Vol 15, No 3 (2017)

Neurobehavioral effects of choninergic drugs in prenatal period
Stashina E.V., Gavrilov N.A., Shabanov P.D.

Environmental toxicants, chemicals exhibiting with cholinotropics properties, and drugs – agonists and antagonists of M- and N-cholinergic receptors by acting on the developing brain of the fetus in the embryonic period of ontogenesis, cause a change the activity of the cholinergic mechanisms of the brain during critical periods of prenatal development with the subsequent disruption of the formation of different brain systems, primarily the ontogeny of nerve cells and brain neurotransmitter systems. These changes in the long term is correlated with neurobehavioral deficits from adult individuals, dysfunction of the reproductive system of adult offspring. The relevance of the study of prenatal effects of cholinergic factors on the central mechanisms of reproductive function, memory processes and learning during ontogenetic development of the organism due to the need of prevention and treatment of subsequent mental, behavioral, and sexual dysfunctions, and abnormal sexual behavior, infertility.

Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(3):5-21
Effects of ghrelin agonist and antagonist on endogenous desacyl-ghrelin content in the brain limbical structures under psychoemotional stress in rats
Khokhlov P.P., Tsikunov S.G., Tissen I.Y., Lebedev A.A., Bychkov E.R., Shabanov P.D.

Background. During last years it has been shown the ghrelin signaling system not only regulates energy balance and food intake. It also takes part in reinforcement mechanisms and addiction formation. So the ghrelin system may be considered as possible molecular target to study addiction treatment and post-stressor pharmacological modulation.

The aim of this work was to study the effects of ghrelin agonist and antagonist administration on des-acyl ghrelin (DAG) content in the brain structures under stress exposure in Wistar rats.

Methods. The acute psychoemotional stress was realized by means of exposure of experimental rats to predator, a tiger python. Ghrelin or ghrelin antagonist D-Lys3-GHRP-6 (Tocris, UK) 10 µg in 20 µl administered intranasally for 7 days after stress exposure. Then brain structures were obtained, homogenized with cryogenic system “Cryomill 200” (Retsch, Germany) and investigated with high-sensitive ELISA (SP-BIO, France). Results. DAG have been detected in every brain structures studied. That are amygdala, hippocampus and hypothalamus. In control group of animals the DAG concentration in hypothalamus was 3-fold more comparning to hippocampus and 2-fold more conparning to amygdala content. The acute stress have dramatically 8-12-fold decrease of DAG concentrations in every brain structures studied. The pharmacological actions on GHSR receptor by ghrelin agonist and antagonist have not affect significant changes in DAG concentrations in every brain structures.

Conclusions. The different concentrations of DAG in brain structures in control gtoup supports the view about ghrelin releasing neurons in the hypothalamus. Intranasal administration of ghrelin agonist and antagonist changes the levels of DAG in the hippocampus and the hypothalamus but not in the amygdala nucleus. Our data confirm the opinion about ghrelin-releasing neurons in hypothalamus. The experiments showed the acute stress had caused great depression of ghrelin system in various brain structures. The response of ghrelin system to acute stress occur possibly besides GHSR receptor pathway. The last have been suggested by absence of significant response to ghrelin agonist and antagonist administration.

Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(3):22-27
Effect of intranasal ghrelin administration on the compulsive behavior patterns and the level of anxiety after the vital stress exposure to rats
Yakushina N.D., Tissen I.Y., Lebedev A.A., Pshenichnaya A.G., Bychkov E.R., Tsikunov S.G., Shabanov P.D.

Aim. The effect of the intranasal ghrelin on the compulsive behavior and the anxiety in rats after exposure to vital stress was assessed in Wistar rats using a number of behavioral tests: marble test, elevated plus maze, open field and “resident intruder” test.

Methods. In the buring marble test, the behavioral components of the obsession (obsessive and obtrusive thoughts) and compulsions (obtrusive behavior), aimed to reduce anxiety, were modeled. Mental trauma was caused by a stressful effect, the essence of which was the experience of the animals of the circumstances of the death of a partner from the actions of a predator. A group of rats were placed once in the terrarium to a tiger python.

Results. After the action of vital mental stress in rats, two connected behavioral phenomena were observed: a high level of anxiety and an increase in the number of buried balls. This was accompanied by a decrease in communicability. Intranasal administration of ghrelin (10 µg in 20 µl for 7 days) after presentation of the vital stress reduced the level of anxiety, and also normalized the commpulsive behavior (the number of buried balls).

Conclusion. Thus, brain ghrelin is an important component of psychotraumatic mechanism. Ghrelin can potentially be considered as correctors of obsessive-compulsive disorders on the background of PTSD. Use of intranasal administration of ghrelin the clinic will allow the use of small doses of substances and thereby reduce their possible toxic effects.

Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(3):28-37
Effect of astressin, a corticoliberin antagonist, on aggression and anxiety-fobic states in male rats reared in social isolation
Lebedev A.A., Pshenichnaya A.G., Yakushina N.D., Bychkov E.R., Shabanov P.D.

Aim. Intraspecific behavior, emotional and explorative activity were investigated after intranasal administration of astressin, a non-selective antagonist of CRF receptors, in the male rats reared in social isolation from 21 to 93 days.

Results. In the “resident-intruder” test there was an increased level of aggression and communications in isolated rats compared to grouped animals. After intranasal administration of astressin (20 μg in 20 μl), rats grown in isolation demonstrated an increase in aggression and decreased in communicability compared to intact animals reared in isolation. In the “open field” test a level of motor activity was increased in rats grown in isolation compared to grouped animals. The anxiety-phobic state, as well as behavior in an elevated plus maze, revealed enhance of anxiety and fear in rats reared in isolation. After astressin administration to isolated animals the levels of anxiety and fear significantly decreased.

Conclusion. The results of the work revealed that the antagonist of the CRF receptor astressin disinhibited aggression, removing anxious and phobic state in male rats reared in social isolation. The results prove the necessity of taking into account CRF mechanisms in the formation of the social isolation syndrome and the possibility of using CRF receptor antagonists to control the central mechanisms of stress and dependence in ontogenesis.

Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(3):38-47
The effect of the ghrelin receptors inhibitor [D-Lys3]-GHRP-6 on the levels and metabolism of monoamines in symmetric brain areas of rats treated chronically with alcohol
Karpova I.V., Bychkov E.R., Tissen I.Y., Lebedev A.A., Shabanov P.D.

Aim. In the course of the study, the impact of the ghrelin receptor GHS-R1a on the condition of symmetric monoaminergic systems of the rat brain was investigated. In particular, it was intended to find out whether the treatment with the ghrelin receptor antagonist [D-Lys3]-GHRP-6, recover the original content of monoamines and their metabolites in the brain of chronic alcoholic rats.

Methods. The experiments were performed on 22 Wistar male rats. Experimental animals instead of drinking water received 10 % ethanol solution. Rats of the control groups continued to consume tap water. 6 months after the beginning of forced chronic alcohol treatement, 6 rats treated with alcohol, and 6 rats received water, in a month, once in three days, were instilled intranasally with the ghrelin antagonist [D-Lys3]-GHRP-6 (1 мкг/мкл, with 10 µl to each nostril). The other animals in the same manner were administered an equivalent volume of saline. 80 minutes after the last intranasal administration of drugs, rats were decapitated. With the HPLC-method, in the hypothalamus, olfactory tubercle, striatum and hippocampus of the left and right sides of the brain the contents of noradrenaline (NA), dopamine (DA), dioxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured. The results were processed by Student’s t-test using the statistical software package GraphPad Prism 6.0.

Results. In the control rats (not exposed to either ethanol or drug) in the left striatum revealed a significant predominance of 5-HIAA compared to the same parameter of the other side of the brain. Under the condition of chronic ethanol intake, the initial left-sided asymmetry disappeared. Ethanol increased the content of 5-HT in the left hippocampus, 5-HIAA in the right olfactory tubercle and DA – in the right hypothalamus. [D-Lys3]-GHRP-6, when administered intranasally to the intact rats, significantly increased the 5-HIAA/5-HT ratio in the right olfactory tubercle, and the 5-HIAA, DOPAC and HVA levels – in the right striatum. In contrast, the left-sided effects in hippocampus were observed: the 5-HT levels increased and the 5-HIAA/5-HT ratio decreased. When instilled to intact rats, [D-Lys3]-GHRP-6 does not alter the monoaminergic systems of the hypothalamus. Between the monoaminergic systems of intact animals and alcoholic rats treated with [D-Lys3]-GHRP-6, the significant differences were shown. So, in the left hippocampus of alcoholic rats treated with [D-Lys3]-GHRP-6, the 5-HT level was higher, and the 5-HIAA/5-HT ratio was lower than in the control intact animals. Besides, in the right striatum of alcoholic rats treated with [D-Lys3]-GHRP-6, the DA metabolites levels were higher than those in the intact control animals. When comparing two groups of rats treated with [D-Lys3]-GHRP-6 (consumed water and alcoholic), the only difference was found: the alcoholic animals the content of DA in the left hypothalamus was lower than that of rats consumed water.

Conclusion. Thus, by its influence on the monoaminergic system of the brain, [D-Lys3]-GHRP-6 is not an antagonist of the ethanol. Rather ethanol, when administered chronically, reduces the reactivity of the majority of monoaminergic systems to the ghrelin antagonist. Herewith, the forced chronic treatement with ethanol selectively increases the sensitivity to the [D-Lys3]-GHRP-6 in the hypothalamus DA-ergic system

Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(3):48-56
Effect of novelty stress on behavioral responses of Danio rerio and assessment of dose-dependent effects of anxiolytics of benzodiazepine structure with phenazepam as an example
Shabanov P.D., Lebedev V.A., Lebedev A.A., Bychkov E.R.

The effect of benzodiazepine anxiolytic phenazepam in Danio rerio was investigated. Previously, Danio rerio showed the effects of other anxiolytics, dia_zepam and chlordiazepoxide. The analysis of the anxiolytic effect of phenazepam in Danio rerio was carried out for the first time.

Methods. A stress test on novelty situation was used: a fish was placed first in a beaker with a dissolved pharmacological substance (or water) and then into a novel tank for 6 min, where the trajectory, the path length, the number of movements to the upper part of the novel tank, the number and time of the pattern of “freezing” for each min of the experiment were measured.

Results. In response to the novelty of tank, the fish was shown to react by submerging to the bottom, increasing the freezing, and reducing the number of movements to the upper half of the novel tank. After phenazepam exposure (administration), the fish was not only in the lower, but also in the upper part of the novel tank. The average path length did not change significantly in the range of the doses used. The number and time of the freezing, as well as the time spent in the lower part of the novel tank, 2-fold decreased compared to the control group of animals and showed a dose-dependent effect. The number of movements to the upper part of the novel tank for the experiment increased significantly from 1 in the control to 57 after phenazepam in a dose of 1 mg/l. When analyzing the dynamics of the parameters for each min, it was shown that the time of the fish in the lower part of the novel tank decreased from 3th min of the experiment with the use of phenazepam in a dose of 0.5 mg/l. At the same time, the number of movements of fish to the upper part of the novel tank significantly increased more than 2 times from 3th min of the experiment with the use of phenazepam in a dose of 1 mg/l.

Conclusion. The described method to study behavioral responses of Danio rerio on novelty stress is high sensitive in comparison with traditional behavioral methods of studing tranquilizers. The prospect of using Danio rerio as animal model in behavioral pharmacology is significant and does not concede research on rodents.

Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(3):57-63
Patriarch of the Soviet pharmacology (to 125 anniversary of S.V. Anichkov)
Shabanov P.D.

Academician of the USSR Academy of Medical Sciences Professor Sergei Viktorovich Anichkov (1892-1981) is a great Soviet scientist pharmacologist, the founder of Soviet neuropharmacology. Educated in Military Medical Academy, Kazan Medical Institute, Petrograd Woman’s Medical Institute. The famous Russian Professors I.P. Pavlov, V.N. Boldyrev, N.P. Kravkov and A.A. Likhachev were his teachers. Headed Department of Pharmacology in Military Medical Academy, Leningrad (1924-1937), Department of Pharmacology in Institute of Experimental Medicine, the USSR Academy of Medical Sciences (1948-1981). The main studies of S.V. Anichkov were devoted to pharmacology of chemoreceptors of the carotid bodies, cholinergic regulation of physiological functions, pharmacology of endocrine regulation, pharmacotherapy of neurogenic dystrophies, toxicology of military toxic compounds. Published more 250 papers including 10 monographs. Under his leadership, more 10 drugs (ethimizol, sygetine, metamizil, paramion etc) were developed and adopted for wide medical practice in the USSR. Founded one of the big scientific school in the field of pharmacology in the USSR. Laureate of Lenin and State prices of the USSR.

Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(3):64-72

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