Browsing by Subject "Serotonin"

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Exzitatorische Pharmakologie der retinalen Spreading Depression
(2010) Sieber, Michaela; Hanke, Wolfgang
The phenomenon of Spreading Depression (SD) is a suppression of neuronal activity, propagating wave-like in the grey matter. This results from a massive ion translocation where potassium ions pour into the cell and sodium-, chlorideand calcium ions pour out of the cell. At the same time there is also a slow negative potential shift up to 30mV. Spreading Depression also occurs in the retina, a part of the central nervous system and can easily be observed there with the naked eye. This dissertation describes the effects of excitatory pharmaceuticals on neuronal tissue, using retinal spreading depression as a model system. By applying different excitatory substances, a reduction of the velocity and an inhibitory effect on the conductivity of the membranes can be observed. In the case of nicotine this may be due to the desensitization of the nicotinic AChreceptors. For caffeine, cocaine, amphetamine and metylphenidate this effect may derive from the hyperpolarisation of the tissue through open cation channels. The latency, a parameter for the excitability of the tissue, increases with the application of any of the investigated substances. This is also caused by the desensitization of the nicotinic ACh-receptors or the hyperpolarisation of the tissue, respectively. A neuroprotective effect reducing excitotoxic cell death induced by activation of NMDA-receptors was successfully verified for all substances. In the case of nicotine, the α7- and α4β2-nACh-receptors are assumed to be involved. The basic mechanism however is still unknown. A possible explanation could be the reduced excitability of the tissue through desensitization of the nACh-receptors. In the case of the remaining substances, the abidance of transmitters in the synaptic cleft suggests a neuroprotective effect through hyperpolarisation. The resulting hyperpolarisation leads to a reduced excitability of the neuronal tissue and most likely prevents over-excitation.
Die Regulation der Futteraufnahme beim Schwein - Untersuchung der Wirkungen eines Serotonin Noradrenalin Wiederaufnahmehemmers (Sibutramin) und eines MCH-R1 Antagonisten (Compound B4)
(2007) Sommer, Torsten; Claus, Rolf
The regulation of food- and feed intake is a highly topical investigative area in animal husbandry as well as in human medicine. Here the focus of medicine is primarily on the reduction of food intake and at the same time change of the metabolism to increased energy expenditure in order to counteract the rising number of adiposity and metabolic syndrome. Therefore, substances from pharmacological research are known which act in different nuclei of the hypothalamus and control food intake and energy expenditure. In the present study two of these new substances were examined with regards to their impact on pigs. The results lead to a more detailed understanding of the corresponding mechanisms in pigs, one of the most important animals used in agriculture. In addition, the pig is also a suitable model for human pharmacological research, as it equals the human physiological regulation more than the rat, which is the most common animal model. Study work flow: Two different regulative substances were examined, on the one hand a serotonin noradrenalin reuptake inhibitor (Sibutramine) and on the other hand, a melanin concentrating hormone receptor antagonist (MCH-R1 antagonist; Compound B4). For the evaluation of the effectiveness the following factors were measured; feed intake, water consumption, weight gain, feed conversion rate and the development of body fat content. The changes caused in the regulation of the metabolism were evaluated by anabolic (Growth hormone and IGF-I) and catabolic (cortisol and aldosterone) hormones. In addition, thyroid hormones and urea in the blood plasma were measured as a parameter of protein turnover. The study was divided in three trials, each of them taking six weeks. During the first trial sibutramine was given per os to three animals and three animals were kept as control. During the second trial sibutramine was given intravenously to two animals and two animals were kept as control. During the third trial the MCH-R1 antagonist, Compound B4, was given per os to six animals. The results are described in the following sections. Results of the sibutramine application: The pharmacological effectiveness of sibutramine is mainly explained through its metabolites (desmethyl sibutramine and didesmethyl sibutramine). It was found that for the per os intake of 20 mg/kg LW sibutramine, as well as sibutramine as the first metabolite desmethyl-sibutramine, a lower concentration in the blood plasma existed compared to the intravenous application. Whereas concentration of the second metabolite didesmethyl-sibutramine was higher for per os application than for intravenous application. Since the effectiveness of sibutramine is mainly based on its second metabolite didesmethyl-sibutramine, the way of application was crucial for its effectiveness. This means that the intravenous application was ineffective. After per os application feed intake was significantly reduced, also dependent on the dose applied, but did not lead to a reduced weight gain of the animals. Further, no impact was found on the feed conversion ratio. In contrast, the treatment with sibutramine per os led to significantly increased water consumption. The application of sibutramine had no impact on the growth hormone secretion. However, IGF-1 concentration was increased while feed intake was decreased. The cortisol concentration in blood plasma was not impacted by any treatment. Results of the application of the MCH-R1 antagonist (Compound B4): The application of the antagonist led to a significant reduction of feed intake, dependent on the dose applied. The means derived for daily weight gain show considerable individual differences per animal, hence the reduction of daily weight gain overall was not significant. Further, changes in water consumption were also detected in this trial. However, it could not be clarified if this was caused by the application of the antagonist or the reduced feed intake. Generally, the application of Compound B4 tends to result in energy saving mechanisms, which have an impact on metabolic active hormones. IGF-1 for example, was slightly lower in the control phase. Neither sibutramine nor the MCH-R1 antagonist Compound B4 had any impact on the concentration of thyroid hormones or cortisol. Conclusions: The studies have shown that the MCH-R1 antagonist leads to a significant reduction of feed intake in pigs, whereas the metabolic active hormones, and therefore the energy expenditure, do not seem to be impacted at all. In addition, it was proven that the pig is a useful animal model for such human pharmacological investigations. However, the large amount of substances required can be seen as disadvantageous and as a limiting factor in the investigation of new agents with an initially small amount of substance synthesis.
Serotonin reuptake transporter deficiency promotes liver steatosis and impairs intestinal barrier function in obese mice fed a Western‐style diet
(2023) Rosa, Louisa Filipe; Haasis, Eva; Knauss, Annkathrin; Guseva, Daria; Bischoff, Stephan C.
Background: Intestinal barrier dysfunctions have been associated with liver steatosis and metabolic diseases. Besides nutritional factors, like a Western-style diet (WSD), serotonin has been linked with leaky gut. Therefore, we aimed to evaluate the role of serotonin in the pathogenesis of intestinal barrier dysfunctions and liver steatosis in mice fed high-fat and high-sugar diets. Methods: 6–8 weeks old male serotonin reuptake transporter knockout mice (SERT−/−) and wild-type controls (SERT+/+) were fed either a WSD or a control diet (CD) ad libitum with or without fructose 30% (F) added to the drinking water for 12 weeks. Markers of liver steatosis and intestinal barrier function were assessed. Key Results: SERT−/− mice showed increased weight gain compared with SERT+/+ mice when fed a WSD ± F for 12 weeks (p < 0.05), whereby SERT−/− mice exhibited reduced energy (−21%) intake. Furthermore, SERT knockout resulted in a more pronounced liver steatosis (p < 0.05), enhanced levels of endotoxin in portal vein plasma (p < 0.05), and increased liver expression of Tnf and Myd88 (p < 0.05), when mice were fed a WSD ± F. Finally, SERT−/− mice, when compared with SERT+/+ mice, had a decreased mRNA expression of Muc2 (p < 0.01), Ocln (p < 0.05), Cldn5 (p = 0.054) and 7 (p < 0.01), Defa5 (p < 0.05) and other antimicrobial peptides in the ileum. On the protein level, ZO-1 (p < 0.01) and DEFA5 protein (p < 0.0001) were decreased. Conclusion and Inferences: Our data demonstrate that SERT knockout causes weight gain, liver steatosis, and leaky gut, especially in mice fed a WSD. Therefore, SERT induction could be a novel therapeutic approach to improve metabolic diseases associated with intestinal barrier dysfunction.
The role of serotonin and gap junctions in left-right development of Xenopus laevis
(2011) Beyer, Tina; Blum, Martin
In vertebrates, the correct determination of the left-right (LR) axis is essential for accurate placement of the inner organs, such that the heart points to the left, lung lobation differs between left and right side, spleen and stomach are located on the left,liver on the right body side and the gut coils asymmetrically. Disturbance of this organization can lead to severe impairments of organ function. In the African clawed frog Xenopus laevis, already in four-day old tadpoles asymmetric organ arrangement is visible. This coordinated organ development strictly requires prior Nodal cascade activity in the left lateral plate mesoderm (LPM) in all model organisms examined so far. The initial symmetry breaking event necessary for unilateral induction of Nodal signaling is still under debate. In X. laevis, two models, namely 'ion-flux' and 'cilia-driven leftward fluid flow', were discussed in this context. Leftward flow was first described in the mouse model and later on in fish and rabbit, whereas the 'ion-flux' hypothesis is supported by data derived from chick development. In the present work it was intended to enlighten this putative discrepancy by re-investigating the function of two 'ion-flux' components in context of leftward flow in the model organism X. laevis. First, a link between cell-cell communication via gap junctional communication (GJC)and LR axis establishment was analyzed by using heptanol for general inhibition of channel conductance on the one hand, and single knock-down (KD) of specific subunits on the other hand. Both treatments resulted in absence of the left-sided Nodal cascade. The KD led to shorter GRP cilia when compared to wildtype embryos and loss of bilateral Nodal expression at the GRP margin, respectively. Furthermore, heptanol treatments of stages in which the GRP already has been fully developed also resulted in laterality defects, thus implying a second function of GJC most likely for the signal transfer to the left side. These results indicated a role of GJC in leftward flow establishment and/or post-flow in neurula stages rather than a function in early cleavage stages for LR determination. Second, the early signaling function of the neurotransmitter serotonin (5-HT) was inhibited by over-expression of either a frog or a human receptor ligand binding domain(LBD). In addition, specific KD of a receptor class 3 subunit was performed. Both applications resulted in impaired left-sided marker gene expression and disturbed GRP morphogenesis. Remarkably, marker gene expression of the superficial mesoderm(SM) which gives rise to the GRP during development, was reduced in 5-HT signaling impaired embryos. Very importantly, receptor 3 specific 5-HT signaling was shown to represent a necessary competence factor required for Wnt-dependent axis development in the frog double axis induction assay. Besides the new function of 5-HT during early development, it was further shown that the expression of the SM marker Foxj1 (a master regulator of motile cilia) depended on maternal factors. Based on the work presented here, the following model is proposed: (1) Foxj1 expression is induced maternally, followed by (2) zygotic refinement in post-MBT stages, i.e. inhibition on the ventral and maintenance on the dorsal side. In the organizer region, an interplay of Wnt and 5-HT signaling is required for dorsal development.(3) Cilia driven leftward flow initiate an unknown downstream signal which is transferred to the left LPM. Both events, leftward flow and transfer, require active GJC. (4) A to date unknown signal gets transferred towards the left LPM in a GJC-dependent process and induces the Nodal cascade activity, a prerequisite for proper organ arrangement. Taken together, the data presented in this study indicate that the directed fluid flow in neurula embryos represent the decisive step for symmetry breakage with the 'ion-flux' components being involved in correct flow function.
Towards a unifying model of symmetry breakage in Xenopus laevis : serotonin signaling and the cilia-driven leftward flow
(2011) Thumberger, Thomas; Blum, Martin
Orientation of the three vertebrate body axes anterior-posterior (AP), dorso-ventral (DV) and left-right (LR) is specified during early embryogenesis. Whereas the formation of the AP and DV axes is well understood, it is not finally resolved how and when the left and right sides get molecularly distinct. All deuterostomes analyzed so far, however, display an asymmetric left-sided expression of the TGF-β factor Nodal during embryonic development which precedes asymmetric organogenesis. In zebrafish, medaka, mouse and rabbit embryos a cilia-driven extracellular leftward fluid flow was shown to be causal for the left asymmetric induction of the Nodal gene cascade during early neurulation. In X. laevis, leftward flow was also shown to be driven by a mono-ciliated epithelium in the posterior part of the archenteron roof (gastrocoel roof plate, GRP). Mechanical blockage of this current resulted in laterality defects. Despite the apparent evolutionary conservation of flow, an earlier mechanism to specify the LR axis during early cleavage stages has been reported in X. laevis. Based on mostly inhibitor experiments, the so-called 'ion-flux' hypothesis was put forward which proposes an electrogenic transport and asymmetric accumulation of determinants as early as at the 32-64 cell stage. The monoamine serotonin is the core-effector of this hypothesis and was reported to asymmetrically accumulate at the ventral right blastomeres of early cleavage stage embryos. The aim of this study was to investigate putative interactions of the two apparently opposing mechanisms for breaking the initial LR symmetry of the Xenopus zygote. Reinvestigation of serotonin localization could not confirm the initial report. Further, serotonin signaling was shown to be necessary for LR axis formation on the dorsal but not ventral side, more specifically as a competence factor for the canonical Wnt-pathway. Detailed analyses of specimens impaired for serotonin signaling revealed requirement of serotonin signaling for specification of the superficial mesoderm (SM) which gives rise to the GRP and, consequently, to leftward flow. Leftward flow thus indirectly depends on dorsal serotonin signaling. In a further part of the present thesis, a re-examination of laterality in Siamese twins was performed. It has been known since the earliest experimental investigations of laterality that in induced and naturally occurring Siamese twins the left twin consistently displays wildtype orientation of the visceral organs whereas the orientation in the right twin is randomized. In experimentally induced conjoined twins, this observation holds true regardless of which twin is the induced. A model of symmetry breakage, in order to be plausible, thus should also be able to account for this phenomenon. When experimentally induced twins were analyzed for leftward flow, in the majority of cases a continuous leftward flow was observed, i.e. both twins shared one GRP. Thus, laterality cue(s) get translocated towards the far left side, i.e. only the left embryo receives the wildtype asymmetric information, regardless if it is the induced or endogenous twin. In rare case X. laevis conjoined axes developed far apart from one another such that two separate GRPs and individual leftward flows were observed, a condition that enabled both axes to exhibit a left-sided Nodal cascade. These experiments strongly suggest that Spemann's organizer itself is necessary and sufficient to establish all three body axes. In conclusion, the present analysis of laterality determination in the frog Xenopus supports evolutionary conservation of leftward flow as symmetry breaking event, as previously reported for mouse, rabbit and bony fish.
Untersuchungen zur Rolle des intestinalen serotonergen Systems in der Entstehung von Adipositas und der nahrungsinduzierten nicht-alkoholbedingten Fettlebererkrankung im Mausmodell
(2011) Haub, Synia; Bischoff, Stephan C.
The worldwide prevalence of overweight and obesity has increased dramatically throughout the last decades. The causes of obesity are numerous and complex and the understanding of the mechanism(s) involved in the disease process are still limited. The same is true for the development of NAFLD, a liver disease for which a strong association with overweight and obesity has repeatedly been shown. High dietary fat intake has long been thought to be the major cause of obesity and NAFLD. However, other factors like carbohydrate intake may also contribute. Alterations at the level of the intestinal tract have also been discussed to be associated with the development of NAFLD and obesity. The enteric nervous system (ENS) might be of particular importance in this context, regulating the fundamental intestinal functions like peristalsis, secretion and permeability through its main neurotransmitter serotonin (5-HT) and different 5-HT receptors. The termination of the 5-HT action is mediated by the 5-HT selective reuptake transporter (SERT), located on epithelial cells. Based on this background the aim of the present work was to investigate the role of the intestinal serotonergic system and herein particularly of SERT and 5-HT3R in the onset of sugar-induced overweight and NAFLD as well as in the progression of NAFLD in mouse models.