolate results of the ground-based experiment on real spaceflight conditions (Mars mission). The modeled factors brought about significant changes in animal behavior and metabolism of neuromediators that persisted for several months, that is roughly a quarter of this animal's life. The behavior analysis (Morris labyrinth) suggests sustained major disorders in spatial memory and orientation. Data of neurochemical analysis demonstrate also lasting shifts in dopamine metabolism.

Parameters of non-spatial and spatial memory were evaluated in sexually mature offspring of outbred rats (females and males F0) consuming a 10% ethanol solution for 30 weeks before mating. We found a significant increase in the recognition index in F1 males and its decrease in F1 females in the novel object recognition test. During the first days of the experiment in T-maze, a decrease in spatial memory was revealed in F1 males, which remained at the trend level until the end of testing; no significant deviations were detected in F1 females. Memory impairment in F1 females was accompanied by a decrease in BDNF level in the hippocampus, but not in the prefrontal cortex. Thus, ethanol consumption by F0 rats before mating led to impairment of long-term working memory only in female F1 offspring.

Immunotherapy with interferon-α (IFN-α) is frequently associated with neuropsychiatric consequences, including depression. Mechanisms underlying adverse effects of IFN-α are not fully understood. This study was aimed to determine whether intranasal administration of IFN-α can provoke depression-like behavior in rats and whether overcrowding stress can interfere or amplify the effects of IFN-α. To achieve this aim, effects of human IFN-α in low (50 IU/kg) and medium (8000 IU/kg) doses on the forced swimming test behavior and monoamines and their metabolite content in the brain structures of Wistar rats housed in standard and overcrowding conditions were investigated. Depressive-like behavior (increased immobility) was observed in rats housed in standard conditions after treatment with both doses of human IFN-α, as well as in vehicle-treated rats housed in stressful, overcrowding conditions. In standard conditions, a low dose of IFN-α produced a subtle alteration in the metabolism of dopamine only in one of the brain structures analyzed ( nucleus accumbens ). The medium dose of IFN-α induced more drastic neurochemical alterations in a larger number of brain structures. Overcrowding led to some changes in monoamine and their metabolite levels similar to those observed after IFN-α treatment with the medium dose in the standard housing conditions. In the overcrowded conditions, in contrast to the standard ones, IFN-α treatment in both doses reduced depression-like behavior and normalized neurochemical alterations induced by overcrowding. The results suggest that the effect of IFN-α on depression-like behavior and brain neurochemistry depends on the ongoing emotional status of animals: whether they are in stressful (overcrowded) or non-stressful (normal) conditions.

A study of the long-term consequences of the combined effect of synchronous quasi-chronic γ‑irradiation and anti-orthostatic suspension (AOS) with further irradiation of the head of rats with carbon 12 C ions, taking into account the typological characteristics of higher nervous activity (HNA) of experimental animals, was carried out. It is shown that within six months the integrative effects of the studied effects are quite successfully leveled. At the same time, significant differences related to the typological characteristics of animals persist in the long term. Study of the spectral and amplitude–frequency characteristics of the EEG of rats after these effects was carried out. Significant differences in the average amplitudes and frequencies of the EEG were revealed in animals with different typological characteristics of the HNA. The change of the dominant rhythm in animals subjected to experimental influences is shown. Thus, in control animals, the θ‑rhythm is dominant, while in irradiated animals, the δ-rhythm dominates. The most important result was the registered significant changes in the electrophysiological activity of the rat brain even six months after irradiation. A significant frequency shift in the area of all rhythms indicates long-term violation of the electrophysiological activity of the brain. The results of neurochemical studies revealed significant differences in the metabolism of monoamines in key brain structures of animals with different typological characteristics of HNA, combined with their manifestation at the integrative level (in animal behavior).

The activity in the open field, short- and long-term memory in the novel object recognition test, and gait features were evaluated in 6- and 12-month-old male C57BL/6 mice. The levels of norepinephrine, dopamine, serotonin, and their metabolites were determined in the cerebellum and frontal cortex. In the observed age range, a decrease in locomotion speed, impairment of gait initiation and stability, and long-term memory deficit were revealed. In the cerebral cortex, reduced levels of dopamine and its metabolites and accelerated metabolism of all neurotransmitters under study were found. In the cerebellum, the content of all studied monoamines was elevated, while dopamine metabolism was decelerated. Analysis of correlations between the neurochemical and behavioral parameters showed that the mechanisms of compensation of brain functions during the early aging may be associated with an increase in activity of the monoaminergic systems in the cerebellum.

Social isolation (SI) is chronic psycho-emotional stress for humans and other socially living species. There are few comparative studies that have measured monoamine levels in brain structures in male and female rats subjected to SI. Existing data is highly controversial. In our recent study, we investigated behavioral effects of SI prolonged up to 9 months on a rather large sample of 69 male and female Wistar rats. In the present study, we measured the levels of monoamines-norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), and DA and 5-HT metabolites-in the brain structures of 40 rats from the same sample. The single-housed rats of both sexes showed hyperactivity and reduced reactivity to novelty in the Open Field test, and impaired passive avoidance learning. Regardless of their sex, by the time of sacrifice, the single-housed rats weighed less and had lower pain sensitivity and decreased anxiety compared with group-housed animals. SI decreased NE levels in the hippocampus and increased them in the striatum. SI induced functional activation of the DA-ergic system in the frontal cortex and hypothalamus, with increased DA and 3-methoxytyramine levels. SI-related changes were found in the 5-HT-ergic system: 5-HT levels increased in the frontal cortex and striatum, while 5-hydroxyindoleacetic acid only increased in the frontal cortex. We believe that SI prolonged for multiple months could be a valuable model for comparative analysis of the behavioral alterations and the underlying molecular processes in dynamics of adaptation to chronic psychosocial stress in male and female rats in relation to age-dependent changes.

Depression is a severe and widespread psychiatric disease that often accompanies epilepsy. Antidepressant treatment of depression comorbid with epilepsy is a major concern due to the risk of seizure aggravation. SAMe, a universal methyl donor for DNA methylation and the synthesis of brain monoamines, is known to have high antidepressant activity. This study aimed to find out whether L-methionine (L-MET), a precursor of SAMe, can have antidepressant and/or anxiolytic effects in the WAG/Rij rat model of depression comorbid with absence epilepsy. The results indicate that L-MET reduces the level of anxiety and depression in WAG/Rij rats and suppresses associated epileptic seizures, in contrast to conventional antidepressant imipramine, which aggravates absence seizures. The antidepressant effect of L-MET was comparable with that of the conventional antidepressants imipramine and fluoxetine. However, the antidepressant profile of L-MET was more similar to imipramine than to fluoxetine. Taken together, our findings suggest that L-MET could serve as a promising new antidepressant drug with anxiolytic properties for the treatment of depression comorbid with absence epilepsy. Increases in the level of monoamines and their metabolites-DA, DOPAC, HVA, NA, and MHPG-in several brain structures, is suggested to be a neurochemical mechanism of the beneficial phenotypic effect of L-MET.

The article is devoted to the scientific activity of K.S. Raevskii, who made an outstanding contribution to the development of neurochemistry. The main scientific achievements of K.S. Raevskii and his students in the study of the role of brain monoaminergic systems in the mechanism of action of neuropsychotropic drugs of various pharmacological classes, which led to the creation of a scientific school, are presented. The recognition of the scientific contribution of K.S. Raevskii and the scientific school he created both at the domestic and world levels is emphasized.

The effect of subchronic administration of the nootropics Phenotropil (100 mg/kg/day) on the behavior of CD-1 outbreed mice in the "closed enriched cross maze" test (CECM) was studied. Predominantly, the mouse population was divided into subpopulations according to their values of individual attention index for novel objects in the maze compartments – highly attentive (ED-high) and low attentive (ED-low). It was found that Phenotropil increased the attention index in ED-low, but disimproved it in the ED-high subpopulation, and also changed parameteres of anxiety and locomotor activity; this distinguished it from the more selective effect of Piracetam (200 mg/kg/day). The higher selectivity of Piracetam was also shown in relation to dopamine metabolism processes in the prefrontal cortex: the drug normalized the metabolic turnover of intracellular (DOPAC/DA) as well as extracellular (HVA/DA) dopamine, while Phenotropil influenced on the former only. Thus, positive effect of Piracetam on the attention level in ED-low mice corresponds to the normalization of both indicators of dopamine metabolism in the prefrontal cortex, while Phenotropil showed non-selectivity onto both behavioral and neurochemical parameters. Piracetam and Phenotropil failed to affect the cortical and striatal serotonin metabolism in both subpopulations.