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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
381

Physiological Effects of Ascaris Suum Intestinal Microflora on 5-Hydroxytryptamine Level and Binding Sites in the Intestinal Epithelial Cells

Shahkolahi, Akbar Mohammadpour 12 1900 (has links)
Serotonin (5-hydroxytryptamine, 5-HT) has been shown to activate carbohydrate metabolism in adult female Ascaris suum. Serotonin may be either absorbed directly from the environment or synthesized de novo from the absorbed L-tryptophan in adult female A. suum. The enzymes necessary for the synthesis of 5-HT have been identified in both intestine and muscle tissues. The serotonin absorbed from the environment is obtained either from the host's gastrointestinal contents or from the 5-HT producing bacteria in the intestine of A. suum. Numerous 5-HT producing bacteria were identified in the intestinal microflora. The physiological contributions of 5-HT producing bacteria to the 5-HT level, turnover and binding sites in the intestinal tissue of A. suum were investigated.
382

Single-cell activity and network properties of dorsal raphe serotonin neurons during emotional behaviors

Paquelet, Grace Elizabeth January 2022 (has links)
The mammalian serotonin system modulates a wide variety of emotional behaviors and states, including reward processing, anxiety, and social interaction. To reveal the underlying patterns of neural activity, we visualized serotonergic neurons in the dorsal raphe nucleus (DRN5-HT) of mice using miniaturized microscopy and calcium imaging during diverse emotional behaviors. In total, we imaged the activity of over 2,000 genetically-identified serotonin neurons. We discovered discrete ensembles of cells with highly correlated activity and found that DRN5-HT neurons are preferentially recruited by emotionally salient stimuli as opposed to neutral stimuli. Individual DRN5-HT neurons responded to diverse combinations of salient stimuli, with some preference for valence and sensory modality. Anatomically-defined subpopulations projecting to either a reward-related structure, the ventral tegmental area, or an anxiety-related structure, the bed nucleus of the stria terminalis, contained all response types, but were enriched in reward- and anxiety-responsive cells, respectively. Our results suggest that the DRN serotonin system responds to emotional salience using correlated ensembles with mixed selectivity and biases in downstream connectivity.
383

Role of Mu-Opioid Receptors in the Behavioral Effects of the Antidepressant Tianeptine

Han, Jaena January 2021 (has links)
For over half a century, the monoamine hypothesis has been the dominant theoretical framework guiding depression research and drug development. This hypothesis posits that depression arises from a deficiency in the monoaminergic neurotransmitters serotonin, norepinephrine, and possibly dopamine, and that antidepressants function by increasing extracellular availability of these monoamines in the brain, especially at the synaptic level. It is clear however, that the monoamine hypothesis cannot fully explain either the pathophysiology of depression nor the mechanisms of antidepressant action. Tianeptine is an atypical antidepressant used in Europe to treat patients who respond poorly to selective serotonin reuptake inhibitors (SSRIs). The recent discovery that tianeptine is a mu opioid receptor (MOR) and delta opioid receptor (DOR) agonist has provided a potential avenue for expanding our understanding of antidepressant treatment beyond the monoamine hypothesis. This dissertation aims to understand the neural circuits underlying tianeptine’s antidepressant effects. We first characterized the acute and chronic effects of tianeptine on depressive-like and other opioid-related behaviors in mice, and used genetic and pharmacological models to test whether these behavioral effects are mediated by MOR and/or DOR. We found that acute tianeptine administration produced an antidepressant-like reduction in immobility time in the forced swim test, as well as classic opioid-like effects including analgesia, hypophagia, hyperactivity, and conditioned place preference. These behavioral responses to tianeptine are abolished in MOR knockout (KO) mice and in mice that have been pretreated with an MOR antagonist. By contrast, all responses to tianeptine remained intact in DOR KO mice. Remarkably, unlike other classic opiates such as morphine, chronic tianeptine treatment did not produce tolerance to tianeptine’s analgesic effect, nor naloxone-precipitated withdrawal. The acute behavioral effects of tianeptine (excluding analgesic effects, which were present at 15 minutes, but not 1 hour) were established to occur at 1 hour post-injection and to be largely absent by 3 hours post-injection. Chronically, tianeptine produced an antidepressant effect in corticosterone-treated mice, and prevented the development of restraint-stress-induced depression-like behavior, both in an MOR-dependent manner. Interestingly, tianeptine’s chronic antidepressant-like effects were evident in mice after as little as one week of treatment, rather than several weeks as might be expected for SSRIs. Using tissue-specific MOR knockouts, we further showed that MOR expression on GABAergic cells, specifically somatostatin-positive neurons, is necessary for the acute and chronic antidepressant-like responses to tianeptine. By contrast, tianeptine’s behavioral effects did not require the expression MORs on D1- and parvalbumin-expressing cells, nor the expression of ß-arrestin 2. These experiments also revealed a dissociation between the antidepressant-like phenotype and other opioid-like phenotypes resulting from acute tianeptine administration such as analgesia, conditioned place preference, and hyperlocomotion. Critically, we found that tianeptine’s mechanism of action is distinct from fluoxetine in three important aspects: 1) tianeptine requires MORs but not DORs for its chronic antidepressant-like effect, while fluoxetine is the opposite, 2) unlike fluoxetine, tianeptine does not promote hippocampal neurogenesis, and 3) tianeptine’s effects appear to persist even after serotonin depletion. Taken together, these results suggest a novel entry point for understanding what circuit dysregulations may occur in depression, as well as possible targets for the development of new classes of antidepressant drugs.
384

Marine Inspired 2-(5-halo-1H-indol-3-yl)-N,N-Dimethylethanamines as Modulators of Serotonin Receptors: An Example Illustrating the Power of Bromine as Part of the Uniquely Marine Chemical Space

Ibrahim, Mohamed A., El-Alfy, Abir T., Ezel, Kelly, Radwan, Mohamed O., Shilabin, Abbas G., Kochanowska-Karamyan, Anna J., Abd-Alla, Howaida I., Otsuka, Masami, Hamann, Mark T. 01 August 2017 (has links)
In previous studies, we have isolated several marine indole alkaloids and evaluated them in the forced swim test (FST) and locomotor activity test, revealing their potential as antidepressant and sedative drug leads. Amongst the reported metabolites to display such activities was 5-bromo-N,N-dimethyltryptamine. Owing to the importance of the judicious introduction of halogens into drug candidates, we synthesized two series built on a 2-(1H-indol-3-yl)-N,N-dimethylethanamine scaffold with different halogen substitutions. The synthesized compounds were evaluated for their in vitro and in vivo antidepressant and sedative activities using the mouse forced swim and locomotor activity tests. Receptor binding studies of these compounds to serotonin (5-HT) receptors were conducted. Amongst the prepared compounds, 2-(1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (1a), 2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (1d), 2-(1H-indol-3-yl)-N,N -dimethylethanamine (2a), 2-(5-chloro-1H-indol-3-yl)-N, N-dimethylethanamine (2c), 2-(5-bromo-1H-indol-3-yl)-N,N-dimethylethanamine (2d), and 2-(5-iodo-1H-indol-3-yl)-N,N -dimethylethanamine (2e) have been shown to possess significant antidepressant-like action, while compounds 2c, 2d, and 2e exhibited potent sedative activity. Compounds 2a, 2c, 2d, and 2e showed nanomolar affinities to serotonin receptors 5-HT1A and 5-HT7. The in vitro data indicates that the antidepressant action exerted by these compounds in vivo is mediated, at least in part, via interaction with serotonin receptors. The data presented here shows the valuable role that bromine plays in providing novel chemical space and electrostatic interactions. Bromine is ubiquitous in the marine environment and a common element of marine natural products.
385

Multiple Binding Sites for [<sup>125</sup>I]RTI-121 and Other Cocaine Analogs in Rat Frontal Cerebral Cortex

Boja, J. W., Carroll, F. I., Vaughan, R. A., Kopajtic, T., Kuhar, M. J. 01 September 1998 (has links)
In an effort to identify novel binding sites for cocaine and its analogs, we carried out binding studies with the high-affinity and selective ligand [125I]RTI-121 in rat frontal cortical tissue. Very low densities of binding sites were found. Saturation analysis revealed that the binding was to both high- and low-affinity sites. Pharmacological competition studies were carried out with inhibitors of the dopamine, norepinephrine, and serotonin transporters. The various transporter inhibitors inhibited the. binding of 15 pM [125I]RTI-121 in a biphasic fashion following a two-site binding model. The resultant data were complex and did not suggest a simple association with any single transporter. Correlational analysis supported the following hypothesis: [125I] RTI-121 binds to known transporters and not to novel sites; these include dopamine, norepinephrine, and serotonin transporters. Immunoprecipitation of transporters photoaffinity labeled with [125]RTI-82 and subsequent analysis of SDS-page gels revealed the presence of authentic dopamine transporters in these samples; displacement of the photoaffinity label occurred with a typical dopamine transporter pharmacology. These data are compatible with the binding properties of RTI- 121 and the presence of several known transporters in the tissue studied.
386

Maternal Lead Exposure Produces Long-Term Enhancement of Dopaminergic Reactivity in Rat Offspring

Szczerbak, Graziyna, Nowak, Przemysław, Kostrzewa, Richard M., Brus, Ryszard 01 October 2007 (has links)
To determine the effect of prenatal lead exposure on brain monoaminergic systems, pregnant rats were given tap water containing 250 ppm lead acetate, for the duration of pregnancy, while tap water without lead (Pb2+) was substituted at birth. Control rats were derived from dams that consumed tap water during pregnancy, and had no exposure to lead afterwards. At 12 weeks after birth, Pb2+ content of brain cortex was increased 3- to 4-fold (P < 0.05). At this time the endogenous striatal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid were 19% lower in Pb2+ exposed rats (P < 0.05), while there was no change in the striatal level of dopamine (DA), noradrenaline, 3,4-dihydroxyphenylglycol, serotonin (5-HT) and 5-hydroxyindoleacetic acid (HPLC/ED). Also there was no change in these monoamines and metabolites in the prefrontal cortex of Pb 2+ exposed rats. However, turnover of 5-HT in prefrontal cortex, as indicated by 5-hydroxytryptophan accumulation 30 min after acute treatment with the decarboxylase inhibitor NSD-1015 (100 mg/kg IP), was lower in the Pb 2+ exposed rats. In the striatum AMPH-induced (1 mg/kg IP) turnover of DA, evidenced as L-DOPA accumulation after NSD-1015, was increased to a lesser extent in the Pb2+ exposed rats (P < 0.05). The nitric oxide synthase inhibitor 7-nitroindazole (10 mg/kg IP) attenuated the latter effect, indicating that neuronal NO mediates this AMPH effect, at least in part. Moreover, DA D2 receptor sensitivity developed in Pb2+ exposed rats, as evidenced by enhanced quinpirole-induced yawning activity and enhanced quinpirole-induced locomotor activity (each, P < 0.05). These findings indicate that ontogenetic exposure to lead can have consequences on monoaminergic neuronal function at an adult stage of life, generally promoting accentuated behavioral effects of direct and indirect monoaminergic agonists, and related to increased dopamine turnover in basal ganglia.
387

Zusammenhang zwischen der Serumkonzentration serotonerger Antidepressiva und der Blutgerinnung / Serum concentration of serotonergic antidepressants and blood coagulation: Is there a relationship?

Simoneit, Franziska January 2019 (has links) (PDF)
Das Verordnungsvolumen von Antidepressiva in Deutschland hat sich in den letzten zehn Jahren etwa verdoppelt. Gleichzeitig liegen zahlreiche Untersuchungen über erhöhte Blutungstendenzen unter der Therapie mit serotonergen Antidepressiva vor. Die aktuelle Studienlage deutet darauf hin, dass es unter anderem über das serotonerge System zu Beeinflussungen der Thrombozyteneigenschaften und in Folge dessen zu Veränderungen der Blutgerinnung kommen könnte. Ziel der vorliegenden Arbeit war es, den Zusammenhang zwischen der Serumkonzentration serotonerger Antidepressiva und der Blutgerinnung zu untersuchen. Im Gegensatz zur Dosis bietet die Serumkonzentration exakte Informationen über die tatsächlich wirkende Antidepressivamenge und berücksichtigt neben der Patientenadhärenz die interindividuelle Variabilität der pharmakokinetischen Eigenschaften. Die Beurteilung der Blutgerinnung erfolgte unter Zuhilfenahme von Gerinnungsparametern (Thrombozytenzahl, mittleres Plättchenvolumen, Quick, INR, partielle Thromboplastinzeit). Es wurde die Hypothese aufgestellt, dass mit steigender Serumkonzentration Veränderungen der Blutgerinnung und in Folge dessen auch der Gerinnungsparameter entstehen können. Darüber hinaus sollte untersucht werden unter welchen Antidepressiva potentielle Veränderungen auftreten. Es wurden Antidepressiva unterschiedlicher Wirkungsgruppen analysiert: Amitriptylin, Doxepin, Es‑Citalopram, Mirtazapin und Venlafaxin. Besonders selektive Serotonin-Wiederaufnahmehemmer standen auf Grund der aktuellen Studienlage im Verdacht Einfluss auf die Gerinnung zu nehmen. Um Antidepressiva spezifische Aussagen treffen zu können, war das Vorliegen einer antidepressiven Monotherapie grundlegendes Selektionskriterium. Alle potenziell gerinnungsbeeinflussenden sowie serotonerg wirkenden Arzneimittel wurden ausgeschlossen. Die Daten wurden retrospektiv erhoben und stammten von stationär therapierten Patienten der Klinik für Psychiatrie, Psychosomatik und Psychotherapie am Universitätsklinikum Würzburg. Die Untersuchungen ergaben für das trizyklische Antidepressivum Amitriptylin signifikante Ergebnisse. Die interindividuelle Analyse zeigte signifikant positive Korrelationen zwischen der partiellen Thromboplastinzeit (PTT) und dem Metabolitenspiegel (Nortriptylin‑Konzentration, rs=0,564; p=0,010, N=20) sowie dem Summenspiegel von Amitriptylin (Amitriptylin- und Nortriptylin‑Konzentration, rs=0,477; p=0,033, N=20). Darüber hinaus stellten sich im Rahmen der intraindividuellen Analyse signifikante Unterschiede zwischen der Thrombozytenzahl unter niedriger und hoher Amitriptylin‑Konzentration dar (Z= ‑2,867; p=0,004, N=45). Ergänzend wurde im Rahmen von explorativen Untersuchungen der Zusammenhang zwischen der verabreichten Dosis und der Serumkonzentration der Antidepressiva analysiert. Die Ergebnisse zeigten Schwankungen um den Faktor 3 bis 11, die im Vergleich zu anderen Studien geringer ausfielen. Der Verdacht, dass besonders selektive Serotonin-Wiederaufnahmehemmer einen erhöhten Einfluss auf die Gerinnungsparameter haben, wurde in der aktuellen Arbeit nicht bestätigt. Ebenso waren unter Doxepin, Mirtazapin und Venlafaxin keine Zusammenhänge zur Serumkonzentration zu beobachten. Die signifikanten Ergebnisse unter Amitriptylin lassen vermuten, dass nicht nur die Inhibition von Serotonintransportern, wie bei selektiven Serotonin-Wiederaufnahmehemmern, sondern zusätzlich auch die Hemmung von Serotoninrezeptoren, wie dem 5‑HT2A‑Rezeptor, eine Rolle im Hinblick auf Veränderungen von Thrombozyteneigenschaften spielen. Dennoch lagen im Rahmen dieser Untersuchung 98% der Gerinnungsparameter aller analysierten Antidepressiva im Normbereich. Die Ergebnisse legen die Vermutung nahe, dass das Risiko immer wieder berichteter Blutungskomplikationen unter der Behandlung mit Antidepressiva trotz zunehmender Verordnungszahlen überschaubar scheint. Entsprechend aktueller Publikationen ist vermutlich erst bei zusätzlicher Einnahme von nichtsteroidalen Antirheumatika sowie antikoagulativen Arzneimitteln von einem erhöhten Blutungsrisiko auszugehen. Besonders gastrointestinale Blutungen spielen bei Kombination dieser Medikamente auf Grund der gesteigerten Magensäuresekretion eine Rolle. Ob die Serumkonzentration der Antidepressiva bei entsprechender Komedikation ebenfalls eine Rolle im Hinblick auf Veränderungen der Gerinnungsparameter spielt, sollte im Rahmen weiterführender Längsschnittstudien genauer untersucht werden. Ergänzend wären Untersuchungen zur Klärung des Kausalzusammenhangs wünschenswert, um das Blutungsrisiko im Zusammenhang mit Antidepressiva in Zukunft weiter minimieren zu können. / Introduction: The prescription of antidepressants has increased worldwide in recent years. Treatment with serotonergic antidepressants has been associated with enhanced risk of bleeding. Correlations to serum concentrations of antidepressants have not been investigated in detail. Methods: Serum concentrations of amitriptyline (AMI), doxepin (DOX), escitalopram (ESC), mirtazapine (MIR) and venlafaxine (VEN) as well as coagulation parameters in 507 patients were retrospectively evaluated in the Department of Psychiatry, Psychosomatics and Psychotherapy at the University Hospital of Würzburg. The coagulation parameters assessed were: platelet count (PLC), mean platelet volume (MPV), prothrombin time (PT), international normalized ratio (INR) and partial thromboplastin time (PTT). The main inclusion criterion was an antidepressant monotherapy. Results: In interindividual analysis significant correlations were observed between PTT and NOR (p=0.010) as well as between PTT and AMI+NOR (p=0.033). Intraindividual analyses showed significant differences of PLC between low and high concentrations of AMI+NOR (p<0.01). For DOX, ESC, MIR and VEN, no statistical significances were found. Discussion: The majority of publications about changes in coagulation during antidepressant drug therapy only considers selective serotonin reuptake inhibitors (SSRI). Nevertheless, as AMI has serotonin transporter and receptor inhibiting properties, significant correlations with PTT and PLC were found. However, since coagulation parameters in all samples were within the normal range, a rather low increase of bleeding risk by antidepressant monotherapy is assumed. The results of our study support the assumption that the documented bleeding events of recent studies are mainly due to the combined use of antidepressants, non-steroidal anti-inflammatory drugs and platelet aggregation inhibitors.
388

Dissecting the Functional Heterogeneity of Serotonergic Systems That Regulate Fear and Panic

Setubal Bernabe, Cristian 10 1900 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Serotonin (5-HT) is heavily implicated in severe anxiety and trauma-related disor-ders, such as panic and post-traumatic stress disorders. Overall, site-specific pharmacolog-ical manipulations show that while 5-HT enhances anxiety-associated/avoidance behaviors in the amygdala, 5-HT inhibits panic-associated escape behaviors in the perifornical hypo-thalamus region (PeFR). Yet, our understanding of how specific serotonergic networks and co-transmitters regulate these conditions, but also other aspects of innate panic (e.g., car-dioexcitation or thermal response that occur during a flight or escape response) or condi-tioned fear behaviors is still elusive. Therefore, utilizing circuit-based gain- and loss-of-function approaches to selectively manipulate amygdala- and PeFR-projecting sero-tonergic systems, we hypothesize that specific serotonergic networks projecting to the amygdala and PeFR respectively enhance conditioned fear responses and attenuate innate panic-associated behaviors and physiological responses. There are two main chapters in this dissertation. In Chapter III, retrograde tracing revealed that the amygdala-projecting neurons from dorsal Raphe (DR) were almost exclusively serotonergic (92-95%) concen-trated in the dorsal/ventral (DRD/DRV) DR, with few non-serotonergic neurons. While selective lesioning of this network with saporin toxin (SAP) facilitated the extinction of conditioned fear behavior, selective optogenetic activation of amygdala-projecting DRD/DRV cell bodies using intersectional genetics reduced extinction of conditioned fear behavior and enhanced anxiety avoidance. In Chapter IV, retrograde tracing showed that the PeFR was innervated by equally selective serotonergic networks concentrated in the lateral wings DR (lwDR) and median Raphe (MR). Contrasting with the results from the amygdala-innervating 5-HT system, lesioning the PeFR-projecting serotonergic network from lwDR/MR was accompanied by reduced extinction of conditioned fear behavior, in-creased anxiety avoidance, and increased CO2-induced panic (elevated escape responses and enhanced cardioexcitation). Conversely, selective activation of lwDR/MR serotonergic terminals in the PeFR decreased anxiety-associated behaviors; inhibited CO2-induced panic, and induced unconditioned and conditioned place preferences. The circuit-based ap-proach data presented here show that amygdala- and PeFR-projecting 5-HT neurons com-prise distinct circuits underlying opposite roles enhancing anxiety/fear responses in the amygdala and dampening fear/panic responses in the PeFR. The identification of distinct circuits controlling anxiety, fear, and panic responses is a fundamental step towards the development of more effective therapies for psychiatric conditions such as anxiety and trauma-related disorders. / 2021-11-04
389

Studies on the analgesic effect of (+)-indeloxazine on neuropathic pain / (+)-Indeloxazineの神経障害性疼痛における鎮痛作用に関する研究

Murai, Nobuhito 25 November 2014 (has links)
京都大学 / 0048 / 新制・論文博士 / 博士(農学) / 乙第12876号 / 論農博第2803号 / 新制||農||1028(附属図書館) / 学位論文||H26||N4875(農学部図書室) / 31594 / (主査)教授 伏木 亨, 教授 保川 清, 教授 入江 一浩 / 学位規則第4条第2項該当 / Doctor of Agricultural Science / Kyoto University / DGAM
390

Psilocybin, ett förteckning I narkotikum med potentiellt medicinskt värde vid behandling av depressiva symtom?

Hansson, Max Daniel January 2021 (has links)
Depression is a potentially life-threatening disease that is one of the leading causes of disability in the world. In 2017, more than 300 million people suffered from depression. That equates to about 4.4% of the world's population, making it the world's second most common public health disease after cardiovascular disease. About 50% who are treated for depression develop unipolar treatment-resistant depression, a type of severe persistent depression in which conventional methods or drugs do not have effect.  Psilocybin is a tryptamine found in a variety of species of psychedelic mushrooms. Psilocybin is a prodrug that breaks down into the active substance psilocin which interacts with serotonin receptors and produces psychoactive effects. Psilocybin is classified as a schedule I drug in most of the world and is therefore not considered to have any medical value. Psilocybin has been researched intensively in recent years, mainly focusing on its potential antidepressant effect. Psilocybin's effects have been widely covered in English literature but hardly at all in Swedish literature. This bachelor thesis will hopefully fill that gap and encourage more research on the subject here in Sweden. The purpose of this bachelor thesis was to evaluate, based on published studies, whether psilocybin potentially can have an effective, safe, and long-lasting antidepressant effect on depressive symptoms. Six studies are presented, and the results indicate that that 20–30 mg of psilocybin together with psychological support in an optimal environment can potentially have a long-acting, safe, and effective antidepressant effect on adult people with moderate to severe unipolar depression. Based on these results, the drug classification of psilocybin should be questioned and investigated.

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