Thesis (Ph. D.)--University of Wisconsin--Madison, 1961. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 47-51).

Thesis (M.A.)--University of Wisconsin--Madison, 1968. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand in fulfilment of the requirements for the degree of Master of Science. University of the Witwatersrand, Johannesburg, March 2016 / A liquid phase microextraction based on single hollow fibre followed by liquid chromatographic determination was developed for the extraction and quantification of the hallucinogenic muscimol and its two precursors, tryptophan and tryptamine from urine samples. A multivariate design of experiment was used in which a half fractional factorial approach was applied to screen six potential factors (donor phase pH, acceptor phase concentration, supported liquid membrane composition, stirring rate, extraction time and salt content) for their extent of vitality on the extraction of muscimol, tryptophan and tryptamine using the developed method. Four factors were identified as essential for an enhanced enrichment of each of the three research analytes from diluted urine samples. The paired vital factors were then optimized using central composite designs where empirical quadratic response models were used to visualize the response surface through contour plots, surface plots and optimization plots of response output. When the muscimol-based optimum factor levels were applied for the simultaneous extraction of the three research analytes, a composite desirability of 0.687 was obtained implying that the set conditions were ideal for a combined extraction of the analytes from the donor phase into the acceptor phase across a supported liquid membrane impregnated with a carrier molecule. This was an acceptable result considering that only the optimized muscimol factor levels were set as universal factor values. Muscimol was the analyte of interest in this research. The composite desirability value was predicted by setting the extraction conditions to 20% (w/w) di-(2-ethylhexyl) phosphoric acid (DEHPA) in dihexyl ether (DHE) supported on the walls of a hollow fibre into a 200 mM HCl acceptor phase inside the hollow fibre from a 20% (v/v) diluted urine donor phase spiked in the 0.1 – 10 μg mL-1 analyte concentration range maintained at pH 4 and stirred at 800 rpm for 60 mins. Experimentally, average enrichments of 4.1, 19.7 and 24.1 were obtained for muscimol, tryptophan and tryptamine, respectively. iv The complexity of urine and the anionic nature of the carrier molecule embedded on the supported liquid membrane resulted in interfering peaks that could not be completely resolved from the analyte peaks. Thus matrix-based calibration curves were used to address matrix effects. Various statistical approaches were used to validate suitability of the developed method for its potential use in quantifying muscimol and its precursors from urine samples. These validation measures were used as a way of determining the method’s ability to maintain the extraction process at equilibrium over a specific range of analyte concentrations over a period of analyte existence in a urine sample. The r² values of the matrix-based linear regression prediction models ranged from 0.9933 to 0.9986. The linearity of the regression line of the matrixbased calibration for each analyte was directly linked to the analyte enrichment repeatability. Simultaneous analyte enrichment repeatability over a 0.1 – 10 μg mL-1 analyte spiking concentration ranged from an RSD value of 8.3% to 13.1%. Limits of detection were 0.021 μg mLˉ¹, 0.061 μg mL-1 and 0.005 μg mL-1 for muscimol, tryptophan and tryptamine, respectively. Other validation parameters that were considered included specificity (and selectivity), accuracy, robustness, extraction range and system suitability. The accuracy of the developed method was reported as the reproducibility of enrichment factor values over six spiking concentrations used in constructing matrix-based calibration curves. System suitability was limited to an HPLC-UV approach. Method suitability was addressed through a comparative summary in which the LOD, LOQ and r² values for the developed method were compared to other methods that have been used to extract muscimol from urine samples. The relevance or acceptability of the enrichment factor values obtained for the extraction of the three analytes was achieved by comparison with enrichment factor values of several compounds with similar polarity that have been extracted from urine samples using carrier-mediated hollow fibre liquid phase microextraction. / GR2016

No description available.

No description available.

Thesis (Ph.D.)--Ohio University, November, 2008. / Abstract only has been uploaded to OhioLINK. Includes bibliographical references (leaves [256]-287)

Thesis (M.A.)--Humboldt State University, 2008. / Includes bibliographical references (leaves 90-92). Also available via Humboldt Digital Scholar.

Thesis (Ph.D.)--McMaster University, 2005. / Supervisor: David Wright. Includes bibliographical references (leaves 272-306). Also available online.

In this study, I investigate how serotonergic modulation of the medial prefrontal cortex (mPFC) affects neuronal activity and impacts cognitive flexibility, anxiety, and fear extinction (Figure 1). I begin in Chapter 1 with general information on the PFC with a focus on the mPFC, then discuss the role and complexity of serotonin and how manipulation of serotonin affects behavior. I, finally, introduce what is understood about how serotonin modulates the mPFC, the significance of which has implications for cognitive and emotional behaviors. In Chapter 2, I studied the role of serotonin in cognitive flexibility. Specifically, I used retrograde tracing to determine the origin of mPFC and assessed how terminal release of 5-HT affects mPFC pyramidal neuron activity using whole-cell electrophysiology in acute brain slices. Furthermore, through in vivo fiber photometry, I evaluated the activity of 5-HTergic neurons projecting to the mPFC during cognitive flexibility behavior. Lastly, by selectively increasing or decreasing mPFC 5-HTergic terminal release through in vivo optogenetics, I assessed the modulatory role of 5-HTergic input into the mPFC on intradimensional rule reversal and extradimensional rule shift performance in the cognitive flexibility task. Furthermore, I evaluated the activity of 5-HTergic neurons projecting to the mPFC during an open field task using in vivo fiber photometry and, in Chapter 3, used in vivo optogenetics to determine the role 5-HT in the mPFC plays in modulating fear-related behavior. In Chapter 4, I examined a pharmacological screen of a psychedelic drug in the cognitive flexibility task outlined in Chapter 2. I conclude in Chapter 5 with a discussion of the study implications and future directions.

Serotonin 2A receptor (5-HT2aR) agonists and κ-opioid receptor (KOR) agonists have been demonstrated to be effective treatments for several central nervous system (CNS) disorders including depression, anxiety, addiction, and pain. In a recent clinical study, psilocybin (a classical hallucinogen) was shown to significantly decrease the symptoms of Major Depressive Disorder (MDD) and Treatment Resistance Depression (TRD) in humans for up to six weeks after a single dose. Several KOR agonists have been shown to be effective treatments of chronic pain without the physical dependence risks of µ-opioid receptor agonists. Also, due to KOR’s involvement in a biological anti-reward system, agonists for this receptor possess anti-addiction properties as demonstrated by their ability to decrease the self-administration of drugs of abuse in multiple different animal species. Despite the great therapeutic potential for both these classes of molecules, their hallucinogenic and disassociate effects have been a major roadblock in the approval new pharmaceuticals.This dissertation describes the synthesis and behavioral evaluation of known and novel 5-HT2aR and KOR agonists. In the first half, the synthesis of several molecules related to the structure of ibogaine are described and the novel “oxa-iboga” class is introduced. One of the molecules in this class, oxa-noribogaine, has been evaluated in a variety of in vivo mouse tests including tail-flick, open field, and forced swim test. The results demonstrate that oxa-noribogaine is a potent KOR agonist and analgesic but has a lower side-effect profile compared to other KOR agonists such as noribogaine, epi-oxa-noribogaine, and U50,488H. In the second half, two emerging classes of antidepressants, NMDAR antagonists and 5-HT2aR agonists, are described. Molecules from both these classes cause rapid acting antidepressant effects that can be induced after a single dose. This is a sharp contrast to traditional antidepressants such as SSRIs which require 4-6 weeks of consistent use before therapeutic effects are achieved. In our lab, a set of substituted phenethylamines which act as 5-HT2aR agonists were evaluated in vivo in the head twitch assay, forced swim test, sucrose preference test, and fear extinction assays. Their hallucinogenic and antidepressant-like effects are reported. One molecule, 4-CT, was designed and synthesized based on the structure of Ariadne, a 5-HT2aR agonist with low or no psychedelics effects. 4-CT produced a decreased number of head twitches compared to DOI (a hallucinogenic research control) and showed possible antidepressant-like effects in the forced swim test.