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Synchronization of circadian clock in rat during ontogenesis and in adulthood
Olejníková, Lucie ; Sumová, Alena (advisor) ; Šlamberová, Romana (referee) ; Mareš, Jan (referee)
The circadian system temporally controls behavioral and physiological processes in most organisms so that they change during the day and night with a period of about 24 h. It is an evolutionary adaptation to anticipate periodic changes in environment on the Earth. In mammals, the circadian system consists of the central pacemaker in the suprachiasmatic nuclei (SCN) of hypothalamus and of oscillators located in numerous peripheral organs and tissues. At the molecular level, the circadian clock is based on the rhythmic expression of so called clock genes. The ontogenetic development of the circadian system is a gradual process and the most important changes undergo during the late embryonic and early postnatal stage. Many behavioral, hormonal and metabolic signals provided by the mother are considered to be involved in circadian clock synchronization during early ontogenesis. The mechanisms of the entrainment are not fully known yet. The aim of this thesis was to study the development of the circadian clock and its entrainment via maternal signals and to compare the development of circadian rhythms in two model rat strains - Wistar rat and spontaneously hypertensive rat (SHR). Firstly, we described the ontogenetic maturation of the Wistar rat circadian clock in the colon from the fetal stage until...
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The role of main excitatory and inhibitory transmitters in epileptic seizures and the effect of antiepileptic drugs in the immature brain
Liptáková, Soňa ; Mareš, Pavel (advisor) ; Komárek, Vladimír (referee) ; Šlamberová, Romana (referee)
Epilepsy affects 50 million people worldwide. Approximately 50% of epilepsies start in the infancy and childhood. In addition, there are several age-bound epileptic syndromes which are difficult to treat. Due to these facts, developmental studies of epileptic seizures are of primary importance. Predominance of excitation over inhibition is a mechanism of nearly all types of epileptic seizures. Hypothesis that this compromised balance can be normalized by drugs affecting main excitatory and inhibitory system at different stages of brain development was tested in models with different pathogenesis. Our studies demonstrated that seizures induced by derrangement of GABAergic inhibition can be suppressed by antagonists of NMDA receptors (MK-801) and vice versa seizures with glutamatergic pathogenesis can be affected by drugs potentiating GABAergic system (valproate, ganaxolone) at all developmental stages in immature rats. Analysis of site of action of NMDA receptor antagonists demonstrated reciprocal function of anterior and posterior parts of substantia nigra, structure important for spread of epileptic activity to spinal cord. Special attention was given to an age-dependent model - flexion, emprosthotonic seizures elicited by administration of NMDA. Valproic acid, which potentiates GABAergic inhibition,...
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Research into the mechanisms of methamphetamine dependence
Havlíčková, Tereza ; Šustková, Magdaléna (advisor) ; Šlamberová, Romana (referee) ; Petrásek, Tomáš (referee)
The presented dissertation deals with the issue of methamphetamine dependence. The first part focuses on a research that seeks a new promising possibilities of using ghrelin antagonist to reduce the potentiating effects of methamphetamine, with the intent of a more effective approach/treatment in current unsatisfactory approach in methamphetamine dependence. Furthermore, it summarizes the already available knowledge that deals with the possibilities of influencing the mechanisms of substance abuse through ghrelin antagonism, and especially focuses on our own experimental work. We tested the efficacy of the GHS- R1A receptor antagonist, JMV2959, in experimental models of methamphetamine dependence. There is only a minimum of work dealing with this issue yet. The experimental part summarizes the results of our two studies examining the effect of a ghrelin antagonist on the development of addictive reinforcing mechanisms, methamphetamine intake itself and the tendency to relapse behavior. Using the drug conditioned place preference (CPP) method in rats, we demonstrated in two experimental settings a significant effect of ghrelin antagonism on the development of methamphetamine binding to the environment and on the already induced search for a drug-related environment. We have shown that a GHS-R1A...
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New synthetic drugs - neurobiology, toxicity and addictive potential
Leca, Nikola ; Páleníček, Tomáš (advisor) ; Šlamberová, Romana (referee) ; Rečková Hroudová, Jana (referee)
Introduction: Since the beginning of this century, new synthetic drugs (NSD) have become a popular component of Czech Republic and worldwide drug scene. The main reason for their popularity and prevalence is their legality and the interest of users to seek new experiences. This leads to a constant production of substances with various chemical structure's modifications, but information about acute and chronic effects, pharmacology and toxicology are mostly missing or they are not sufficient. Aims: The main aim of this doctoral thesis was to evaluate NSD from the ranks of cathinones. The subobjectives were as follows: 1) evaluation of stimulation potential 2) evaluation of potency to disrupt sensorimotor gating 3) evaluation of acute toxicity in terms of the risk of hyperthermia 4) evaluation of addictive potential. Methods: The NSDs tested in this thesis were mephedrone (2.5, 5, 20 mg/kg), methylone 5, 10, 20, 40 mg/kg) and naphyrone (5, 10, 20 mg/kg). All NSDs were administered subcutaneously in a volume of 2 ml/kg. Adult male Wistar rats were behaviourally tested in the open field test (n = 10/group), the prepulse inhibition test (n = 10/group) and the conditioned place preference test (n = 13/group). For pharmacokinetic experiments, serum and organs (brain, lungs, liver) were collected at...
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Drug sensitization in rats prenatally exposed to methamphetamine
Schutová, Barbora ; Šlamberová, Romana (advisor) ; Šulcová, Alexandra (referee) ; Kršiak, Miloslav (referee)
Methamphetamine (MA) is a psychostimulant drug with high potential for abuse. Psychostimulants were shown to cause behavioral sensitization - a progressive increase of their psychomotor activating effects. Since half of MA users are women of reproductive age, there is an increased risk of negative consequences for their children. The aim of my dissertation thesis was to find out whether prenatal MA exposure is able to increase sensitivity to the same drug in adulthood. Pregnant dams were injected daily with MA 5 mg/kg or saline (S) subcutaneously (s.c.) during the whole gestation. The absolute control group of adult females (C) was not exposed to any injection application. To test the sensitivity of the offspring to MA in adulthood, half of each prenatally exposed group (MA, S, C) were administered MA 1 mg/kg while the other half received S s.c. The sensitizing effect of prenatal MA exposure was tested in the open field, elevated plus maze, Laboras (Metris B.V., Netherlands), Morris water maze, tail-flick test and in the tests of susceptibility to epileptic seizures. Our results showed that the animals prenatally exposed to MA were more susceptible to flurothyl seizures and demonstrated better performance in the test of memory. On the other hand, acute MA application in adulthood increased motor activity,...
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Does prenatal methamphetamine exposure induce cross-sensitisation to drugs in adult male and female rats?
Macúchová, Eva ; Šlamberová, Romana (advisor) ; Šulcová, Alexandra (referee) ; Valeš, Karel (referee)
Women, who abuse drugs during pregnancy, expose not just themselves but also their developing foetus to impairing effects, which can have potentially harmful and even long- term effects on the exposed children. For some years, methamphetamine (MA) has dominated the illicit drug market in the Czech Republic and Slovakia; additionally this drug is on the rise worldwide. It is one of the most accessible drugs, and in many cases the first choice drug for many drug-addicted pregnant women; in part due to its anorectic and stimulant effects. These women are rarely aware of the consequences of their behaviour and their pregnancy is hardly ever a good enough reason for giving up drug use. These findings are supported by many experimental studies that show the damaging effects of maternal MA exposure on their offspring. There is growing evidence that exposure to MA in utero not only causes birth defects and delays in infant development, but also impairs the brain reward neural pathways of a developing offspring in such a way, that it could increase the predisposition for drug addiction later in life. Previously published animal studies have shown that offspring of mothers exposed to MA during pregnancy are more sensitive to MA when they encounter this drug later in adulthood. With respect to increased...
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Determination of critical developmental periods for effects of methamphetamine on rat behavior in adulthood
Hrebíčková, Ivana ; Šlamberová, Romana (advisor) ; Cendelín, Jan (referee) ; Valeš, Karel (referee)
Aim: The aim of the Ph.D. thesis was to find out which of the neuro-ontogenetic stages of laboratory rat is more significant for the methamphetamine (MA) exposure on the behavior in adulthood and to determine a critical developmental period for the effects of this drug. In the experimental part of the study was to test the influence of prenatal and neonatal MA exposure on behavior, social interaction, cognition and drug-seeking behavior in adulthood. Methods: Adult female rats were exposed to MA (5 mg/ml/kg) or saline (S) (1 mg/kg) during different stages of gestation and lactation. The tested substances were administered subcutaneously during the first half of gestation (ED 1-11), the second half of gestation (ED 12-22) or during early lactation (PD 1-11). The effect of prenatal MA exposure was transmitted to pups via placental barrier; the effect of MA exposure during early lactation was transmitted via the breast milk. In order to compare the rate of drug transmission by indirect MA exposure via the breast milk, we chose another group of offspring that we administered the tested substances directly subcutaneously during the same application period (PD 1-11). In this way we obtained 8 groups of exposed pups: ED 1-11 MA, S; ED 12-22 MA, S; PD 1-11 indirectly MA, S; PD 1-11 directly MA, S. These...
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The effect of prenatal MA exposure and crossfostering on functional changes in laboratory rat
Hrubá, Lenka ; Šlamberová, Romana (advisor) ; Tejkalová, Hana Barbora (referee) ; Šulcová, Alexandra (referee)
The aim of our study was to investigate the impact of prenatal methamphetamine (MA) exposure and cross-fostering on development of rat pups during preweaning period and on behavior, anxiety, cognitive function and nociception in adulthood. Mothers were daily exposed to injection of MA (5 mg/kg) or saline (S) approximately for 9 weeks: three weeks prior to impregnation, throughout the entire gestation period and for 23 days of lactation. Control females (C) did not receive any injection. On postnatal day (PD) 1, pups were cross-fostered so that each mother received some of her own and some of the pups of mother with the other two treatments. We obtained 9 experimental groups (C/C, C/S, C/MA, S/C, S/S, S/MA, MA/C, MA/S, MA/MA). Pups were tested during postnatal development by means of following behavioral tests: negative geotaxis, tail pull, righting reflex on surface and in mid-air, rotarod and bar-holding and were examined for physiological maturation. In adulthood, males and females rats were tested in the Open field (OF) and in the Elevated plus maze (EPM) for behavior and anxiety and in the Plantar test for thermal nociception. Adult male rats were tested on cognitive function in the Morris water maze (MWM). In adult female rats, phases of the estrous cycle were recognized and compared. Our...
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Possible perspective use of ghrelin mechanisms in the treatment of opioid addiction
Jeřábek, Pavel ; Šustková, Magdaléna (advisor) ; Šlamberová, Romana (referee) ; Petrásek, Tomáš (referee)
This dissertation deals with the narrow issue of the new perspective research direction, which is research of the possibility of using ghrelin antagonism in the treatment of opioid addiction, which has been rarely studied yet. It summarizes the general principles of neurobiological mechanisms of drug addiction as well as treatment guidelines and procedures based on these findings. The definition of addiction as a disease together with the factors contributing to its formation and course, are presented in this dissertation. The definition includes individual repetitive phases (cycles) of the substance addiction, along with a description of the anticipated involvement of individual brain structures and basic neuromediators involved in these phases, including references to the most important literary findings on the role of ghrelin in the mechanisms of addiction, focused on mechanism of action of ghrelin in the opioid addiction. In the experimental part, the results of the CNS microdialysis experiments in rats, using the GHS-R1A antagonist (JMV2959 pretreatment), were presented in both acute single dose morphine experiment and sub-chronic experiment in which morphine was administered in increasing doses for five consecutive days. The results are presented in relation to changes in the level of...
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Synchronization of circadian clock in rat during ontogenesis and in adulthood
Olejníková, Lucie ; Sumová, Alena (advisor) ; Šlamberová, Romana (referee) ; Mareš, Jan (referee)
The circadian system temporally controls behavioral and physiological processes in most organisms so that they change during the day and night with a period of about 24 h. It is an evolutionary adaptation to anticipate periodic changes in environment on the Earth. In mammals, the circadian system consists of the central pacemaker in the suprachiasmatic nuclei (SCN) of hypothalamus and of oscillators located in numerous peripheral organs and tissues. At the molecular level, the circadian clock is based on the rhythmic expression of so called clock genes. The ontogenetic development of the circadian system is a gradual process and the most important changes undergo during the late embryonic and early postnatal stage. Many behavioral, hormonal and metabolic signals provided by the mother are considered to be involved in circadian clock synchronization during early ontogenesis. The mechanisms of the entrainment are not fully known yet. The aim of this thesis was to study the development of the circadian clock and its entrainment via maternal signals and to compare the development of circadian rhythms in two model rat strains - Wistar rat and spontaneously hypertensive rat (SHR). Firstly, we described the ontogenetic maturation of the Wistar rat circadian clock in the colon from the fetal stage until...
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