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Vol 20, No 2 (2022)

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Original articles

Principles of modeling brain diseases and their therapy based on zebrafish studies

Kalueff A.V.

Abstract

Here, we introduce the multidisciplinary readers of the present specialized issue of the journal to the significance and principal approaches to modeling various brain disorders in laboratory fish species — the zebrafish (Danio rerio).

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):119-122
pages 119-122 views

Assessment of general locomotor activity and anxiety in zebrafish (Danio rerio) in the light-dark box (tank), the shoaling test, in the novel tank and the open field tests

Galstyan D.S., Kolesnikova T.O., Kositsyn Y.M., Zabegalov K.N., Gubaidullina M.A., Maslov G.O., Demin K.A., Kalueff A.V.

Abstract

Anxiety is a complex and multifaceted neurobehavioral disorder that includes various forms of chronic pathological anxiety and fears, and is also the cause for various comorbid pathologies, such as depression or cardiovascular diseases. Behavioral testing of various model organisms, including the zebrafish (Danio rerio), is widely used to study neurobiological mechanisms of anxiety. Here, we discuss the novel tank test, the open field test, light-dark box and shoaling test that are widely used in translational biological psychiatry to characterize anxiety-related behavioral phenotypes in zebrafish.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):123-133
pages 123-133 views

Studying social behavior in zebrafish (Danio rerioo) in the tests of social interaction, social preference, behavior in the shoaling and aggression tasks

Galstyan D.S., Kolesnikova T.O., Kositsyn Y.M., Zabegalov K.N., Gubaidullina M.A., Maslov G.O., Demin K.A., Kalueff A.V.

Abstract

Social interactions between conspecifics are an important factor in normal development of an individual in a community, and their deficits correlate with multiple psychiatric disorders. Several methods for assessing social behavior and its deficits have been described for zebrafish (Danio rerio), and include tests for social preference and social interaction. These tests are commonly used to model a wide range of social phenotypes that are potentially relevant to studying depression, pathological aggression, schizophrenia, autism, and other brain diseases. An important and widely used method for determining social behavior is the shoaling test, based on the innate, genetically fixed feature of zebrafish to form shoals/schools, the density of which depends on many factors, such as the presence of a predator, the effect of pharmacological drugs, etc. Aggression, along with shoaling, is an important manifestation of social behavior, which is also a core symptoms of multiple brain diseases, such as control disorder and conduct disorder. Here, we discuss various methods for assessing aggressive behavior in zebrafish (e.g., the mirror reflection tests), and their shoaling agonistic behaviors.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):135-147
pages 135-147 views

Modeling depression in zebrafish

Galstyan D.S., Kolesnikova T.O., Kositsyn Y.M., Zabegalov K.N., Gubaidullina M.A., Maslov G.O., Demin K.A., Khatsko S.L., Kalueff A.V.

Abstract

Depression is a widespread, severely debilitating mental disorder characterized by low mood, anhedonia, fatigue, decreased attention, suicidality and psychomotor retardation, accompanied by neuroendocrine and molecular disorders. Zebrafish have neuroendocrine and neurotransmitter systems similar to humans, as well as high genetic homology, and are rapidly becoming popular model organisms for modeling depressive-like conditions. Here, we discuss modern behavioral, pharmacological and genetic models of depression in zebrafish, their methodological applications and translational implications.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):149-156
pages 149-156 views

Despair-like behavior in fish based on the zebrafish (Danio rerio)

Galstyan D.S., Kolesnikova T.O., Kositsyn Y.M., Zabegalov K.N., Gubaidullina M.A., Maslov G.O., Demin K.A., Kalueff A.V.

Abstract

The zebrafish tail immobilization test is a relatively new method for analyzing zebrafish behavior, based on the paradigm of learned helplessness, when the animal is exposed to an uncontrollable stressor, and soon abandons all attempts to avoid the aversive stimulus, adopting a posture of immobility. As an aversive stimulus acts restraining fish tail in a viscose sponge, without restricting the mobility of the lateral fins and the front of the body. The zebrafish tail immobilization test is suitable for detecting depressive-like ‘despair’ behavior in zebrafish, paralleling clinical apathy and lethargy in depression.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):157-162
pages 157-162 views

Cognitive tests in zebrafish (Danio rerio): T- and Y-mazes

Galstyan D.S., Kolesnikova T.O., Kositsyn Y.M., Zabegalov K.N., Gubaidullina M.A., Maslov G.O., Demin K.A., Kalueff A.V.

Abstract

T- and Y-shaped mazes are traditionally used to assess spatial learning and memory of zebrafish. In the installation of the T-shaped maze, the fish are taught to swim into the desired sleeve and not swim into the “wrong” one using both positive (for example, food reinforcement) and negative (for example, electric current) stimuli to form more persistent reflexes. The Y-shaped maze is based on the principle of spontaneous choice. Spontaneous choice behavior describes the tendency of animals to change their direction of rotation in a series of successive turns. Each choice statistically depends on the previous one, which indicates its mnestic origin. Unlike other types of memory tasks, testing in the Y-shaped maze does not require prior training or reinforcement (as in the T-shaped maze). Both aquatic mazes are becoming useful tools for assessing zebrafish cognitive phenotypes.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):163-168
pages 163-168 views

Using zebrafish (Danio rerio) to assess short-term memory: the habituation and the homebase tests

Galstyan D.S., Kolesnikova T.O., Kositsyn Y.M., Zabegalov K.N., Gubaidullina M.A., Maslov G.O., Demin K.A., Kalueff A.V.

Abstract

Environmental novelty is one of the most potent stressors in animals and is often used in behavioral neuroscience to study affective and cognitive impairments. However, in the process of studying an unfamiliar environment in experimental animals, there is a decrease in stress due to habituation (adaptation, habituation). In various behavioral tests in zebrafish, this manifests as swimming in areas that pose a potential danger to them: the upper part of the aquarium in the novel tank test and the central part in the open field test. When building an effective survival strategy, it is important to navigate in an unfamiliar environment from a home base — the safest area that serves as a starting point in exploring a novel arena. Both discussed here, habitation and establishing the home base, are important for assessing cognitive behavioral traits in zebrafish related to short-term spatial working memory.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):169-175
pages 169-175 views

Experimental approaches to modeling delirium in zebrafish (Danio rerio)

Maslov G.O., Kolesnikova T.O., Zabegalov K.N., Kalueff A.V.

Abstract

Delirium is an acute psychiatric syndrome characterized by impaired attention, perception and orientation in space. Albeit known for millennia, the mechanisms and risk factors of delirium remain poorly understood. Experimental animal models, especially rodents, become widely used to understand these pathogenetic aspects. However, a new model organism — zebrafish (Danio rerio) also has promise in this field. Discussed here, recent behavioral tests and protocols for zebrafish enable assessing their behavioral and cognitive function, and its experimental modulation by deliriant drugs and other factors.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):177-183
pages 177-183 views

Modeling the drug withdrawal syndrome in zebrafish (Danio rerio)

Zabegalov K.N., Galstyan D.S., Kolesnikova T.O., Kositsyn Y.M., Gubaidullina M.A., Maslov G.O., Demin K.A., Khatsko S.L., Kalueff A.V.

Abstract

The central pathological link in addictive states is the drug withdrawal syndrome. Usually, severe manifestations of the withdrawal syndrome are associated with reduced sensitivity of postsynaptic receptors (desensitization), lower density of receptors and impaired transport of neurotransmitters, and the rebound effect. Zebrafish is an effective tool in the study of classic withdrawal symptoms and special cases of withdrawal of other selected psychoactive drugs.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):185-191
pages 185-191 views

Modeling and assaying seizure activity in zebrafish (Danio rerio)

Galstyan D.S., Kolesnikova T.O., Kositsyn Y.M., Zabegalov K.N., Gubaidullina M.A., Maslov G.O., Demin K.A., Kalueff A.V.

Abstract

Epilepsy is a common neurological disease that has many causes with unclear pathophysiological mechanisms. Epilepsy, commonly studied in rodents, can also be modeled in zebrafish (Danio rerio). There are effective pharmacological and genetic models for zebrafish, sensitive to both pro and anticonvulsant effects. These aquatic models are likely to help expand the fundamental knowledge about the mechanisms of epilepsy pathogenesis and develop epilepsy therapy.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):193-199
pages 193-199 views

Effects of kisspeptin analogues on the behavior of Danio rerio

Lebedev A.A., Blazhenko A.A., Goltz V.A., Devyashin A.S., Lebedev V.A., Kazakov S.V., Bayramov A.A., Khokhlov P.P., Bychkov E.R., Shabanov P.D.

Abstract

BACKGROUND: Previously has been shown that fish kisspeptin 1 (Kiss1) acts on the brain’s serotonin system to reduce anxiety-phobic reactions in Danio rerio. The kissspeptin gene (kiss1) of teleost fish is also a conservative orthologue of the kissspeptin gene (KISS1/Kiss1) of mammals.

AIM: In this work we investigated the possible anxiolytic effect of mammalian kisspeptin analogs Kiss1 in Danio rerio in comparison with antidepressants of the serotonin-type of action.

MATERIALS AND METHODS: A novelty test was used: the fish was first placed in a beaker with a dissolved pharmacological substance (or H2O), and then in a viewing tank for 6 min, where the trajectory of movement, the length of the path, the number of movements to the upper part of the tank, the time spent in the lower part of the tank, number and time of the “freezing” were automatically recorded.

RESULTS: It is shown that, in response to the novelty of being placed in a viewing tank, fish react by moving to the bottom, increasing friezing, and reducing the number of movements to the upper half of the tank. Against the background of antidepressants clomipramine, paroxetine or trazodone (0.5–1 mg per 1 l of water), the fish were not only in the lower, but also in the upper part of the viewing tank. The average path length did not change significantly. The time in the lower part of the tank decreased by more than 2 times compared with the control group of animals and showed a dose-dependent effect. The number of movements to the upper part of the tank per experience increased significantly. Mammalian kisspeptin analogues Cloud Clone (USA) in a dose 0.01–1 mg per 1 l of water caused a similar patterns of behavior in fish in response to novelty. At the same time, the effects of kisspeptin analogs were lower than those of antidepressants. The most effective dose for the action of the studied kisspeptin analogs was 0.1 mg per 1 l of water.

CONCLUSIONS: Thus, mammalian kisspeptin analogs Kiss1 reduce anxiety-phobic responses to novelty in Danio rerio. Data on the unidirectional effects of mammalian kisspeptin analogs and serotonin-type antidepressants support the potential role of Kiss1 in modulating serotonin-dependent behaviours in Danio rerio. The data obtained support the hypothesis that kisspeptin may be involved in the regulation of anxiety-phobic states, apparently to maintain the emotional aspects of reproductive behavior, such as sexual motivation and arousal.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):201-210
pages 201-210 views

The changes of protein kinases activities in the brain structures after ghrelin antagonists administration in previously stressed Danio rerio

Blazhenko A.A., Reikhardt B.A., Khokhlov P.P., Bychkov E.R., Lebedev A.A., Shabanov P.D.

Abstract

BACKGROUND: Nowadays there are a lot of data to suggest about an important role of ghrelin signaling system in stress response and reinforcement mechanisms. There is a common opinion that a protein kinase system plays a role of a second intracellular messenger for ghrelin system.

AIM: So, the aim of our study was to measure the total protein kinase activity in brain structures of Danio rerio. The all procedures have been approved according to the Local Ethical Committee of Institute of Experimental Medicine.

MATERIALS AND METHODS: In our study it has been used 50 specimen Danio rerio 6–8 months of age. There also has been used a predator (Hypsophrys nicaraguensis). During experiment a fish has been firstly placed into a tank of water with a dissolved pharmacological substance for 5 min, then has been transferred into a tank with predator also for 5 min. Two ghrelin antagonists have been used in our experiment in 0.333 mg/l dosage [D-Lys3]-GHRP-6 and Agrelax, a recombinant peptide analogue of ghrelin with molecular weight 3.5 kD, which has been invented in our Institute. The brain has been divided into three anatomical parts: telencephalon, midbrain and cerebellum. After that the material for kinase activity assay was made (ADP sensor Universal Kinase Activity Assay kit, BioVision).We also have used GraphPad Prism 6 for statistical estimation. Kolmogorov–Smirnov test Mann–Whitney U-test have been used as statistical tests.

RESULTS: In control group, the kinase activity has been determined in all tested brain structures. After predator exposure, the kinase activity has significantly changed. After [D-Lys3]-GHRP-6 administration there has not been determined any protein kinase activity in all brain structures. In the cerebellum the kinase activity has been the highest after Agrelax administration. Protein kinase system demonstrates significant stress response.

CONCLUSIONS. Pharmacological action on ghrelin receptors leads to changes in kinase system in Danio rerio’s brain structures.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):211-217
pages 211-217 views

The influence of the extract of Panax ginseng on the behavior of chronically alcoholized Danio rerio during ethanol withdrawal

Airapetov M.I., Eresko S.O., Galustyan A.N., Lebedev A.A., Shabanov P.D.

Abstract

BACKGROUND: The search for new ways to correct the pathophysiological mechanisms underlying the alcohol withdrawal syndrome is an urgent and promising direction in the pharmacotherapy of alcoholism. The extract of Panax ginseng is of interest in relation to the correction of pathological behaviors caused by long-term alcohol consumption. With the help of behavioral tests, you can evaluate the features of various forms of behavior.

AIM: To study the effect of Panax ginseng extract solution on the behavior of Danio rerio fish during the period of alcohol withdrawal after prolonged alcoholization.

MATERIALS AND METHODS: Prolonged alcoholization was modeled by placing the fish in an aquarium with 0.3 ethanol solution for 14 days. After the abolition of ethanol, intraperitoneal injections of Panax ginseng root extract solution (0.3 mg / 1 g) were performed for 7 days. The behavior of fish was studied in the test “Motor activity in a new place and after habituation”.

RESULTS: The article presents the results of the effect of Panax ginseng extract solution on the behavior of Danio rerio fish during the period of alcohol withdrawal after prolonged alcoholization. The time spent in sections in the Panax ginseng (0.3 mg / 1 g) injection group was restored to control levels compared to the alcohol withdrawal group of fish injected with saline.

CONCLUSIONS: The study showed that the behavior of Danio rerio fish in the test “Motor activity in a new place and after habituation” was subject to changes, while the Panax ginseng extract recover the behavioral changes of the fish up to control indexes.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):219-224
pages 219-224 views


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