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 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.

The results demonstrate and confirm the significant role of monoamine imbalance in the ictogenesis of Krushinsky–Molodkina rats with genetically determined audiogenic epilepsy and in the development of audiogenic kindling (AuK) in them. The experiments were carried out on rats of the Krushinsky–Molodkina (KM) line without sound stimulation (KM-background) and after the development of AuK (KM-AuK). The control group was rats of line “0”, in which convulsions in response to sound were completely absent. AuK was generated using 20-fold sound stimulation (120 dB). Neurochemical analysis was performed by HPLC/ED in the frontal cortex, hippocampus, hypothalamus, nucleus accumbens, and brainstem. It has been established that AuK in KM rats leads to the appearance of myoclonic and attenuation of stem convulsions, which is accompanied by a change in the functional activity of the noradrenergic and serotonergic systems of the brain. KM rats exhibiting tonic convulsions in the “background” have a low content of norepinephrine in the hippocampus and hypothalamus, and when audiogenic myoclonic convulsions develop, norepinephrine deficiency is observed in the frontal cortex. After the formation of AuK, the excessively intense serotonin metabolism revealed in KM slows down in the hippocampus, nucleus accumbens, and, especially, in the brainstem, and the serotonin deficiency in the striatum also disappears. The peculiarities of norepinephrine metabolism in KM rats before and after AuK emphasize the important role of the cortex in the development of myoclonic convulsions, and of the hippocampus and hypothalamus in the implementation of stem convulsions. Excessive functional activity of the serotonergic system, revealed in KM “background” rats, slows down in a number of brain structures during the production of AuK.

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.

The effects of acute swimming stress (ASS) on the behavioral and neurochemical actions of a pyrazolo[C]pyridine derivative GIZh-72 (20 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) were studied. Increased anxiety reactions were seen in the open field test 1 h after ASS in BALB/c mice and the marble burying test in C57BL/6 mice. Weakening of anxiety reactions in BALB/c and C57BL/6 mice in the open field test and in C57BL/6 mice in the marble burying test was noted at 24 h. Serotonin levels increased and noradrenaline levels decreased in the hypothalamus of BALB/c and C57BL/6 mice 1 h after ASS, while the prefrontal cortex showed increases in noradrenaline, 3,4-dihydroxyphenylacetic acid, and the 3,4-dihydroxyphenylacetic acid/dopamine ratio in BALB/c mice. These changes correlated with increases in anxiety reactions, while their reversal in response to GIZh-72 and diazepam or 24 h after ASS coincided with weakening of anxiety reactions in mice. Diazepam and GIZh-72 weakened anxiety reactions in BALB/c and C57BL/6 mice in the open field and marble burying tests in the absence of stress. At 1 h after ASS, the effects of GIZh-72 were retained in BALB/c and C57BL/6 mice in the open field and marble burying tests, while the effects of diazepam persisted in C57BL/6 mice and increased in BALB/c mice in the open field test. At 24 h, the effects of GIZh-72 in the open field test increased in BALB/c mice but weakened and were accompanied by a tendency to a sedative action in C57BL/6 mice. The effects of diazepam in the open field increased only in C57BL/6 mice and were absent in BALB/c mice. The effects of GIZh-72 and diazepam in the marble burying test 2 h after ASS persisted in BALB/c but not C57BL/6 mice.

Abstract—Alcohol-related mental health problems, including an increased risk of development of anxiety-depressive disorders and alcohol addiction, are often passed down from generation to generation. Currently, there are no studies that consider the effect of prolonged alcohol exposure on the content of neurotransmitter monoamines and neurotransmitter amino acids in the brain structures responsible for the formation of emotional and motivational behavior patterns in the first F1 generation in the absence of direct alcohol exposure to the fetus. The aim of the present work was to study the anxiety behavior and neurochemical changes in the insular cortex and anterior cingulate cortex (ACC) in the intact offspring of rats that consumed ethanol solution for 30 weeks before mating. In the “elevated plus maze” test, females spent more time in open arms compared to males, however, no significant differences in the stress response between the offspring of rats exposed to and not exposed to ethanol were found. In ex vivo experiments, a decrease was observed for the insular cortex in the turnover of extracellular dopamine in animals of both sexes (p < 0.05) and multidirectional shifts in the total turnover of dopamine in the absence of changes in the content of neurotransmitter amino acids. In the ACC, a decrease in the glycine content (p < 0.05) was observed only in females. The data obtained indicate that prolonged oral administration of ethanol induces sex-dependent changes in the content of neurotransmitter monoamines and amino acids in the brain structures that determine the formation of emotional and motivational behavior in previously unaffected offspring.

Behavioral and neurochemical effects of the new racetam derivative GIZh-290 were studied in a mouse attention deficit model (the ED-Low animals subpopulation selected during preliminary behavioral typing in the "closed enriched cross maze" test). Subchronic administration of GIZh-290 (1 mg/kg, 3 mg/kg and 5 mg/kg, intraperitoneally, for 6 days), increased the initially low level of attention in ED-Low animals; the highest selectivity was observed at a dose of 3 mg/kg. Radioligand analysis showed that at this dose, the drug changed density (Bmax) of D2 and GABAB receptors as markers in the pre-frontal cortex of the ED-Low subpopulation to Bmax values observed in the ED-High subpopulation. In the prefrontal cortex of the ED-Low rodents treated with GIZh-290 in dose of 3 mg/kg, there was a normalization of tissue concentrations of both dopamine itself (DA) and its intra- and extracellular metabolites (DOPA/DA and HVA/DA). The obtained results indicate the effectiveness of the studied drug for pharmacotherapy of attention deficit in experimental modeling and impact on potential molecular targets identified in the study.

The aim of this study was to compare neurochemical changes induced by the dipeptide analogue of piracetam, the ethyl ester of N-phenylacetyl-L-prolylglycine (noopept), in the brain structures of BALB/c and C57BL/6 mice with different genetically determined responses to emotional stress. It was found using the HPLC technique that noopept at doses of 0.5 and 2.5 mg/kg after acute administration reduced the content of dopamine (DA) and its metabolite homovanillic acid (HVA) in the frontal cortex of both strains of mice. In "highly anxious" BALB/c mice, noopept increased the intracellular DA turnover (DOPAC/DA) and the total DA turnover (HVA/DA) in the frontal cortex, increased the level of noradrenaline and the metabolic rate of DA and serotonin in the hypothalamus, and increased the total DA turnover in the striatum. Noopept had no effect on the content of neurotransmitter amino acids in the brain structures of mice of both strains.

The aim of this study is to find out whether maternal methyl-enriched diet affects the content of monoamines and their metabolites in brain structures of adult WAG/Rij offspring. It has been shown for the first time that maternal methyl-enriched diet (choline, betaine, folic acid, vitamin B12, L-methionine, zink) during the perinatal period increases dopaminergic tone of the mesolimbic brain system in adult offspring of WAG/Rij rats, which is accompanied by the suppression of the symptoms of genetic absence epilepsy and comorbid depression. Results suggest that maternal methyl-enriched diet during the perinatal period may be served as a new therapeutic strategy to prevent the development of a hypofunction of the mesolimbic dopaminergic brain system and associated genetic absence epilepsy and comorbid depression in offspring.

The effect of intraperitoneal administration of the nootropic drug phenibut (70 mg/kg) and atomoxetine hydrochloride (3 mg/kg) on the neurochemical parameters of dopaminergic and serotonergic systems in the brain structures of C57BL/6 mice was studied by HPLC/ED. It was found that under in vivo blockade of L-aromatic amino acid decarboxylase (DAAA), both drugs in the selected doses did not affect directly on biosynthesis processes of both dopamine and serotonin in the prefrontal cortex and striatum of rodents. The observed effects of phenybut and atomoxetine hydrochloride, in comparison with the used D 2 receptor ligands quinpirole (0.1 mg/kg) and sulpiride (25 mg/kg), suggest the absence of direct participation of dopamine autoreceptors regulating the functional activity of dopaminergic synapses.

Abstract —Parkinson’s disease is a widespread, progressive, age-related neurodegenerative disease. The neurochemical basis of motor and non-motor disorder in Parkinson’s disease is the dysfunction of many neurotransmitter systems of the brain and, first of all, the functional deficit and imbalance of monoaminergic systems, which result from the degradation and death of certain populations of nerve cells caused by misfolding of the α-synuclein protein and the action of its amyloidogenic neurotoxic conformations. Analysis of age-related changes in monoaminergic systems and the development of motor and non-motor disorders at the preclinical and clinical stages of the disease are of particular interest. We studied the effect of α-synuclein oligomers administered intranasally for 14 days on locomotor activity, emotional state, short- and long-term memory, and the content and metabolism of dopamine, serotonin, and norepinephrine in the hippocampus, frontal cortex, and cerebellum of male C57Bl/6 mice at the age of 3 months. In behavioral experiments, the following tests were used: “open field,” “novel object recognition,” “passive avoidance,” and “elevated plus maze.” The content of monoamines and their metabolites in the brain tissue of animals was determined by high performance liquid chromatography with electromagnetic detection. It was found that mice treated with α-synuclein oligomers showed manifestations of affective-like behavior with signs of apathy. The animals showed no disorders in motor activity, short-term and long-term memory, and no changes in anxiety level. Oligomers of α-synuclein caused a significant decrease in the content of dopamine and its metabolites DOPAC and HVA in the frontal cortex, as well as a decrease in the concentration of the dopamine metabolite, 3-MT, and opposite directed changes in serotonin and dopamine metabolism in the hippocampus. However, a significant increase in the content of 3-MT in the cerebellum was recorded. We performed comparative analysis of the data obtained in this work and the results of our previous study of the neurochemical and behavioral effects of α-synuclein oligomers in 6-month-old mice. The results indicate that oligomers of α‑synuclein, when administered chronically intranasally, induce non-motor disorders and neurochemical changes in mice of 3 months of age, which are also observed at the preclinical stage of PD.

We analyzed delayed effect of intranasal administration of anti-glutamate antibodies on mnestic function and tissue concentrations of neurotransmitters in the hippocampus and prefrontal cortex in aging C57BL/6 mice. It was found that after 14-day administration of anti-glutamate antibodies, improvement of the passive avoidance conditioning persisted for 7 days after the treatment was discontinued. In 7 days after discontinuation of treatment, increased content of dopamine and its metabolites as well as aspartic acid and taurine was observed in the hippocampus of mice treated with anti-glutamate antibodies. In the prefrontal cortex, administration of anti-glutamate antibodies had no effect on the levels of neurotransmitters, but increased the concentration of glutamate.