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Molecular mechanisms engaged in the development of drug addiction
Pallag, Gergely ; Novotný, Jiří (advisor) ; Nerandžič, Vladimír (referee)
Drug use is part of the human life from the ancient times. Besides their recreational utilization, sustained misuse of these substances can lead to the development of drug addiction especially in susceptible individuals and thus cause serious health and social problems. The aim of this thesis is to briefly introduce brain structures which are affected by addictive substances, and describe some of the mechanisms and molecules that contribute to addiction. A crucial brain structure which plays a role in drug addiction is the reward system, with dopamine as the main neurotransmitter. After repeated use of drugs, in neurons of this system certain molecules and epigenetic changes are accumulating that promote chronic nature of addiction. Especially important is the highly stable transcription factor ΔFosB, which in cooperation with other molecules promotes relapse even after several months or years of the last drug use. Powered by TCPDF (www.tcpdf.org)
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Computer modeling of ion protein interactions: Allo steric effects of phenolic ligands and ions on insulin hexamer struct ure
Palivec, Vladimír ; Jungwirth, Pavel (advisor) ; Fišer, Jiří (referee)
Title: Computer modeling of ion protein interactions: Allosteric effects of phenolic ligands and ions on insulin hexamer structure Author: Vladimír Palivec Department: Department of Physical and Macromolecular Chemistry Faculty of Science UK Advisor: prof. RNDr. Pavel Jungwirth, DSc., IOCB AS CR, v.v.i. Advisor's email address: pavel.jungwirth@uochb.cas.cz Abstract: Insulin hexamer is an allosteric protein capable of undergoing conformational changes between three states: T6, T3R3, and R6. Transitions between them, as well as the formation of insulin hexamers, are mediated through binding of phenolic ligands or ions. This thesis presents a molecular dynamics study of allosteric behavior of insulin using empirical force fields. Two effects are closely inspected - cation (Zn2+ , Ca2+ , K+ , and Na+ ) binding to the insulin hexamers and a possible binding of two neurotransmitters - dopamine and serotonin to the phenolic pocket. The results show that high charge density cations (Zn2+ and Ca2+ ) are mostly localized in the B13 glutamate cavity, slow- down diffusion, while preventing other cations from entering. In contrast, low charge density cations (Na+ and K+ ) do not have this effect. Concerning neurotransmitters, dopamine does not bind to the phenolic pocket whereas serotonin binds in a similar way like...
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Neuropharmacology of spatial navigation, cognitive coordination and flexibility tests in animal models
Prokopová, Iva ; Stuchlík, Aleš (advisor) ; Vyklický, Ladislav (referee) ; Blahoš, Jaroslav (referee)
Spatial navigation, cognitive coordination and behavioral flexibility belong amongst cognitive functions, which play a role in many neuropsychiatric disorders. Behavioral tasks have proved to be useful paradigms to test these functions in pharmacological or genetic animal models. First aim was to determine a potential interaction between β-adrenergic and α1-adrenergic or D2-dopaminergic systems. Spatial navigation and coordination were impaired in both studies during co-aplication of subthreshold doses of drugs. Used substances belong to group of widely prescribed drugs, thus our results could be implicated in clinical practice. Another study examined an acute effect of MK-801 (animal model of schizophrenia) on behavioral flexibility in Carousel maze and the Morris water maze (MWM). Carousel maze showed higher sensitivity with impairments from 0.08 mg.kg-1 compared to 0.10 mg.kg- 1 in MWM. The final experiment aimed at testing the effect of reduced expression of Nogo-A protein on spatial navigation and behavioral flexibility of rats. A battery of tests in the Carousel maze revealed impairment in cognitive functions, MWM showed unaffected working memory of rats. Our results support the hypothesis linking Nogo-A knock-down rats with neuropsychiatric symptoms and cognitive disorders. Key words:...
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The influence of central serotoninergic and dopaminergic activity on nutritional and metabolic parameters
Brunerová, Ludmila ; Anděl, Michal (advisor) ; Haluzík, Martin (referee) ; Yamamotová, Anna (referee)
THE INFLUENCE OF CENTRAL SEROTONINERGIC AND DOPAMINERGIC ACTIVITY ON NUTRITIONAL AND METABOLIC PARAMETERS MUDr. Ludmila Brunerová SUMMARY Introduction: Neuromediators dopamine and serotonin play a significant role in homeostatic and hedonic regulation of food intake, may exert direct metabolic effects and particularly serotonin influences affectivity. Their central activity could be quantified by functional tests. Common regulatory mediators of metabolism and affectivity represent an interesting research goal. Aims of study: The first aim was to describe the relationship between central serotoninergic activity measured by citalopram challenge test, affectivity, preference of macronutrients in food and metabolic profile in healthy men. The second aim was to confirm the use of sublingual apomorphine test as a functional test for assessment of central dopaminergic activity. The third aim was to reveal the relationship between central dopaminergic activity measured by sublingual apomorphine test, preference of macronutrients and metabolic profile. Methods: The study was performed on 42 healthy men (average age 43.5 ± 7.4 years and average BMI 27.4 ± 5.7 kg/mš) within 4 days with a week interval in between them. Anthropometric and...
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Risk factors for development of schizophrenia
Dunglová, Eva ; Flegr, Jaroslav (advisor) ; Kodym, Petr (referee)
Schizophrenia is a severe disease. There is a complicity of genetic and environmental factors in schizophrenia onset. Factors with probable influence on development of schizophrenia are rate of urbanization, geographic location, migration, month of birth, maternal nutrition during pregnancy and birth complications, stress during pregnancy, length of lactation period, prenatal and postnatal infection exposure, exposure to a cat during childhood or cannabis abuse. Until now the information on the environmental risk factors of schizophrenia mentioned above concludes in possibility of existence of one factor which would be determinative in schizophrenia onset. Vitamin D deficiency could be this key factor. Lack of vitamin D in prenatal and postnatal period is linked with most of the environmental risk factor for schizophrenia mentioned above, so they could be just the indicators of vitamin D deficiency. Powered by TCPDF (www.tcpdf.org)
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Stimulant drugs and their physiological effects
Nováková, Pavlína ; Novotný, Jiří (advisor) ; Hejnová, Lucie (referee)
The category of stimulant drugs is a heterogenous group of substances which benefit-to-harm ratio varies widely. This work attempts to use a systemic approach in order to characterize the underlying basis of the physiological effects of their selected representatives in brain. A brief pharmacological description of caffeine, nicotine, cocaine, amphetamine and methamphetamine is followed by an identification of main molecular targets of these drugs in the context of respective neurotransmitter systems. Major attention is given to both acute and chronic molecular mechnisms of action of the selected stimulant drugs up to the level of selected relevant neural circuits. In the next section stimulant drugs are presented as Trojan horses that attack the motivational system of the brain. Initially, a theoretical analysis of reward together with a neuroanatomical dissection of reward-related circuitry serves as a basis for the formulation of contemporary theories of drug addiction. Finally, an effort is made to synthesize common molecular events with specific aspects of reward in order to draw a picture of the neurobiological view of addiction.
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Molecular dynamics simulations of biomolecules
Naništa, Ján ; Barvík, Ivan (advisor) ; Bok, Jiří (referee)
This study deals with classical molecular dynamics simulations of time evolution of a biomolecular system. The simulated system consists of the D3 GPCR membrane receptor for dopamine surrounded by a cell membrane and covered with water molecules and ions. The aim was to analyze the ability of Eticlopride to bind into the active site of the GPCR receptor.
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Hormonal induction of ovulation in whitebarred catfish (Agamyxis pectinifrons)
KNOWLES, Jindřiška
The aims of presented work are reviewing of current knowledge about biology and artifical reproduction, evaluation of dopamine inhibition of LH secretion and identification of optimal hormonal treatment of ovulation in tropical whitebarred catfish. Two trials were conducted in years 2012 and 2013. The experiments differed from each other only in the water temperature 29,5 °C (Experiment No.1) and 26 °C (Experiment No.2). In each experiment, the fish were divided into 4 groups. Group A was injected only with mGnRHa, group B was injected with dopamine inhibitor metoclopramide, group C was injected with mGnRHa plus metoclopramide and group D was injected only with physiological saline (0,9 % NaCl). Ovulation occurred only in the groups injected with the combination of GnRHa and dopamine inhibitor, however in both experiments. In Experiment No.1, the ovulation rate was around 60%, relative fecundity was 331,025 +- 47,508 eggs . kg-1, latency interval was at 10.3 +- 0.6 hours and the fecundity index was determined at 13, 8. In Experiment No. 2 ovulation, the level of ovulation was 50%, relative fecundity was 408,561 +- 34,934 pieces of eggs . kg-1, latency interval was 13.7 +- 0.7 hours and fecundity index was 15.35. The results clearly show a strong inhibition of dopamine on LH secretion and show that the combination of GnRHa with dopamine inhibitor can be successfully used to induce ovulation in whitebarred catfish.
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ELECTROCHEMICAL DETECTOR WITH ELECTRODES ARRAY AND ROTATING DISK
SAJDLOVÁ, Zuzana
The thesis deals with the testing and optimization of hydrodynamic conditions of the electrochemical detector, which consists of a flow cell containing the electrochemical sensor with an array of electrodes. The flow cell includes a rotating disc-shaped component, which allows radial flow of analytes along the sensor electrodes. This principle imitates the rotating disk electrode, with the difference that here the electrodes are immobile. Hydrodynamic phenomena in this case are similar to RDE. Therefore, the theoretical part of my work deals with hydrodynamics and mass transfer for the well-described case of rotating disk electrode. It was found that in the current set-up under certain conditions, an analyte flowed back from the output cell channel to the sensor, even at the laminar flow. This causes a nonlinear response of the electrodes and their low reproducibility. The solution is to reduce the distance between the rotation component and the electrodes surface and reduce flow speed of analyzed liquid towards the sensor. A novel type of sensor with annular electrodes was designed and tested. It showed four times higher conversion rate of the analyte compared with the originally used AC9 electrochemical sensor having electrodes in the form of full circles lying on a circumference of a common circle. Based on calculations, conversion of the analyte on the plane electrode can be increased up to 100% when using this annular sensor, adjusting flow cell and reducing of the input flow rate. The detector was connected to the liquid chromatograph and its function was tested on two substances - ascorbic acid and dopamine. For the current detector these parameters were set: dynamic range, linearity, noise, detection limit, time constant and the temperature range at which the detector can be operated.
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