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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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Human in vitro models for epilepsy research
Hebenstreitová, Kristýna ; Danačíková, Šárka (advisor) ; Valeš, Karel (referee)
Epilepsy is the most common chronic neurological disease that affects around 1 % of the world population. It is a multifactorial disease, which is characterised by recurrent seizures. Present pharmacological treatment is symptomatic and approximately one third of the patients develop pharmacorezistant epilepsy. This bachelor thesis presents an overview of current knowledge about the modelling of epilepsy, while focusing on human in vitro models. Cell lines appear to be very promising in vitro models for modelling genetic epilepsies. For example, cell lines derived from human induced pluripotent stem cells or human neural stem cells, which both allow for introduction of potentially pathological mutations and further differentiation into many different cell types. Human in vitro models of epilepsy play important role in understanding the process of epileptogenesis, ictogenesis, mechanism of antiepileptic drugs effects and are used in the search for new active substances. Epilepsy comes with great burden of disease for the patients, that is why it is very important to research not only the molecular mechanisms of epileptogenesis, but also advancements of personalised therapy, which could give hope to many (even pharmacorezistant) patients.
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Effects of a neuroactive steroid on motor skills of young laboratory rat.
Košťálová, Tereza ; Mareš, Pavel (advisor) ; Valeš, Karel (referee)
The steroid substances with effect on nervous tissue are plenteously studied in last years. Their biggest benefits are especially anticonvulsant and anxiolytic effects. This thesis inspects the influence of newly discovered neruactive steroid pregnanolone pyroglutamate synthesized in The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science (IOCB CAS), which offer potential opportunity of a new therapy of epilepsy from actual pharmacokinetic results. Our goal was to detect, if this substance has any negative effects on locomotor skills of young laboratory rats. In theoretical part of the thesis the development of laboratory rat is briefly descibed, especially its motor skills and sensory functions in comparison with human. The process of the experiments and choice of especially motor skill tests are described in Metogology part. The results of experiment and its comparation with the effect of other neuromediators are introduced and discussed in the practical part of this thesis. There were no serious effects of pregnanolonepyroglutamate applied repeatedly in perinatal period on motor performance. Acute administration of the highest dose of PPG to 12-day-old rat pups resulted in prolongation of time in surface righting and negative geotxis tests. This data are positive for...
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The role of intestinal microbiota in the development of Alzheimer's dementia
Hakenová, Kristina ; Valeš, Karel (advisor) ; Vodička, Martin (referee)
Preserving health at a higher age depends on the function of biological homeostatic systems (neural endocrine and immune activities), where the biological interaction between these systems and the intestinal microflora plays a key role. One of the most serious diseases associated with aging is Alzheimer's dementia (AD) and it is the most common cause of dementia in the world. This disease is accompanied by cognitive impairment associated with accumulation of amyloid plaques and neurofibrillary fibres in brain tissue. Naturally, biological changes occur during the process of aging, resulting in reduced functional capacity of the organism, accompanied by an increased risk of inflammatoryprocesses involved in the etiology of several chronic, pathologies, including neurodegenerative processes. These modulatory processes are associated with oxidative stress and intestinal dysbiosis. It is already well documented in the scientific literature that significant changes in the composition of intestinal microbiota occur in aging. These changes can lead to several biological changes, including increased permeability of the intestinal barrier, thereby causing the increased penetration of many biologically active substances into the body. This may be a risk factor for the development of inflammation in both...
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Neuronal activity during stereotypical behavior in quinpirole induced animal model of Obsessive Compulsive Disorder (OCD)
Alexová, Daniela ; Valeš, Karel (advisor) ; Kopřivová, Jana (referee)
The main aim of this study was to determine the changes in neuronal activity of anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and medial prefrontal cortex (MPC) in rats sensitized to D2/D3 receptor agonist quinpirole (QNP) during exploration of enriched open field arena. During the experiment, the evaluation of behavioural changes induced by quinpirole sensitization were also assessed and compared to previous results. For the purpose of this study, twenty-two adult male Long-Evans rats were used. The half of the rats was sensitized to QNP by receiving daily subcutaneous injections of quinpirole (0,5 mg/kg) while the other half received saline. Both groups were habituated for ten days to open-field arena enriched with two metal objects. The behaviour of animals was videotaped and the data about locomotion and the number of visits of each locale was obtained. On the eleventh day, the part of saline and quinpirole treated groups explored the open-field arena (t = 5 min) while the other two subgroups were left as respective cage-controls. Immediately after the end of experiment, all rats were sacrificed, and the extracted brains were cryopreserved. To determine the changes in neuronal activity of selected brain regions, fluorescence in situ hybridization of immediate early gene Arc was...
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The importance of NMDA antagonists in animal models of ischemic injury and major depressive disease
Kletečková, Lenka ; Valeš, Karel (advisor) ; Zach, Petr (referee) ; Ježek, Karel (referee)
Glutamatergic system is the main excitatory system and glutamatergic receptors are the most abundantly expressed in whole central nervous system. The most widespread type of glutamatergic receptors are N-methyl-D-aspartate (NMDA) receptors which are essential for physiological development of nervous tissue, synaptic plasticity and cognitive processes. On the other hand, over-activation of these receptors leads to excitotoxic damage of nervous tissue and serious neurological consequences for future quality of life. Disruption of glutamatergic system is common feature for hypoxic-ischemic damage, traumatic brain injury, neurodegenerative and neuropsychiatric diseases. Therefore glutamatergic system and specifically NMDA receptors are an attractive target for neuropharmacological research. Presented thesis explores the effect of several molecules with modulating inhibiting effect on NMDA receptor. Work is preferentially focused on application research; the main aim is evaluated therapeutic potential of studied compounds. First group of compounds is represented by neuroactive steroids pregnanolone glutamate and pregnanolone hemipimelate, which are allosteric inhibitors of NMDA receptor. Here, their neuroprotective effect is demonstrated in hypoxic-ischemic and excitotoxic damage of nervous tissue....
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Regulation of NMDA receptor trafficking in mammalian cells
Hemelíková, Katarína ; Horák, Martin (advisor) ; Novotný, Jiří (referee) ; Valeš, Karel (referee)
N-methyl-D-aspartate (NMDA) receptors are a subclass of glutamate receptors that play an essential role in mediating excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system (CNS). The activation of NMDA receptors plays a key role in brain development and memory formation. Abnormal regulation of NMDA receptors plays a critical role in the etiology of many neuropsychiatric disorders. NMDA receptors form a heterotetrameric complex composed of GluN1, GluN2(A-D) and GluN3(A, B) subunits. The NMDA receptors surface expression is regulated at multiple levels including early processing (synthesis, subunit assembly, endoplasmic reticulum (ER) processing, intracellular trafficking to the cell surface), internalization, recycling and degradation. NMDA receptors are regulated by the availability of GluN subunits within the ER, the presence of ER retention and export signals, and posttranslational modifications including phosphorylation and palmitoylation. However, the role of N-glycosylation in regulating of NMDA receptor processing has not been studied in detail. The aim of this study was to clarify the mechanisms of regulation of surface expression and functional properties of NMDA receptors. We used a combination of molecular biology, microscopy, biochemistry and...
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