Assessment of dose-dependent effects of anxiolytics of benzodiazepine structure with diazepam as an example in Danio Rerio

Rev Clin Pharm Drug Ther

2023

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The neuropeptide kisspeptin is currently most widely known as a regulator of mammalian sexual behavior. For pharmacological analysis, mammalian Kiss1 kisspeptin analogues were used, Clone (USA): KS4, KS5, KS6, KS7, KS8, KS9 and Kiss 10. Kisspeptins were dissolved in aquarium water and applied in two doses: 1). 0.01 mg per 1000 ml of water; 2). 0.1 mg per 1000 ml of water. Phenazepam was dissolved in water and used in three doses: 1) 0.1 mg per 1000 ml of water; 2) 0.5 mg per 1000 ml of water; 3) 1 mg per 1000 ml of water. This paper compares kisspeptines with anxiolytics using phenazepam as an example in the novelty test. It was shown that in response to the novelty of being placed in the viewing tank, fish responded by diving to the bottom, increasing freesing, and decreasing the number of movements to the upper half of the tank. Fish residence time in the lower part of the tank after administration of phenazepepam decreased, especially when used at a dose of 0.5 and 1 mg/liter. Kisspeptin analogues decreased the indices characterizing the anxious state of the fish. Against the background of Kiss1 kisspeptin analogues, the average fish path length differed significantly in contrast to the effects of phenazepam. KS 4 at a dose of 0.1 mg/L showed a 1.4-fold decrease in the number of freesing, 1.4-fold decrease in the freesing time and 1.4-fold decrease in the trajectory length. The number of transitions to the upper part of the tank increased 1.5 times. The dose of 0.01 mg/l decreased the number of freesing by 1.5 times, freesing time by 1.5 times, trajectory length by 3 times. KS 5 at a dose of 0.1 mg/L decreased the number of freesings by a factor of 1.6, the freesing time by a factor of 1.6, and the trajectory length by a factor of 1.17. The number of transitions to the upper part of the tank increased 1.5 times. The dose of 0.01 mg/l decreased the number of freesing by 3 times, freesing time by 2.8 times, trajectory length by 2.8 times. KS 6 at a dose of 0.1 mg/l decreased the number of freesings by 2.7 times, the freesing time by 2 times, and the trajectory length by 2.5 times. The number of transitions to the upper part of the aquarium increased 2.5 times. The dose of 0, 01 mg/ml decreased the number of freesing by 2.6 times, freesing time by 2.6 times, trajectory length by 1.7 times. KS 7 at a dose of 0.1 mg/L decreased the number of freesing by a factor of 1.7, freesing time by a factor of 1.4, and trajectory length by a factor of 1.3. The number of movements to the top of the aquarium increased 1.6-fold. The dose of 0.01 mg/l decreased the number of freesing by 1.7 times, freesing time by 1.4 times, trajectory length by 1.6 times. KS8 at a dose of 0.1 mg/L decreased the number of freesings by 1.6 times, the freesing time by 1.7 times, and the trajectory length by 1.6 times. The dose of 0.01 mg/l decreased the number of freesing by 2.3 times, the freesing time by 2.2 times, and the trajectory length by 1.8 times. KS9 at a dose of 0.1 mg/l decreased the number of freesing by 2.2 times, the freesing time by 2.2 times, and the trajectory length by 1.2 times. The dose of 0.01 mg/L reduced the number of freesings by 1.5 times, the freesing time by 1.5 times, and the trajectory length by 1.6 times. In Kiss 10 at a dose of 0.1 mg/L, there was a 1.6-fold decrease in the number of frizzings, a 1.5-fold decrease in freezing time, and a 1.4-fold decrease in trajectory length. There was a 2.7-fold increase in the transitions to the upper part of the aquarium. The dose of 0.01 mg/l decreased the number of freesing by 1.7 times, freesing time by 1.6 times, trajectory length by 1.3 times. We observed a 1.3-fold increase in the number of trajectories. Summarizing the obtained indicators, we came to the conclusion that kisspeptin analogues were not inferior in their effect to the effects obtained after taking the tranquilizer phenazepam. Among mammalian kisspeptin analogues, KS6 at a dose of 0.1 mg/L showed the best performance. It is concluded that mammalian Kiss1 kisspeptin analogues and Kiss 10 reduce anxiety-phobic reactions to novelty in Danio rerio. At the same time, the effects of the studied kisspeptin analogues are lower than those of phenazepam. Kisspeptin is involved not only in the modulation of 5-HT-dependent behavior in Danio rerio, but also in the GABA-ergic system as benzodiazepine-type tranquilizers. The results 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.

Section: тест стресса новизныunclassified

Study of the effects of kisspeptin analogs on the behavior of Danio rerio

Goltz¹,

Rev Clin Pharm Drug Ther

2023

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“…Тест стресса новизны. Для экспериментов оценки новизны применяли стандартный просмотровый аквариум, используемый для изучения тревожно-фобических реакций у Danio rerio [15,16]. Он имел водоизмещение 1,5 л, трапециевидную форму, высоту 15 см и ширину 7 см.…”

Section: материалы и методыunclassified

Effects of kisspeptin analogues on the behavior of Danio rerio

Rev Clin Pharm Drug Ther

Blazhenko

Goltz

et al. 2022

BACKGROUND: Previously has been shown that fish kisspeptin 1 (Kiss1) acts on the brains 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 (0.51 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 0.011 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.

Comparison of anxiolytic effects of mammalian and bony fish kisspeptins in <dfn>Danio rerio</dfn>

Galstyan

Psychopharmacology & biological narcology

Blazhenko

et al. 2023

In our previous work, we suggested that analogues of mammalian kisspeptin Kiss1 reduce anxiety-phobic reactions to novelty in Danio rerio. The most effective dose for the action of the studied analogues of kisspeptin corresponded to 0.1 mg per 1000 ml of water. In this work, it was shown that other analog of mammalian kisspeptin Kiss1 at a dose of 0.1 mg per 1000 ml of water also reduced the anxious behavior of Danio fish. The effect of Kiss 1 and Kiss 2 kisspeptins on the behavior of Danio rerio was also evaluated. In the novel test it was revealed that the number of freezings decreased by 2 times against the background of the introduction of kisspeptin 10, and by 3 times after the introduction of the analogue of kisspepin. An analogue of mammalian kisspeptin reduced the freezing time by 2 times. The length of the trajectory decreased by 2 times under the influence of the mammalian Kiss 1 analogue of kisspeptin. Also, against the background of the action of kisspeptin 10, the number of transitions to the upper part of the tank increased by 2 times. After the introduction of the kisspeptin analogue, the number of transitions to the upper part of the aquarium increased by 3 times. In the predator test, the number and time of freezings decreased by 1.5 times against the background of the action of mammalian kisspeptins. The length of the trajectory after the introduction of kisspeptin bony fish and kisspeptin 10 mammals increased. The length of the trajectory after the introduction of Kiss1 increased by 1.5 times. The length of the trajectory after the introduction of Kiss2 increased by 3 times. After the introduction of kisspeptin 10, the trajectory increased by 2 times, and the time spent in the lower part of the tank decreased by 2 times. Kisspeptins of bony fish also reduced anxiety-phobic reactions in fish, but to a lesser extent. Thus, kisspeptin 10 and an analogue of mammalian kisspeptin in response to the presentation of a predator had more significant effects on anxiety in Danio rerio compared to the action of kisspeptin bony fish Kiss 1 and Kiss 2. It is concluded that bony fish kisspeptins and mammalian kisspeptins can reduce anxiety-phobic reactions in Danio rerio, but mammalian kisspeptins are most effective. Bony fish kisspeptin Kiss 1 has an anxiolytic effect in contrast to Kiss 2, which suggests that it affects the reduction of fear, and Kiss 2 seems to be responsible for social and sexual behavior. The results support the hypothesis that kisspeptins 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.