Recent research, that has been focused on recognition memory, has revealed that two processes contribute to recognition of previously encountered items: recollection and familiarity (Aggleton & Brown, 1999; Eichenbaum, 2006; Eichenbaum, Yonelinas, & Ranganath, 2007; Rugg & Yonelinas, 2003; Skinner & Fernandes, 2007; Squire, Stark, & Clark, 2004; Wixted, 2007a; Yonelinas, 2001a; Yonelinas, 2002). The findings of neural correlates of recollection and familiarity lead to the assumption that there are different brain regions activated in either process, but there are, to the best of my knowledge, no studies assessing how these brain regions are working together in a recollection or a familiarity network, respectively. Additionally, there are almost no studies to date, which directly searched for overlapping regions. Therefore, in study I of the current thesis, brain regions associated to both recognition processes are searched investigated. Additionally, a connectivity analysis will search for functional correlated brain activations that either build a recollection or a familiarity network. It is undoubtable that the Brain Derived Neurotrophic Factor (BDNF) is strongly involved in synaptic plasticity in the hippocampus (Bramham & Messaoudi, 2005) and there is evidence that a genetic variant of this neurotrophin (BDNF 66Met) is related to poorer memory performance (Egan, et al., 2003). Therefore, in study II of the current thesis, the effect of BDNF Val66Met on recollection and familiarity performance and related brain activations is investigated. Finally, one could summarize, that serotonin, like BDNF, is strongly involved in brain development and plasticity as well as in learning and memory processes (Vizi, 2008). More precisely, there is evidence for alterations in the structure of brain regions, which are known to be involved in emotional memory formation and retrieval, like amygdala and hippocampus (Frodl, et al., 2008; Munafo, Brown, & Hariri, 2008; Pezawas, et al., 2005). One study found an slight epistatic effect of BDNF and 5-HTTLPR on the grey matter volume of the amygdala (Pezawas, et al., 2008). Therefore, in study III, it is investigated if such an interaction effect could be substantiated for the amygdala and additionally revealed for the hippocampus. The results of the current thesis allow further comprehension of recollection, hence episodic memory, and point to a special role of the BDNF in temporal and prefrontal brain regions. Additionally, the finding of an epistatic effect between BDNF and serotonin transporter function point to the need of analyzing interactions between genes and also between genes and environmental factors which reveals more information than the study of main effects alone. In conclusion, analyzing behavioral and neural correlates of episodic memory reveal allowed insights in brain functions that may serve as guideline for future studies in clinical populations with memory deficits, including susceptibility factors such as good or bad environment, as well as promising gene variants that influence episodic memory.

The objective was to examine duloxetine 60–120mg/day treatment for relapse prevention in adults with generalized anxiety disorder (GAD). Adult patients (N=887; mean age=43.3 years; 61.0% female) with DSM-IV-TR-defined GAD diagnosis were treated with duloxetine for 26 weeks. Patients who completed open-label phase and were treatment responders (≥50% reduction in Hamilton Anxiety Rating Scale total score to ≤11 and “much”/“very much improved” ratings for the last 2 visits of open-label phase) were randomly assigned to receive duloxetine or placebo for a 26-week double-blind continuation phase. Relapse was defined as ≥2-point increase in illness severity ratings or by discontinuation due to lack of efficacy. During the double-blind phase, placebo-treated patients (N=201) relapsed more frequently (41.8%) than duloxetine-treated patients (13.7%, N=204, P≤0.001) and worsened on each outcome measure (P≤0.001, all comparisons). Duloxetine 60–120 mg/day treatment was efficacious and reduced risk of relapse in patients with GAD.

The deleterious effects of MPO make it a new target for medicinal research. The aim of our study is to find promising inhibitors of MPO for using them as starting point of new anti-inflammatory drugs. Depending on previous researches on MPO inhibitors, we selected 5-fluorotryptamine as starting compounds. Using docking experiments, we designed a series of compounds derived from 5-fluorotryptamine. Two modifications were proposed: <p>& / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

This thesis aims to investigate fluoxetine, a widely prescribed SSRI antidepressant, for its role in the pathogenesis of NAFLD and uncover novel mechanisms by which it may contribute to drug-induced steatosis. We demonstrated that increased hepatic lipid accumulation was mediated, in part, via elevated serotonin production. The inhibition of hepatic serotonin synthesis prevented lipid accumulation in fluoxetine-treated hepatocytes demonstrating a causal role for serotonin in fluoxetine-induced hepatic steatosis. Interestingly, in several studies, serotonin signaling has been shown to impact prostaglandin biosynthesis. As prostaglandins have been implicated in the development of NAFLD, and fluoxetine has previously been shown to alter the production of prostaglandins I assessed the role of prostaglandins in fluoxetine-induced hepatic lipid accumulation. Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes, increased production of prostaglandin 15-deoxy-Δ12,14PGJ2 (PPARG agonist), and elevated PPARG targets involved in fatty acid uptake. Fluoxetine-induced lipid accumulation, 15-deoxy-Δ12,14PGJ2 production, and the expression of PPARG lipogenic genes were attenuated with a PTGS1 specific inhibitor. Taken together these findings suggested that fluoxetine-induced lipid accumulation was mediated via PTGS1 and its downstream product 15-deoxy-Δ12,14PGJ2. Given that Pparg was elevated following fluoxetine treatment, and PPARG regulates microRNA involved in hepatic lipid accumulation, my final project focused on PPARG’s role in altered miRNA expression. Indeed, fluoxetine treatment increased the miRNA expression of miR-122, an effect that was attenuated when fluoxetine treatment was combined with the PPARG antagonist GW9662, suggesting a fluoxetine-PPARG-miR122 axis contributing to hepatic steatosis. While these studies have only been performed in vitro, an understanding of the molecular changes associated with SSRI treatment may lead to the development of strategies to prevent the increased risk of adverse metabolic outcomes associated with the use of SSRI antidepressants. / Dissertation / Doctor of Philosophy (Medical Science) / In adults, major depressive disorder (depression) is one of the most common psychiatric illnesses. Recent data suggests that there are more than 4.1 million Canadians who currently suffer from depression. Depression is commonly treated using selective serotonin reuptake inhibitor (SSRI) antidepressants. While these antidepressants do help manage depressive symptoms, they can also cause unwanted side effects including a build-up of fat in the liver, leading to fatty liver disease. The goal of my research is to understand the link between SSRI use and the development of fatty liver disease. This thesis investigates the effects of fluoxetine (Prozac®), a commonly used SSRI antidepressant, on molecular pathways that can lead to the development of fatty liver disease. An understanding of the molecular changes with SSRI treatment may lead to the development of strategies to prevent the harmful effects of SSRI antidepressants on the liver.

Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [11C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [11C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m2) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes.

Fragestellung: Ein neues Modell der kortikalen Kontusion (Controlled Cortical Impact Injury, CCII) soll in der vorliegenden Arbeit für den Einsatz von Therapiestudien evaluiert werden. Material und Methoden: Bei 89 Sprague Dawley Ratten wurden eine links parieto-temporale Kontusion appliziert. 23 Stunden nach Trauma erfolgte eine neurologische Untersuchung. Die Gehirne wurden 24 Stunden nach Trauma entnommen. Das posttraumatische Hirnödem wurde gravimetrisch anhand des Wassergehalts und der Hemisphärenschwellung bestimmt. Das Kontusionsvolumen wurde mittels TTC-Färbung planimetrisch gemessen. Die Extravasation von Evans blue wurde spektralfotometrisch quantifiziert. Die histologische Charakterisierung erfolgte anhand der Hämatoxylin/Eosin-Färbung, Bielschowsky-Färbung und Evans blue Fluoreszenzmikroskopie. In einer repräsentativen Therapiestudie mit einem 5-Hydroxytryptamin1A-Agonisten (Bay X 3702) wurden 24 Stunden nach Trauma vergleichend das Kontusionsvolumen, der Wassergehalt und die Hemisphärenschwellung bestimmt. Ergebnisse: Neurologisch zeigten sich Einschränkungen in der Spontanaktivität und der Balancierfähigkeit nach Trauma. Der posttraumatische Wassergehalt war in der traumatisierten Hemisphäre (82,5 ± 0,12%) gegenüber der Kontralateralen (79,98 ± 0,07%) signifikant erhöht. Die posttraumatische Hemisphärenschwellung lag bei 14,3 ± 1,2%. In der traumatisierten Hemisphäre zeigte sich eine signifikant höhere Evans blue Extravasation (47,28 ± 11,8 ng/mg TG). Das Kontusionsvolumen wurde mit 58,9 ± 9,1 cmm bestimmt. Histologisch zeigte sich eine kortikale hämorrhagische Nekrose. Der axonalen Schaden war auf das perikontusionelle Gewebe beschränkt. Evans blue zeigte sich perikontusionell im Intra- und Extrazellulärraum. In der Therapiestudie mit Bay X 3702 zeigten der Wassergehalt und die Hemisphärenschwellung keine signifikanten Unterschiede in den Versuchsgruppen. Im Gegensatz zu neuroprotektiven Eigenschaften in Modellen der zerebralen Ischämie war das Kontusionsvolumen nach Bay X 3702 Gabe mit 126 ± 21,8 cmm signifikant größer als in der Plazebo-Gruppe (58.6 ± 7.5 cmm). Es wurde eine signifikante Abnahme des arteriellen Blutdrucks bis 30 Minuten nach Injektion der Substanz gemessen. Die Abnahme des mittleren Blutdrucks und die Zunahme des Kontusionsvolumens korrelierte signifikant. Schlußfolgerung: Das CCII imitiert wichtige Aspekte des menschlichen Schädel-Hirn-Traumas. Der posttraumatische Schaden ist reproduzierbar und quantifizierbar. Trotz fehlendem Nachweis eines neuroprotektiven Effekts in der durchgeführten Therapiestudie konnte gezeigt werden, daß das CCII als Modell der fokalen Kontusion für Therapiestudien geeignet ist. / Objective: A new model of focal contusion (Controlled Cortical Impact Injury, CCII) should be evaluated to proof potential neuroprotective drug effects on posttraumatic alterations. Materials and Methods: In 86 Sprague Dawley rats a left temporo-parietal contusion was applied. 23 h following CCII rats were examined neurologically. In all animals brains were removed 24 hours after contusion. Posttraumatic hemispheric swelling and water content were determined gravimetrically. Using the triphenyltetrazoliumchloride (TTC) staining contusion volume was measured planimetrically. Extravasation of Evans blue was quantified sepctrophotometrically. For histological characterization hematoxylin/eosin staining, Bielschowsky staining and Evans blue fluorescence microscopy was used. In a representative study the potential neuroprotective effect of a 5-hydrxoytryptamine1A receptor agonist (Bay X 3702) on contusion volume and brain edema following CCII was determined. Results: Neurological examination showed deficits in motility and beam balance task, respectively. Posttraumatic hemispheric water content increased significantly after contusion (82.5 ± 0.12%) versus contralateral hemisphere (79.8 ± 0.08%). Posttraumatic swelling was 14.3 ± 1.2%. Spectrophotometrically, concentration of extravasated Evans Blue was 47.3 ± 11.8 ng/mg dry weight. Contusion volume was 58.9 ± 9.1 cmm. Histologically, a hemorrhagic necrosis was observed following CCII. Axonal injury was found in pericontusional area, only. Evans Blue was detected pericontsionally in the ipsilateral extra- and intracellular space. Bay X 3702 had no significant effect on posttraumatic hemispheric swelling and water content. In contrast to neuroprotective effect, shown following focal and global ischemia Bay X 3702 administration resulted in significant increase of contusion volume to 126 ± 21.8 cmm, versus placebo group (58.6 ± 7.5 cmm) following CCII. MABP showed significant decreased values after injection of Bay X 3702 up to 30 Minutes following trauma. A significant correlation could be shown between decrease of MABP and increase of contusion volume. Conclusion: The Controlled Cortical Impact Injury represents important aspects of human focal traumatic brain injury. The posttraumatic lesion is reproduceable and quantifiable. Although a neuroprotective effect of the 5-hydroxytryptamine1A agonist could not be verified, effects of potential neuroprotective agents can accurately be proved in this model.

An mit Urethan narkotisierten männlichen "Wistar"-Ratten erfolgte die extrazelluläre Einzelableitung der Aktionspotenziale von insgesamt 159 striatalen Neuronen. Mit Hilfe einer Mehrkanalelektrode wurden in die Nähe der Zellen mikroiontophoretisch verschiedene Substanzen appliziert. Die separate Gabe von Serotonin (5-HT), dem 5-HT1A-Rezeptoragonisten 8-OH-DPAT und dem sulfatierten Oktapeptid Cholezystokinin (CCK-8S) führte überwiegend zur Erhöhung der neuronalen Entladungsraten (Wilcoxon-Test signifikant mit p < 0,05), wohingegen der 5-HT2A/2C-Rezeptoragonist DOI nur an wenigen Neuronen einen Effekt induzierte, der hauptsächlich aus einer Reduktion der Entladungsraten bestand. Nach Koapplikation von Serotonin und CCK-8S überwogen ebenfalls aktivierende Effekte (Wt p < 0,05), jedoch wurde die neuronale Responsivität im Vergleich zur Einzelapplikation der beiden Substanzen signifikant reduziert (Chi2 p< 0,01). Da die Serotonin- bzw. 8-OH-DPAT-induzierten Effekte durch die spezifischen 5-HT1A-Rezeptorantagonisten WAY 100635 und S-UH 301 geblockt wurden und eine positive Korrelation der Serotonin- bzw. 8-OH-DPAT-Effekte (p < 0,05) nachgewiesen werden konnte, kann, trotz der entgegengesetzten Ergebnisse früherer Studien, das Vorhandensein von 5-HT1A-Rezeptoren im Neostriatum angenommen werden. Die Grundaktivität der durch Serotonin aktivierten Population war signifikant geringer (p > 0,05) als die der durch Serotonin gehemmten Neurone. Trotzdem zeigte sich keine Abhängigkeit der Responsivität der hier betrachteten Populationen auf die applizierten Serotoninagonisten von der Höhe der neuronalen Ruheentladungsrate. Die meisten der Serotonin-, 8-OH-DPAT-, DOI- bzw. CCK-8S-responsiven Neurone verteilten sich diffus über das gesamte Neostriatum. Nur die durch Serotonin aktivierte Population zeigte eine Präferenz der ventromedialen Bereiche des Neostriatum. Zusammenfassend kann gesagt werden, dass aufgrund der Ergebnisse der vorliegenden Studie die Existenz von 5-HT1A-Rezeptoren innerhalb des Neostriatum der Ratte in hohem Maße angenommen werden kann. Des Weiteren lässt sich vermuten, dass das Zusammenwirken von Serotonin und CCK-8S einen modulatorischen Einfluss auf die normale neuronale Funktion hat. Ob und in welchem Maße dieses letztgenannte Ergebnis eine therapeutische Relevanz zur Behandlung bestimmter Erkrankungen hat, bei denen Störungen im Neostriatum mit ursächlich sind, bleibt zu erforschen. / In rats anaesthetized with urethane single unit activity of 159 neostriatal neurones was extracellularly recorded and several drugs were microiontophoretically ejected. Separate administration of serotonin (5-HT), 8-OH-DPAT (a 5-HT1A/7-receptor-agonist) and the sulfated octapeptide cholecystokinin (CCK-8S) predominantly induced increases in the neuronal discharge rates (Wilcoxon test significant with p < 0,05), whereas the 5-HT2A/2C-receptor agonist DOI affected only a few neurones and mainly reduced firing. After coadministration of CCK-8S and serotonin activating effects also predominated (Wt p < 0,05), but the neuronal responsiveness was significantly reduced (Chi2 p

Der Hippokampus spielt eine wichtige Rolle bei der Erfassung, Festigung und dem Wiederabrufen von Gedächtnisinhalten. Diese Prozesse werden von Oszillationen begleitet, die synchronisierte neuronale Aktivität wiederspiegeln. Der erste Teil dieser Arbeit konzentriert sich auf ‘ripples’, eine schnell schwingende Netzwerkaktivität, die an der Festigung von Gedächtnisinhalten beteiligt ist. Das Subikulum ist eine der Hauptausgangsstationen des Hippokampus und überträgt Informationen zu Zielregionen außerhalb dieser Region. Um dies besser zu verstehen, habe ich hier die Eigenschaften von subikulären Pyramidenzellen und deren Regulierung während ripples untersucht. Es zeigte sich, dass eine Untergruppe von Zellen, burst (in Salven) feuernde Zellen, ihre Aktivität erhöht, während eine zweite Untergruppe, regulär feuerende Zellen, ihre Aktivitaet während ripples vermindert. Ferner ist bei regulär feuernden Zellen das Verhältnis zwischen Inhibition und Exzitation höher als bei burst feuernden Zellen. Zusammen mit Erkenntnissen aus früheren Studien lassen diese Ergebnisse vermuten, dass Information während ripples hauptsächlich zu Zielregionen der burst feuernden Zellen geleitet wird. Neben Pyramidenzellen beherbergt der Hippokampus auch eine Vielzahl verschiedener Interneurone. Im zweiten Teil dieser Arbeit habe ich O-LM Interneurone der hippokampalen Region CA1 untersucht. Diese spielen eine wichtige Rolle bei der Kontrolle von Eingängen aus dem entorhinalen Kortex. Wir konnten zeigen, dass die exzitatorische Übertragung auf O-LM Interneurone durch Serotonin, einem von den Raphe-Kernen ausgeschütteten Neuromodulator, vermindert wird. Dies geschieht durch einen präsynaptischen Mechanismus, der wahrscheinlich eine Verminderung des Kalziumeinstroms in präsynaptische Endigungen umfasst. Eine Verminderung der Aktivität von O-LM Interneuronen durch Serotonin könnte die synaptische Übertragung von Signalen aus dem entorhinalen Kortex auf CA1 Pyramidenzelldendriten erleichtern. / The hippocampus plays an important role in the acquisition, consolidation and retrieval of memory. These processes are accompanied by hippocampal oscillations, which reflect synchronized neuronal activity. The first part of this thesis focuses on ripples, a fast oscillatory activity which is involved in memory consolidation. The subiculum as one of the main output areas of the hippocampus is ideally suited to mediate information transfer to extrahippocampal targets. Here I investigated the properties of subicular pyramidal cells and their modulation during ripples. I found that a subset of subicular pyramidal cells increases its firing rate during ripples whereas another subset decreases its firing rate. Furthermore I was able to identify a correlate between modulation and cell subtype: burst firing cells increased their firing rate, and regular firing cells decreased their firing rate. We could further show that regular firing cells receive a higher ratio of inhibition to excitation as compared to burst firing cells. Together with earlier work, these results suggest that information transferred during ripples is likely to be routed preferentially to target regions of the burst firing subtype. Besides pyramidal cells, the hippocampus hosts a variety of interneuron types. The second part of this thesis focuses on GABAergic O-LM interneurons of hippocampal area CA1, which play an important role in controlling input from the entorhinal cortex. We could show that excitatory transmission from local pyramidal cells onto O-LM interneurons is decreased by serotonin, a neuromodulator released from the midbrain raphe nuclei. This modulation is mediated by a presynaptic mechanism and is likely to involve a decrease in calcium influx into presynaptic terminals. We conclude that serotonin, by decreasing O-LM output, might release fibers from entorhinal cortex impinging onto CA1 pyramidal cell dendrites from inhibition.

Master of Science / Department of Psychological Sciences / Mary Cain / Individuals suffering from depression primarily rely on pharmacological interventions to alleviate the incapacitating symptoms of the disorder. In addition to genetic differences underlying the etiology of depression, environmental factors play a key role as well. For example, environmental enrichment results in various neurotransmitter alterations, significantly affecting serotonin. To test the efficacy of novel antidepressant drugs in the preclinical laboratory setting, researchers commonly implement the forced swim test (FST) for rats or mice. However, the effect of environmental enrichment on the expression of depressive-like states in the FST is unclear, and it is unknown whether environmental enrichment or social isolation can alter the efficacy of the commonly prescribed antidepressant drug, fluoxetine. In the present study, locomotor activity and FST performance were measured after 30 days of rearing in enriched (EC), standard (SC), and isolated (IC) conditions. Results showed that regardless of the significant effect of fluoxetine on locomotor activity in EC, SC, and IC rats, fluoxetine failed to increase swimming and decrease immobility in all three environmental conditions, with enriched-fluoxetine rats displaying significantly less swimming behavior in the FST than enriched rats receiving vehicle control injections. These results suggest that differential rearing, specifically environmental enrichment, can alter the efficacy of antidepressants and may suggest that enrichment reverses the effects of fluoxetine.

The amphetamine derivative, 3,4-methylenedioxymethamphetamine (MDMA), is a popular drug often taken by young adults at dance clubs or rave parties. Laser light shows, fast-paced electronic music, and hot crowded dance floors are characteristic of these events, and Ecstasy users report that the acute effects of the drug are potentiated by these stimulatory conditions. However, it remains largely unknown how environmental stimuli impact the neurochemical and physiological effects of MDMA. The aim of the first study presented in this dissertation was to investigate how auditory stimuli (music, white noise, and no additional sound) influence MDMA conditioned place preference (CPP), self-administration, and nucleus accumbens (NAcc) dopamine (DA) and serotonin (5-HT) responses. Findings revealed a significant CPP for animals exposed to white noise during MDMA conditioning trials. After self-administration of MDMA (1.5 mg/kg), NAcc DA and 5-HT were highest in rats exposed to music during the test session. The second study aimed to investigate the effects of ambient temperature (23°or 32°C) on long-term MDMA self-administration and neurochemical responses. Results indicated no difference in self-administration or locomotor activity rates for the high versus room temperature groups across sessions. However, MDMA (3.0 mg/kg) administered in high ambient temperature resulted in significantly greater NAcc serotonin release compared to when taken at room temperature, but no differences in dopamine response was determined between the two conditions. Overall, these results indicate that auditory and thermal stimuli can effect MDMA-induced behavioral and neurochemical responses. The last aim tested a novel apparatus and method for use in animal models of drug reinforcement. By combining traditional CPP and self-administration procedures, this approach provided more informative data and circumvented some inherent drawbacks of each method alone. In addition to confirming the ability to produce drug conditioned place preferences after short- and long-term experiments, the long-term version of the procedure revealed a significant positive relationship between lever response rate and CPP magnitude. Therefore, this experimental design can be used to identify subgroups of rats that may vary in sensitivity to drug motivational effects. Further study of these populations may be useful in the development of behavioral and pharmacological therapies for drug addiction. / text