Dissertations / Theses: 'Neurochemistry'

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Pearson, Sally Jane. "The neurochemistry of Huntington's disease." Thesis, University of Nottingham, 1992. http://eprints.nottingham.ac.uk/28467/.

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This thesis describes the study of the neurochemistry of Huntington's disease using a large series of post mortem brain tissue taken from patients with Huntington's disease and from matching controls with no previous history of neuropsychiatric disorder. There were two main aims: firstly, to identify and characterise any altered parameters of neurotransmitter systems, especially in relation to the symptomatology of the disease; secondly, to understand the role of neurotoxins in the aetiology of the disease, particularly endogenous compounds that may have derived from aberrant metabolism. Concentrations of the amino acid transmitters, GABA and glutamate, were generally significantly decreased throughout the brain in Huntington's disease, including cortical and limbic regions. Cortical deficits were not associated with the dementia of the disease, whereas caudate levels of GABA and glutamate showed a relationship with the dementia. In patients with severe chorea, the medial pallidum was found to have a relatively smaller GABA deficit than mildly choreic patients. Another novel finding was that 5HT and 5HIAA concentrations were significantly increased in most regions of the brain in Huntington's disease, perhaps reflecting abnormal tryptophan metabolism. Such changes in the cortex provide evidence for a cortical involvement in the disease. Dopamine metabolism appeared to be reduced in Huntington's disease, reflected by the significantly decreased concentrations of its major metabolite, homovanillic acid, in most regions except for the cortex (where it was increased). Neuroactive compounds of the kynurenine pathway of tryptophan metabolism were measured in Huntington's disease. Quinolinic acid concentrations were not significantly altered, however 3- hydroxykynurenine concentrations were significantly increased in the striatum and cortex. This provides the first evidence for increased concentrations of an endogenous neurotoxic compound in the brain in Huntington's disease.

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Hadjihambi, Anna. "Neurochemistry of the hepatic encephalopathy." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10038691/.

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The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and the role of ammonia remains controversial. Experimental studies conducted in animal (rat) models of HE, in combination with pharmacological approaches, were used to test the hypothesis that during HE, chronic exposure to elevated ammonia concentrations alters cerebral oxygenation, compromises lactate transport between astrocytes and neurons, and impairs uptake of neurotransmitters. It was also hypothesised that HE impairs glymphatic clearance mechanisms, either as a cause or a consequence of the disease, which exacerbates the detrimental central nervous effects of the accumulated toxins. The results of the experiments described in this thesis suggest that in HE: a) ammonia compromises cerebral oxygenation, but does not affect cerebrovascular reactivity, b) ammonia mediates cortical hemichannel dysfunction and impairs channel-mediated lactate release, potentially interfering with the astrocyte-neuron lactate shuttle, c) hyperammonemia results in a significant increase in cortical extracellular glutamate concentration, which is exacerbated under hypoxic conditions, and d) efficacy of glymphatic clearance is affected in discrete regions of the brain, which aligns with specific cognitive/behavioral impairments. These findings provide the first evidence of a critical pathophysiological role of ammonia in inducing neuronal energy deficit in HE due to impaired cerebral oxygenation, compromised hemichannel-mediated lactate transport between astrocytes and neurons and affected glymphatic clearance.

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Myint, Aye Mu. "Neurochemistry immune systems interaction in depressions." Maastricht : Maastricht : Universitaire Pers Maastricht ; University Library, Universiteit Maastricht [host], 2007. http://arno.unimaas.nl/show.cgi?fid=6834.

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4

Warren, Naomi M. "The cholinergic neurochemistry of progressive supranuclear palsy." Thesis, University of Newcastle upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432505.

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McAfee, Ghia. "Smoking and brain dopaminergic neurochemistry / Ghia McAfee." Thesis, North-West University, 2004. http://hdl.handle.net/10394/590.

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Tobacco use is not only a major health concern worldwide but also a grotesque economic burden on the smoker as well as the health care system. The most well-known and most researched constituent of tobacco products is nicotine. There are a variety of products on the market that ensure nicotine intake, including cigarettes, cigars, pipe tobacco and smokeless tobacco. Once absorbed by the body, nicotine undergoes phase I metabolism by cytochrome P450 (CYP) 2A6 (humans) or CYP2B1 (rat) to cotinine, the major metabolite. Since nicotine is a blood flow marker, its transport across the blood-brain barrier (BBB) has been well documented. However, data on the BBB penetration of nicotine and cotinine in animals subject to chronic nicotine exposure are limited. This gap in literature was identified and subsequently the focus of our first objective. Our data indicate that neither nicotine or cotinine uptake by the BBB is altered after chronic nicotine exposure in rat. Nicotine exerts its effect by binding to nicotinic cholinergic receptors (nAChRs) on dopaminergic neurons in the striatum and the ventral tegmental area (VTA). The addictive property of nicotine is attributed to its effects on the mesocorticolimbic system, which serves a fundamental role in the acquisition of behaviours. Smoking not only plays a role in addiction but also in Parkinson's disease (PD), where epidemiological studies have shown that smokers have a lower incidence of PD as opposed to non-smokers. Dopamine (DA) is one of the major neurotransmitters that plays a critical role in addiction and PD. Centrally, the biosynthesis of DA occurs intraneuronally through the ratelimiting enzyme, tyrosine hydroxylase (TH). DA undergoes metabolism by monoamine oxidase (MAO) intraneuronally. DA, that is not metabolized by MAO, is subsequently transported into the storage vesicles. After stimulation of nAChRs, DA is released into the synaptic cleft after membrane depolarization. Released DA stimulates post-synaptic dopaminergic receptors, is metabolized by catecholamine-0-methyl-transferase or transporter back into the pre-synaptic neuron by DA transporter (DAT). Little is known about the effects of whole cigarette smoke on the dopaminergic system. Therefore, our second objective of this study was to determine the effect of whole cigarette smoke extract (nicotine-containing and nicotine-free smoke extract), nicotine and cotinine on TH and DAT expression in undifferentiated pheochromocytoma cells. Our third objective was closely developed from our second. After investigating the effect in vitro, we determined the effect in vivo in rats after 28 day exposure of whole cigarette smoke extract (nicotine-containing and nicotine-free smoke extract), nicotine and cotinine on TH and DAT regulation. Both the in vitro and in vivo TH as well as the in vivo DAT regulation data implicated nicotine to be responsible for TH and DAT upregulation. It is known that nicotine releases DA from rat striatal synaptosomes. We therefore aimed to determine whether a component of tobacco leaf extracts which is a MAO-A and MAO-B inhibitor, 2,3,6-trimethyl-I,4-naphthoquinone (TMN) release DA from rat striatal synaptosomes. We found that TMN releases DA from synaptosomes, to a greater extent when compared to nicotine. Our data conclude that cotinine does cross the BBB and that both nicotine and cotinine transport do not vary after chronic nicotine exposure. We also found that nicotine, as the major constituent of tobacco smoke, is responsible for increased DA synthesis and DA transport back into the presynaptic neuron. TMN, is not only a MAO-A and MAO-B inhibitor but experiments from our laboratory indicate that in striatal synaptosomes, TMN releases DA to a greater extent than nicotine.
Thesis (Ph.D. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2005.

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Ghazaleh, Haya Abu. "The neurochemistry of rat imidazoline binding sites." Thesis, University of Bristol, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442183.

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Aguilar, Carolina. "Pesticides and pesticide combinations on brain neurochemistry." Thesis, Virginia Tech, 2004. http://hdl.handle.net/10919/34697.

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Pesticides have been suggested to play a role in the development of many neurodegerative diseases including Parkinson's disease and Alzheimer's disease. Additionally, it has been suggested that exposure to pesticides and other environmental chemicals during the early stages of life could result in an increased vulnerability to such substances that could lead to neurotoxicity and degeneration late in life. We hypothesized that exposure to mixtures of certain pesticides could change neurotransmitter levels and cellular oxidative stress and that this would be greater in mice exposed early and later in life than mice exposed only as adults. We studied the effects of permethrin (PR) (a pyrethroid type I) and endosulfan (EN) (an organochlorine) on the levels of catecholamines, indolamines, acetylcholinesterase, lipid peroxidation and α-synuclein in the brain of mice. These pesticides have different structures but both are known to modify the kinetics of voltage-sensitive ion channels and calcium ion flux/homeostasis that could affect the release of several neurotransmitters. The study consisted of two experiments: In the first experiment, adult C57Bl/6 mice (7-9 months old) were injected, intraperitoneally, with the following treatments: EN 4.3, 2.15 mg/kg; PR 150, 15 mg/kg and their mixtures EN 4.3 + PR 150 and EN 2.15 + PR 15 mg/kg. Mice were sacrificed 24 hrs after the last injection. In the second experiment, doses consisted of EN 0.7, 1.4 mg/kg, PR 1.5, 15 mg/kg and their mixtures EN 0.7 + PR 1.5 mg/kg and EN 1.4 + PR 15 mg/kg were given to juvenile mice intraperitoneally daily during a period of two weeks from postnatal day 5 to 19. Mice were then, left undisturbed with their dams. Re-challenge was performed when mice were 7-9 months old and dosages of EN 4.3, 2.15 mg/kg, PR 150, 15 mg/kg and their mixtures, EN 4.3 + PR 150 and EN 2.15 + PR 15 mg/kg were given intraperitoneally every other day during a period of two weeks to match the treatments when pesticide exposure was only as adults. Mice were sacrificed 24 hrs after the last injection.

The corpora striatum was extracted and analyzed by HPLC for catecholamines (dopamine, DOPAC, homovalinic acid and norepinephrine) and indolamines (serotonin and 5-HIAA). In general low doses of permethrin and endosulfan alone and in combination (EN 2.15 + PR 15 mg/kg) altered the levels of catecholamines and indolamines in both studies with adult mice and mice dosed as juveniles and re-challenged as adults. Catecholamine and indolamines levels were affected to a greater extent in the adult mice than in mice dosed as juveniles and re-challenged as adults, when compared to controls.

Acetylcholinesterase was increased under both exposure situations but again adult mice seemed to be more affected than mice dosed as juveniles and re-challenged as adults.

Because reactive oxygen species have been implicated in the development of Parkinson's disease, and are known to cause degradation of certain neurotransmitters, we monitored the levels of lipid peroxides in brain cortex as an indicator of free radical tissue damage. The peroxide levels were measured by thiobarbituric acid reactive products (TBARS). Increased levels of lipid peroxides were significant in the low dose treatment groups of the adult study. However, there seemed to be a pattern between the levels of dopamine and DOPAC in the striatum and the levels of peroxidation in cortex. The presence of dopamine metabolites appeared to be related to high levels of peroxidation within the basal ganglia and up-regulation of proteins such as α-synuclein. Western blots of α-synuclein in both experiments of the study showed intense double and triple bands that corresponded to aggregated α-synuclein. In general, when compared with controls, mice dosed as juveniles and re-challenged as adults did not alter the above parameters as much as mice dosed only as adults. Instead, the mice first dosed as juveniles seemed to develop an adaptation response to the later exposure of these pesticides.

Taking all these results into account, early exposure and re-challenge with permethrin and endosulfan in this study appeared to induce a protective response against neurochemical changes in the brain of these mice. In addition, low doses of these pesticides and the low dose combination mixture seem to exert an effect on the parameters studied.

Therefore, exposure to pesticides such as endosulfan and permethrin and their combinations could make a contribution towards the initiation or aggravation of biochemical neurodegenerative diseases such as Parkinson's and Alzheimer's diseases.

Master of Science

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Furnish, Oehrtman Elizabeth Jean. "The role of gelsolin upregulation and overexpression in neurite outgrowth for PC12 cells." Access restricted to users with UT Austin EID Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3031599.

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Durieux, Alice Marie Sybille. "Neurochemistry in autism spectrum disorder : a translational approach." Thesis, King's College London (University of London), 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.718590.

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The pathogenesis of autism spectrum disorder (ASD) may include dysfunction of brain Redox homeostasis and abnormalities in the balance between neuronal excitation (E) and inhibition (I). Both systems have therefore been put forward as potential treatment targets for the development of new pharmacotherapies for the condition. However, ASD is a highly heterogeneous disorder, and it is unclear whether altered oxidative metabolism and/or E/I imbalance occur in all individuals with ASD. Therefore in the first part of this thesis (Study 1), I examined markers of Redox metabolism in a cohort of adult males with ASD already known to have E/I anomalies. Next, I undertook a series of preclinical studies (Studies 2- 4) to investigate whether pharmacological modulation of Redox and/or E/I alters neurochemistry and behaviour in mouse models of ASD. I used in vivo proton magnetic resonance spectroscopy ([1H]MRS) to quantify glutathione (GSH - the major endogenous antioxidant), as a marker of Redox metabolism; and glutamate and GABA (respectively the major excitatory and inhibitory neurotransmitters), as markers of E/I balance. In Study 1, I found GSH was unaltered in adult males with ASD already known to have glutamatergic anomalies. Therefore, my preclinical work focussed upon the regulation of E/I balance. Because the role of glia in E/I and ASD is under-explored, I examined modulation of glutamate by glial mechanisms. In Study 2, I provided proof-of-concept evidence that N-Acetylcysteine (NAC), a compound that activates the cystine-glutamate antiporter of glial cells, reduces glutamate in wild-type C57BL/6J mice. I then sought to translate this finding to a mouse model of ASD with baseline E/I imbalance. After finding that mice lacking synaptic protein Neurexin 1α, a genetic model of ASD, have normal levels of striatal glutamate (Study 3), I excluded this model and instead administered NAC to BTBR mice, an inbred strain with a behavioural phenotype reminiscent of ASD (Study 4). I found that BTBR mice have a baseline E/I imbalance in the striatum and the prefrontal cortex, two brain regions involved in the core symptoms of ASD. These anomalies were partially normalised by NAC treatment, which also improved social interactions and repetitive digging, two behaviours relevant to the core symptoms of ASD. My results suggest that the glial regulatory mechanisms of E/I balance can be modulated pharmacologically, and have consequences for behaviours relevant to ASD. While my preclinical results suggest that the clinical utility of NAC in ASD deserves further exploration, the broader implications of my work are that glial cells are a potential target for the development of new treatments for ASD.

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Berners, Manfred Otto Maria. "Development of enzyme based sensors for use in neurochemistry." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307034.

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Graham, Michelle Karen. "The neurochemistry and control of motility in parasitic platyhelminths." Thesis, Queen's University Belfast, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301714.

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12

Alteryd, Olivia. "Think your pain away : The neurochemistry of placebo analgesia." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-17615.

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Placebo treatments are inert but are known to alleviate symptoms across numerous clinical conditions. One of the most studied placebo effects is placebo analgesia, which is a placebo effect limited to pain relief. This thesis aims to introduce the current state of research regarding the neuroscience of placebo analgesia and specifically to present research findings regarding the neurotransmission. Studies have demonstrated that placebo analgesia can be elicited through two separate processes interacting with each other; manipulation of expectations and through conditioning. These processes seem to affect neurotransmission in different ways. Many brain areas have been found to be correlated to placebo analgesia. Besides the pain-processing brain areas, studies point to that the prefrontal cortex can have a vital role in the placebo analgesic effect. Known neurotransmitters that have shown to be involved in placebo analgesia are endogenous opioids, cholecystokinin (CCK), and endocannabinoids. Studies point to that endogenous opioids are involved in the placebo analgesic effect when elicited by expectation or conditioned by an opioid drug. CCK act on placebo analgesia by affecting the release of endogenous opioids and endocannabinoids seem to be involved in placebo analgesia while it occurs due to conditioning with non-opioid drugs. Getting a better understanding of placebo analgesia and find ways to apply this knowledge in the clinical context could powerfully develop the whole medical society.

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VACCHINI, MATTIA. "DESIGN, SYNTHESIS AND DEVELOPMENT OF GLYCOTOOLS FOR NEUROCHEMISTRY STUDIES." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2020. http://hdl.handle.net/10281/262350.

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Contesto scientifico. I glicani rivestono un ruolo cruciale nel sistema nervoso centrale (SNC) e il loro studio è fondamentale per un'accurata comprensione della neurochimica, ma la conoscenza scientifica riguardo ai glicani presenti nel SNC è ancora limitata. Lo scopo di questa tesi è fornire nuovi strumenti al glicochimico e al glicoanalista per condurre studi di neurochimica, funzionali all'esplorazione del ruolo dei glicani nel SNC. Questa tesi presenta un nuovo metodo analitico per lo studio degli N-glicani da tessuti cerebrali (LSD); lo stato dell'arte di un lavoro in corso riguardante l'investigazione di N-glicani e N-glicoproteine differentemente espresse in tessuti cerebrali appartenenti a diverse specie; un efficiente metodo di marcatura chimica per (glico)proteine, applicato con successo a una N-glicoproteina, Neuroserpina (NS), che polimerizza nel SNC con conseguenze patologiche; e le sintesi di glicosidi e glicodendrimeri con potenziali applicazioni in studi neurochimici. Metodi. LSD si sviluppa a partire dalla lisi chimica di tessuti cerebrali (tc), con conseguente precipitazione del proteoma (i.e., metanolo/cloroformio), deglicosilazione enzimatica (i.e., PNGase F), purificazione degli N-glicani, marcatura chimica (i.e., amminazione riduttiva su N-acetilglucosammina terminale) e analisi tramite approcci LC-MS. LSD è stato ottimizzato su campioni di tc e accuratamente validato (i.e., sensibilità, precisione, linearità, range dinamico, selettività, robustezza). L'analisi degli N-glicani è stata anche effettuata tramite deglicosilazione enzimatica in-gel da elettroforesi di proteine, mentre un protocollo di digestione con Tripsina in-gel è stato usato per l'identificazione di N-glicoproteine e siti di N-glicosilazione tramite approcci LC-MS su peptidi. NS è stata dimetilata chimicamente (i.e., amminazione riduttiva su lisina), nella sua forma monomerica (mhNS) e polimerica (phNS) e l'esito della reazione è stato valutato tramite MS, per l'investigazione dei determinanti molecolari coinvolti nel meccanismo di polimerizzazione. I glicosidi sono stati sintetizzati usando una reazione di glicosilazione di tipo Fischer, condotta su monosaccaridi deprotetti, usando alcol allilico e decenolo come accettori glicosidici, mentre i glicodendrimeri sono stati ottenuti sfruttando la chimica delle ossime per la decorazione con gruppi maltosilici di dendrimeri sintetizzati tramite metatesi delle olefine. Risultati. LSD presenta il più basso limite di rivelabilità (1 mg di tc) rispetto a molti altri lavori riportati in letteratura ed è attualmente il metodo di neuro-N-glicomica più accuratamente validato. La deglicosilazione in-gel per l'analisi degli N-glicani cerebrali ha prodotto cromatogrammi informativi per ogni frazione del proteoma con elevata risoluzione (e.g., sensibilità fino a 100 EU da una singola banda di gel), permettendo l'analisi dei peptidi deglicosilati dallo stesso campione (i.e., un totale di 1200 peptidi, 570 proteine, 57 N-glicoproteine, e nuovi siti di N-glicosilazione identificati). La marcatura chimica di NS si è dimostrata efficiente (i.e., 80-90% di resa), compatibile con la struttura nativa della proteina, e funzionale all'uso designato, in quanto capace di evidenziare differenze statisticamente significative nel profilo di marcatura di mhNS e phNS (i.e., 9 lisine). La sintesi di glicosidi ha fornito prodotti con buona resa (e.g., 70%) e alfa-stereoselettività, mentre quella dei glicodendrimeri ha generato molecole esponenti gruppi maltosilici, utilizzabili nel contesto di studi di neurochimica. Conclusioni. I metodi e le molecole contenuti in questa tesi apporteranno beneficio alla comunità scientifica glicochimica, incrementando il numero di strumenti che il glicochimico e il glicoanalista possono utilizzare per portare avanti lo studio degli effetti dei glicani in contesto neurologico e neuromedico.
Background. Glycans play crucial roles within the central nervous system (CNS) and their study is essential for a thorough comprehension of neurochemistry, but the scientific knowledge about CNS glycans remains scarce. The aim of this thesis is to provide the glycochemist and glycoanalyst with novel tools for neurochemistry studies, towards the exploration of glycan roles in the CNS. This thesis presents a novel analytical method for brain N-glycans investigation (LSD); the state of the art of an ongoing work for the investigation of N-glycans and N-glycoproteins differentially expressed in brain tissues of different species; an efficient chemical labelling method for (glyco)proteins, successfully applied on Neuroserpin (NS), a pathologically-polymerising CNS N-glycoprotein; and the syntheses of glycosides and glycodendrimers with potential room for neuromedical studies. Methods. LSD comprised brain tissue (bt) chemical lysis, proteome precipitation (i.e., methanol/chloroform), enzymatic deglycosylation (i.e., PNGase F), N-glycans purification, chemical labelling (i.e., reductive amination on terminal N-acetylglucosamine), and LC-MS bioanalysis. The method has been optimised on bt and thoroughly validated (i.e., sensitivity, precision, linearity, range, selectivity, robustness). N-glycans analysis has also been carried out through protein electrophoresis in-gel deglycosylation, while in-gel trypsinisation was used for the LC-MS identification of N-glycoproteins and N-glycosylation sites. NS has been dimethylated (i.e., reductive amination on lysine) in its monomeric (mhNS) and polymeric (phNS) forms, and the reaction outcome has been evaluated using MS, towards the investigation of NS polymerisation-driving molecular features. Glycosides were synthesised with a Fischer- type glycosylation reaction on unprotected monosaccharides using either allyl alcohol or decenol as glycosyl acceptors, while glycodendrimers were obtained decorating olefin-metathesis-synthesised dendrimers with maltose moieties, exploiting oxime chemistry. Results. LSD displayed the lowest detection limit (1 mg of bt) in comparison to many other works reported in the literature and is the most thoroughly validated neuro-N-glycomic method reported to date. In-gel deglycosylation for brain N-glycans analysis furnished informative chromatograms for every proteome fraction with high resolution (e.g., sensitivity up to 100 EU from a single gel band), permitting the analysis of deglycosylated peptides from the same sample (i.e., a total of 1200 peptides, 570 proteins, 57 N-glycoproteins, and novel N-glycosylation sites identified). NS chemical labelling displayed high efficiency (i.e., 80-90% yield), compatibility with the protein folding, and suitability towards the intended purpose, being able to highlight statistically significant differences in mhNS and phNS labelling patterns (i.e., 9 lysines). The syntheses of glycosides furnished products with good yield (i.e., 70%) and a- stereoselectivity, while that of glycodendrimers afforded molecules exposing several maltose moieties, employable in the context of neurochemistry studies. Conclusions. Methods and molecules delivered within this thesis will benefit the glycochemistry community, by enlarging the glycochemist and glycoanalyst toolkits to carry on the investigation of glycans- related effects in neurological and neuromedical context.

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Lundström, Linda. "Subtype selective activation and molecular characterization of galanin receptors." Doctoral thesis, Stockholms universitet, Institutionen för neurokemi, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-1344.

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Showing an extensive distribution in the nervous system, and often in co-localization with the classical neurotransmitters, neuropeptides are functioning as important modulators of neuronal signaling. Subsequently, compelling evidence has implicated a modulatory role for the neuropeptide galanin in several physiological functions. The effect of galanin is trancduced intracellularly by three different receptors, and defining the explicit effect from these receptor subtypes is of outmost interest, and likely to result in future therapeutic utilization of the galanin system. The main aim of this thesis was to improve the development of subtype selective ligands utilized to differentiate between the galanin receptor subtypes. To achieve this, we have designed and developed novel galanin receptor ligands and characterized the molecular interactions necessary for ligand bindig at the GalR2 subtype. The major findings include the introduction and characterization of two galanin receptor ligands, selectively activating GalR1 or inhibiting GalR2. Although having moderate selectivity, the two ligands have been utilized in a number of studies, pursuing their initial presentation, in order to differentiate between the galanin receptors and to establish their specific function. Further optimization is likely to improve the selectivity and utilization of these ligands. By identifying the major pharmacophores in the Gal(2-11) ligand and the residues in the GalR2 subtype participating in ligand binding, we have been able to characterize the binding site in this receptor subtype and interactions that are of significance for recognition of subtype specific ligands. Together, these findings on GalR2 and Gal(2-11) are of importance for future design of ligands acting on this receptor.

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Novales-Li, Philipp. "Human brain acetylcholinesterase." Thesis, University of Oxford, 1993. https://ora.ox.ac.uk/objects/uuid:8f0d7a87-9df9-40be-89a5-bc9953f27f03.

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Procedures for the preparative purification of human acetylcholinesterase (AChE; EC 3.1.1.7) have been examined. Chromatofocussing showed caudate nucleus and cerebrospinal fluid (CSF) AChE eluting between isoelectric points (pi) of 5.2 - 5.57, whilst isoelectric focussing (IEF) revealed heterogeneous AChE isoforms migrating between pI 4.5 - 6. Affinity chromatography proved to be better in yielding highly pure samples. The ligands used were either acridinium or procainamide, which yielded brain AChE recoveries of 10.1% and 42.8%, respectively. Various other methods were used such as gel filtration and ion-exchange chromatography on a Pharmacia SMART System. Purified brain AChE was used as antigen to generate anti-AChE monoclonal antibodies (mAbs) by in vivo immunization. BMS-3E4, -7G10, and -9F4 reacted with erythrocyte (G2) AChE, whilst BMS-6D6 bound to brain (G4) AChE in dot blot, titration, and sedimentation experiments. Conversely, the four mAbs recognized only the G4 form and not the G₂ form on immunoblotted IEF and non-denaturing Clarke gels. Deglycosylation studies suggest that the four mAbs recognize a carbohydrate epitope linked to AChE. As a preparative step, tissue culture media containing these mAbs were ammonium sulphate precipitated and purified on a gel filtration column. Under reducing conditions, two bands migrating at 80 and 25 kDa were seen, corresponding to the heavy and light chains of Immunoglobulin M (IgM). Four additional mAbs were raised by the novel method of in vitro immunization, using a synthetically-produced C-terminus peptide as antigen. BMS-5, -6, -7, and -8 are all IgMs which recognize soluble brain and not erythrocyte nor membrane-bound AChE in dot blots, IEF, and sedimentation analyses. Although immunocytochemistry of the above-mentioned mAbs did not demonstrate any positive cholinergic binding, the present mAbs may still offer potential clinical and biochemical applications.

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Cartmell, Jayne. "A pharmacological study of metabotropic glutamate receptors in brain-derived preparations." Thesis, University of Nottingham, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.259876.

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Evans, Suzanne Marie. "The effects of inhibition of monoamine oxidase activity on the characteristics of 5-hydroxytryptamine release from rat brain synaptosomes." Thesis, Cardiff University, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375944.

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Malizia, Andrea Ladislao. "Positron emitting ligands in the study of the clinical psychopharmacology of anxiety and anxiety disorders." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341497.

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Vogel, Ursula Sigrid. "Molecular characterization of 2',3'-cyclic nucleotide 3'-phosphohydrolase." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.330234.

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Palm, Apergi Caroline. "Design and evaluation of drug delivery vehicles." Doctoral thesis, Stockholm : Department of Neurochemistry, Stockholm university, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8256.

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Puts, Nicolaas. "The in vivo functional neuroanatomy and neurochemistry of vibrotactile processing." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/15635/.

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Touch is a sense with which humans are able to actively explore the world around them. Primary somatosensory cortex (S1) processing has been studied to differing degrees at both the macroscopic and microscopic levels in both humans and animals. Both levels of enquiry have their advantages, but attempts to combine the two approaches are still in their infancy. One mechanism that is possibly involved in determining the reponse properties of neurons that are involved in sensory discrimination is inhibition by γ-aminobutyric acid (GABA). Several studies have shown that inhibition is an important mechanism to “tune” the response of neurons. Recently it has become possible to measure the concentration of GABA in vivo using edited Magnetic Resonance Spectroscopy (MRS), whereas magnetoencephalography (MEG) offers the possibility to look at changes in neuromagnetic activation with millisecond accuracy. With these methods we aimed to establish whether in vivo non-invasive neuroimaging can elucidate the underlying neuronal mechanisms of human tactile behaviour and to determine how such findings can be integrated with what is currently known from invasive methods. Edited GABA-MRS has shown that individual GABA concentration in S1 correlates strongly with tactile frequency discrimination. MEG was used to investigate the neuromagnetic correlates of a frequency discrimination paradigm in which we induced adaptation to a 25 Hz frequency. We showed that S1 is driven by the adapting stimulus and shows that neural rhythms are modulated as a result of adaptation. This is the first time that behavioural psychophysics of tactile adaptation has been investigated using complimentary neuroimaging methods. We combined different methods to complement both physiological and behavioural studies of tactile processing in S1 to investigate the factors involved in the neural dynamics of tactile processing and we show that non-invasive studies on humans can be used to understand physiological underpinnings of somatosensory processing.

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22

Palm, Marisha Emily. "The neurochemistry, neuropsychology and functional neuroanatomy of generalised anxiety disorder." Thesis, University of Manchester, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492844.

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Generalised anxiety disorder (GAD) is a common mental illness characterised by excessive worry and anticipatory anxiety. The present study aims to elucidate the neuropsychology, neurochemistry, structural and functional neuroanatomy of female patients with GAD using dietary manipulation of 5-HT and magnetic resonance imaging (MRI).

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Stein, Dan J. "The neurobiology of obsessive-compulsive disorder : neuroanatomy, neurochemistry, and pharmacotherapy." Thesis, Stellenbosch : Stellenbosch University, 2001. http://hdl.handle.net/10019.1/52550.

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Dissertation (PhD)--Stellenbosch University, 2001.
ENGLISH ABSTRACT: Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts (obsessions) and repetiti ve mental acts or behaviours (compulsions) . For many years, it was considered a rather uncommon condition, caused by unconscious conflict, and somewhat resistant to treatment. In recent decades, however, it has emerged that OCD is a highly prevalent disorder, mediated by particular neuroanatomical circuits (e.g. striatal pathways) and neurochemical systems (e.g. the serotonin system), and responsive to treatment with serotonin reuptake inhibitors (SRIs) . Nevertheless, many questions remain; about the specificity of neuroanatomical findings to OCD, about the role of the multiple serotonin (5-HT) receptor subtypes (e.g. 5-HT10)' and about the appropriate pharmacotherapy for patients resistent to SRI treatment? In a series of studies, 1) the neuroanatomy of OCD was assessed by means of magnetic resonance imaging and neuropsychological testing, 2) the neurochemistry of OCD was assessed by means of functional brain imaging after administration of a 5-HT10 agonist, and 3) the pharmacotherapy of OCD was explored in a series of treatment-refractory OCD and OCD spectrum disorder patients using SRI augmentation with a dopamine blocker. Although no significant difference was found in the volume of the caudate in women with OCD and controls, there was a significant correlation between caudate volume and neuropsychological dysfunction in patients, consistent with evidence of striatal involvement in OCD. Functional imaging demonstrated behavioural heterogeneity, but brain-behaviour correlations were positive, consistent with preclinical evidence of a role for the 5-HTlD receptor in the mediation of OCD. Finally, preliminary treatment findings with dopamine blocker augmentation of a SRI were promising, consistent with preclinical understandings of the interactions between the dopamine and serotonin systems. Although oeD is a complex disorder, a number of future research avenues hold promise for providing a thorough delineation of its pathogenesis.
AFRIKAANSE OPSOMMING: Obsessief-kompulsiewe steuring (OKS) word gekenmerk deur indringende gedagtes (obsessies) en herhalende gedagtes of gedrag (kompulsies). Vir baie jare is dit beskou as 'n redelik seldsame toestand wat veroorsaak word deur onbewustelike konflik, en wat in 'n mate teen behandeling weerstandig is. Meer onlangs het dit egter na vore getree as 'n toestand wat baie dikwels voorkom, wat deur spesifieke neuroanatomiese siklusse (bv. striatale bane) en neurochemiese sisteme (bv. die serotonien-sisteem) teweeg gebring word, en wat op behandeling met serotonien heropname inhibeerders (SHIs) reageer. Nogtans is daar steeds baie vrae; oor die spesifisiteit van neuroanatomiese bevindinge vir OKS, oor die rol van die veelvuldige serotonien (5-HT) reseptor subtipes (bv. 5- HT1D), en oor die toepaslike farmakoterapie vir pasiënte wat weerstandig is vir SHI behandeling. In' n reeks van navorsingstudies, is 1.) die neuroanatomie van OKS deur middel van magnetiese resonans beelding en neurosielkundige toetse ondersoek, 2. ) die neurochemie van OKS deur middel van funksionele breinbeelding na toediening van 'n 5-HT1D agonis bepaal, en 3.) die farmakoterapie van OKS in 'n reeks van behandelingsweerstandige OKS en OKS-spektrum steuring pasiënte - waar gebruik gemaak is van SHI aanvulling met 'n dopamien-blokker - ondersoek. Alhoewel daar geen beduidende verskil in die volume van die caudata in vroue met OKS en kontroles gevind is nie, was daar 'n beduidende korrelasie tussen die caudata volume en neurosielkundige wanfunksionering in pasiënte, in ooreenstemming met striatale betrokkenheid in OKS. Funksionele beelding het positief, in demonstreer, maar ooreenstemming met brein-gedrag pre-kliniese heterogeneïteit korrelasies was in gedrag bewyse vir 'n rol vir die 5-HT1D reseptor in die bemiddeling van OKS. Ten laaste, voorlopige behandelingsbevindinge oor dopamienblokker aanvulling van 'n SHI is belowend, in ooreenstemming met v

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24

Gibson, Sarah Jane. "The neurochemistry of the spinal cord and its peripheral projections." Thesis, Imperial College London, 1989. http://hdl.handle.net/10044/1/47447.

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25

Häidkind, Riina. "Monoaminergic mechanisms in mood-associated behaviours and neurochemistry in rats /." Tartu : Tartu University Press, 2004. http://dspace.utlib.ee/dspace/bitstream/10062/704/5/Haidkind.pdf.

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26

Sullivan, Aideen Margaret. "The use of organotypic cultures of rat cerebellum for the study of neuromodulatory interactions in the mammalian brain." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243197.

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27

Sepulveda, Maria-Isabel. "Receptors for L-glutomate in the insect nervous system." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335241.

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28

Grönbladh, Alfhild. "Growth Hormone and Anabolic Androgenic Steroids : Effects on Neurochemistry and Cognition." Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-206069.

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Growth hormone (GH) stimulates growth and metabolism but also displays profound effects on the central nervous system (CNS). GH affects neurogenesis and neuroprotection, and has been shown to counteract drug-induced apoptosis in the brain. Anabolic androgenic steroids (AAS), mainly abused for their anabolic and performance-enhancing properties, can cause several adverse effects, such as cardiovascular complications, sterility, depression, and aggression. GH and AAS are both believed to interact with several signaling systems in the CNS. The aim of this thesis was to further investigate the impact of GH and AAS on neurochemistry and cognitive functions. Recombinant human GH (rhGH) and the steroid nandrolone decanoate (ND) were administered, separately and in combination with each other, to male rats. The results demonstrated that administration of GH improved spatial memory, assessed in a water maze test. Furthermore, GH induced alterations of the GABAB receptor mRNA expression, density, and functionality in the brain, for example in regions associated with cognition. GH also altered the mu opioid peptide (MOP) receptor, but not the delta opioid peptide (DOP) receptor functionality in the brain. Thus, some of the GH effects on cognition may involve effects on the GABAB receptors and MOP receptors. ND, on the contrary, seemed to induce impairments of memory and also altered the GABAB receptor mRNA expression in the brain. Furthermore, ND lowered the IGF-1 plasma concentrations and attenuated the IGF-1, IGF-2, and GHR mRNA expression in the pituitary. In addition, significant effects of GH and ND were found on plasma steroid concentrations, organ weight, as well as body weight. In conclusion, this thesis contributes with further knowledge on the cognitive and neurochemical consequences of GH and ND use. The findings regarding ND are worrying considering the common use of AAS among adolescents. GH improves memory functions and affects signaling systems in the brain associated with cognition, hence the hypothesis that GH can reverse drug-induced impairments is further strengthened.

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29

Cuffe, Jennifer. "A rhetorical tale : neurochemistry and the efficacies of antidepressants in Canada." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=79756.

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Recent work in anthropology has speculated on how developments in molecular biology and medicine might bring about new bodies, selves, and forms of sociality. This thesis explores how herbal and pharmaceutical antidepressants differently affect experiences of one's neurochemistry. It does so in two ways. First, it outlines the historical 'social life' of pharmaceutical antidepressants, including their co-production with depression, and the neurochemical body in a particular style of reasoning in biological psychiatry. Second, it presents and analyzes claims made for the efficacy of antidepressants made in vernacular North American books, advertisements, and pamphlets. Although the claims for both herbal and pharmaceutical antidepressants allude to the same realms of value---those of science, nature/history, and personal experience---their different social lives enable different access to the neurochemical body.

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30

Frick, Andreas. "Imaging Anxiety : Neurochemistry in Anxiety Disorders Assessed by Positron Emission Tomography." Doctoral thesis, Uppsala universitet, Institutionen för psykologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-261983.

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Anxiety disorders, including social anxiety disorder (SAD) and posttraumatic stress disorder (PTSD) are common and disabling conditions. Largely based on animal and pharmacological studies, both the serotonergic and substance P/neurokinin-1 (SP/NK1) systems have been implicated in their underlying pathology. However, only few neuroimaging studies have directly assessed these neurotransmitter systems in human sufferers of anxiety disorders, and none have addressed possible between-systems relationships. The overall aim of this thesis was to study possible neurochemical alterations associated with anxiety disorders. To this end, three studies using positron emission tomography (PET) for in-vivo imaging of the brain serotonergic and SP/NK1 systems in patients with SAD and PTSD were conducted. The radiotracers [11C]5-HTP, [11C]DASB, and [11C]GR205171 were used to index serotonin synthesis rate, serotonin transporter (SERT) availability, and NK1 receptor availability respectively. In Study I, patients with SAD relative to controls exhibited enhanced serotonin synthesis rate and serotonin transporter availability. Serotonin synthesis rate in the amygdala was positively related to social anxiety symptom scores. Study II demonstrated increased NK1 receptor availability in the amygdala in patients with SAD relative to controls. In Study III, patients with PTSD showed elevated NK1 receptor availability in the amygdala as compared to controls. SERT availability in the amygdala was negatively related to PTSD symptom severity, a relationship that was moderated by NK1 receptor levels. The regional overlap between SERT and NK1 receptor expression was altered in patients with PTSD, with reduced overlap linked to more severe symptoms. Collectively, the findings are consistent with the view that serotonin in the amygdala induces rather than reduces anxiety and links exaggerated anxiety to an overactive presynaptic serotonin system. In addition, the involvement of the SP/NK1 system in stress and anxiety, as suggested by animal studies, was demonstrated in two common human anxiety disorders. Finally, PTSD symptomatology is better accounted for by interactions between the serotonergic and SP/NK1 systems in the amygdala than by each system separately. In conclusion, this thesis supports that both the serotonergic and SP/NK1 systems in and of themselves, but also interactively, may be important contributors to anxiety symptomatology.

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31

Bozorgzadeh, Bardia. "Integrated Microsystems for High-Fidelity Sensing and Manipulation of Brain Neurochemistry." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1432223568.

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32

Rooney, Thomas A. "Inositol phospholipid metabolism in rat brain." Thesis, University of Leicester, 1987. http://hdl.handle.net/2381/33609.

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In the studies described in this thesis the ability of muscarinic and ?1-adrenoceptor, as well as depolarising stimuli to initiate phosphoinositide metabolism in various regions of rat brain were examined. Furthermore, the ability of these stimuli to initiate phosphoinositide hydrolysis in developing brain was observed. Both muscarinic and ?1-adrenoceptor-induced phosphoinositide hydrolysis have marked regional distributions in rat brain. This regional distribution of functional responsiveness seems to correlate reasonably well with measurements of known receptor density. It is also clear that there is no variability in the coupling of both of these receptors in rat brain, thus implying a relationship between the functional responses and receptor occupancy. Pirenzepine appears to be able to differentiate between muscarinic receptor-induced phosphoinositide responses in the hindbrain from those in the forebrain regions. Both elevated K+ and veratrine can initiate phosphoinositide hydrolysis in rat brain. The regional responses to elevated K+ seem, at least, in part to be due to transmitter release, although a role for voltage-sensitive Ca++ channels in such responses is indicated by the effects produced by dihydropyridine Ca++ channel antagonists and activators. Muscarinic and ?1-adrenoceptors show different developmental patterns of phosphoinositide responsiveness. The ?1-adrenoceptor seems to be more efficiently coupled during the first two weeks of postnatal development whereas the muscarinic receptor shows no variability in coupling. Instead, carbachol produces supramaximal responses in young rats. Lithium also potentiates [3H]-InsP1 and [3H]-InsP2 accumulations more in young rats. Moreover lithium produces a time-dependent inhibition of [3H]-InsP3 and [3H]-InsP4 in both young and adult rats. Physostigmine produces no enhancement of the response to elevated K+ in young rats. Furthermore, brain slices from young rats seem to be more sensitive to the Ca++ channel activator BAY-K8644. The significance of these results are discussed in the text.

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33

Hicks, Gareth A. "Adenosine 5'-triphosphate-sensitive potassium channels in the rat substantia nigra." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321402.

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34

Marshall, Fiona. "Cholecystokinin/dopamine interactions in the rat basal ganglia." Thesis, University of Cambridge, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386170.

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35

Stephens, P. "Neurochemical studies on the basal forebrain." Thesis, University of Oxford, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.371574.

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36

Emmett, Stevan Richard. "Non-classical effects of acetylcholinesterase and related peptide fragments on neurochemical regulation in the midbrain." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365712.

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37

Jackson, V. Margaret. "Calcium dynamics in postganglionic sympathetic neurones." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365441.

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38

Santangeli, Sarah. "Preclinical investigations with remacemide hydrochloride." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390778.

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Thomas, David Nigel. "Noradrenergic effects of various antidepressant therapies as studied by in vivo microdialysis : a common mechanism?" Thesis, University of Reading, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293774.

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40

Thomson, Fiona Elspet. "Application of monoclonal antibodies to the assay of neuron specific enolase." Thesis, University of Aberdeen, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.253680.

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(1) Human neuron specific enolase (NSE) was purified from human brain tissue and used as an immunogen in the production of murine monoclonal antibodies. It was also used as a standard preparation of NSE in the screening of monoclonal antibodies and in the investigations of an enzyme-linked immunosorbent assay (ELISA) for NSE. (2) Four monoclonal antibodies were raised to NSE. These did not cross react with the alpha isoenzyme of enolase (NNE). Approximately 76% of positive well supernatants reacted with both NSE and NNE. (3) All four monoclonal antibodies reacted in an ELISA but only two of the four reacted on an immunoblot. (4) The monoclonal antibodies were purified by precipitation by ammonium sulphate and by Protein A-affinity column chromatography. The latter resulted in immunoglobulin which was pure by SDS-PAGE. (5) The purified monoclonal antibodies were labelled with horseradish peroxidase by the periodate oxidation method, with ¹²⁵I using the Chloramine T and the Bolton-Hunter methods, and with biotin. (6) Labelling with biotin was the most effective method. (7) The labelled monoclonal antibodies were used in the investigation of a sandwich ELISA for NSE. These experiments showed that high binding occurred with no antigen present. It was surmised that monoclonal antibody-monoclonal antibody binding may be occurring. (8) The high no-antigen control was investigated in a number of ways including altering the assay pH, the detergent concentration, the type of solid support and by using Fab fragments in the assay instead of whole molecule.

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41

Hawkins, Lynda Mary. "An investigation of non-NMDA glutamate receptors : using novel derivatives of the amino acid, willardiine." Thesis, University of Bristol, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337290.

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42

Thorne, Beverley Ann. "Nicotinic regulation of acetylcholine release from rat brain hippocampus." Thesis, University of Bath, 1990. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.237086.

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43

Schuliga, Michael, and michael schuliga@deakin edu au. "Steroidogenesis in cultured mammalian glial cells." Deakin University. School of Biological and Chemical Sciences, 1998. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20061207.154152.

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A protocol for culturing mammalian type 1 astrocytic cells, using female post-natal rat cerebral cortical tissue, was established and refined for use in steroidogenic metabolic studies incorporating progestin radioisotopes. Cultures were characterised for homogeneity using standard morphological and immunostaining techniques. Qualitative and quantitative studies were conducted to characterise the progesterone (P) metabolic pathways present in astrocytes in vitro. Of particular interest was the formation of the P metabolite, 5á-pregnan-3á-ol-20-one (THP). THP is a GABA(A) receptor agonist, believed to play a vital role in neural functioning and CNS homeostasis. One aim of this study was to observe any modulatory effects selected neuroactive ligands have on the conversion of P into THP, in an attempt to link astrocytic steroidogenesis with neuronal control. In qualitative studies, chromatographic procedures were used to establish the progestin profile of cerebral cortical astrocytes. Tritiated P, DHP (5á-pregnan-3,20-dione) and THP incurbates were preliminary fractionated by either normal phase (NP) or reverse phase (RP) high performance liquid chromatography (HPLC). The radiometabolites associated with each fraction were further chromatographed, before and/or after chemical derivatistation, by the aforemention HPLC procedures and thin layer chromatography (TLC). Steroid radiometabolites were tentatively identified by comparing their chromatographic mobility with authentic steroids. The identity of the main putative 5á-reduced P metabolities, DHP, THP and 5á-pregnan-3á,20á-diol (20áOH-THP) were further confirmed by isotopic dilution analysis. Their conclusive identification, along with the tentative identification of 20á-hydroxypreg-4-en-3-one (20áOH-P) and 20á-hydroxy-5á-pregnan-3-one (20áOH-DHP), verify the localisation of 5á-reductase, 3á-hydroxy steroif oxidoreductase (HSOR), and 20á-HSOR activity in the cultured astrocytes utilised in this study programme. Other minor metabolites detected were tentatively identified, including 5á-pregnan-3á,21-diol-20-one (THDoc), indicating the presence of 21-hydroxylase enzymatic activity. THDoc, like THP, is a GABA(A) receptor agonist. The chemical and physical characterisation of several yet unidentified progestin metabolites, associated with a highly polar RP HPLC fraction (designated RP peak 1*), indicate the presence of one or more extra hydroxylase enzymes. Quantitative analysis included a preliminary study. In this study, the percentage yields of radiometabolites formed in cultures incubated with increasing substrate concentrations of (3)H-P for 24 hours were determined. At the lower concentrations examined (ie 0.5 to 50nM), the metabolites associated with the polar RP HPLC fraction (RP peak 1*) collectively have the highest percentage yield. They are subsequently considered metabolic end products of degradative catabolic P pathways. The percentage yield of THP peaks in the medium concentration ranges (ie 5 to 500nM), whereas DHP remains fairly static at a low level with increasing concentration. Both DHP and THP are considered metabolic pathway intermediates. The percentage yield of 20áOH-THP continues to increase with increasing concentration over 5nM, superseding THP approaching the highest concentration examined (5000nM). This indicated the formation of 20áOH-THP does not occur entirely via THP. 20áOH-THP also possibly serves as the direct intermediate in the formation of the main radiometabolites associated with RP peak 1*. A time/yield study incorporating incubation times from one to 24 hours was also conducted. The full array of radiometabolites (individually or in groups) formed in astrocyte cultures incubated with 50nM tritiated P, DHP of THP, were assayed. Cultures were observed to rapidly convert any DHP into THP, showing astrocytic 3á-HSOR activity is very high. The study also showed 5á-reduction (ie the conversation of P into DHP) is the rate limiting reaction in the two step conversion of P into THP. 5á-Reduction also appears to be a rate limiting step in the formation of 20á-hydroxylated metabolites in astrocytes. Cultures incubated with the tritiated 5á-reduced pregnanes from one to four hours form greater quantities to 20á-hydroxylated radiometabolites compared to cultures incubated with (3)H-P. The time yield/studies also provided further evidence the unidentified polar radiometabolites associated with RP peak 1* are metabolic end products. For the P and DHP incubates, the collective formation of the aforementioned polar radiometabolites initially lags behind the formation of THP. As the formation of the latter begins to plateau with increasing time between four to 24 hours, the net yield of radiometabolites associated with RP peak 1* continues to rise. The time/yield studies also indicate 5á-reduction and perhaps 3á-hydroxylation are pre-requisite steps in the formation of the polar metabolites. Cultures incubated with the 5á-reduced progestins from one to four hours form higher yields of the radiometabolites associated with RP peak 1* compared to cultures incubated with P as substrate. The net yields of the radiometabolites associated with RP peak 1* for cultures incubated with THP were substantially higher compared to cultures incubated with DHP after equivalent times. The effect selected neuroligands have on the yield of radiometabolites formed by cultured astrocytes incubated with 50nM (3)H-P was also examined. Dibutyryl cyclic adenosine monophosphate (DBcAMP), not actually a neuroligand per se, but an analog of the intracellular secondary messenger cAMP, was also utilised in these studies. The inhibitory neurotransmitter ã-amino-nbutyric acid (GABA), DBcAMP and isoproterenol (a â-adrenergic receptor agonist) all quickly induce a transient but substantial increase in 20á-HSOR activity in cultured astrocytes. Cultures pretreated with these three compounds (10, 20 and 1µM respectively) form substantially higher yields of 20á-hydroxylated metabolites, including 20áOH-THP (between 200 to 580% greater), when incubated with 50nM (3)H-P for one to four hours. These increases also coincide with increases in the net yield of metabolites formed (by 16 to 48%). The same pre-treated cultures form significantly lower yields of THP, by 25 to 41%, after one hour. This is most likely due to the increased metabolism of any formed THP into 20áOH-THP. Octopamine (an á-adrenergic agonist) only induces a slight increase in 20á-HSOR activity, having relatively little effect on the yield of 20áOH-THP formed. Pretreatment with octopamine induces a significant increase in the yield of THP for cultures incubated with (3)H-P for four hours (by 24%). The increase in THP formation appears to be due to an increase in 3á-HSOR activity, as judged by the concomitant drop in the yield of the 5á-reduced, 3-keto substrates. An increase in 5á-reductase activity cannot be excluded however. Isoproterenol appears to induce an increase in 5á-reductase activity as isoproterenol appears to induce an increase in 5á-reductase activity as isoproterenol one and four hour incubates have higher yields of DHP. This is in contrast to the other three incubates. After 12 hours, all incubates have higher yields of THP (15-30%).

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44

Nasrallah, Fatma Faculty of Medicine UNSW. "A metabolic approach to the GABAergic system." Publisher:University of New South Wales, 2008. http://handle.unsw.edu.au/1959.4/43413.

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Here, we investigated the effects of modulation of the GABAergic system using a targeted neuropharmacological, 1H/13C NMR spectroscopy and metabolomic approach in Guinea pig cortical brain slices. The effects of exogenous GABA, agonists, antagonists and allosteric modulators at GABAA receptors were described and classified on the basis of metabolic activity; this corresponded to receptor location rather than pharmacology. The effects of agonists and antagonists at the GABAB receptor were described and classified into inhibitory and excitatory components, consistent with context dependent outcomes of receptor activity. Metabolic evidence for GABAC mediated activity in the cerebral cortex was identified for the first time indicating a strong role for this receptor in the control of neuronal activity. Inhibition of GABA uptake was examined using inhibitors of these transporters. The major effect of individual transporter subtype blockade was increased synaptic inhibition. The paradoxical activity of the GABA-transaminase inhibitor vigabatrin was resolved, with a direct demonstration of a single inhibitory mechanism mediated via this drug, via a mechanism also induced by antagonists at the GABAC receptor. These data were then integrated using multivariate statistics to identify 5 subclasses of activity which corresponded to receptor location (e.g. synaptic or extrasynaptic) rather than receptor pharmacology. This represents a novel and powerful new approach to the study of brain metabolism and the GABAergic system.

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45

Series, Hugh George. "The characterisation of two distinct ascending serotonergic projections in rats by anatomical, pharmacological and functional methods." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337566.

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Hidaka, Seiko. "The interneurons and their synaptic organisations in the rat nucleus accumbens." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365867.

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East, Simon Zachary. "5-htâ†6 and 5-HTâ†7 receptor gene expression in schizophrenia." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343531.

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48

Wallam, Catherine. "An ultrastructural and immunocytochemical investigation of GABAergic, glycinergic and colocalizing terminals in the guinea-pig anteroventral cochlear nucleus." Thesis, Keele University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.344093.

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Griffiths, Martin Huw. "#beta#-Amyloidosis and the cholinergic system in ageing and Alzheimer's disease." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263021.

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Coulter, J. C. "Chick brain cholinergic receptors studied by antagonist labelling : Distribution, ontogency and function." Thesis, Open University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382192.

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Dissertations / Theses on the topic 'Neurochemistry'

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