Typescript (photocopy) / iv, 201 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.) Dept. of Organic Chemistry, University of Adelaide, 1981

Thesis (Ph.D.) Dept. of Organic Chemistry, University of Adelaide, 1981. / Typescript (photocopy).

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Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

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Part I of this thesis describes the synthesis of dehydro - perloline ( 3 ), a non basic material obtained from the degradation of the alkaloid perloline ( 1 ), the major alkaloid of New Zealand rye grass. Since a crucial reaction in this sequence involved a Schmidt reaction of fluorenols 4 or 5, some of the mechanistic aspects of this reaction have been investigated. Part II describes the synthesis of caprolactam derivatives 7 with the aim at finding new antagonists or analogues of the CNS inhibitory transmitter, gamma - aminobutyric acid ( GABA ). In Chapter 1, the synthesis of N - alkyl and N - arylcaprolac - tams is described. In Chapter 2, the synthesis, by several methods, of simple 3 - alkylcaprolactams is investigated. Chapter 3 describes synthetic methods for the preparation of 4 - substituted caprolactams. Chapter 4 presents the preparation of 5 - alkyl and 7 - alkyl - caprolactams by the Schmidt reaction on 4 - alkyl and 2 - alkylcyclo - hexanones. Chapter 5 describes some investigations of possible syntheses of 6 - alkylcaprolactams. Chapter 6 contains the results of testing of some lactams and thiolactams as well as their structure - activity relationships. / Thesis (Ph.D.)--Department of Organic Chemistry, 1976.

Part I of this thesis describes the synthesis of dehydro - perloline ( 3 ), a non basic material obtained from the degradation of the alkaloid perloline ( 1 ), the major alkaloid of New Zealand rye grass. Since a crucial reaction in this sequence involved a Schmidt reaction of fluorenols 4 or 5, some of the mechanistic aspects of this reaction have been investigated. Part II describes the synthesis of caprolactam derivatives 7 with the aim at finding new antagonists or analogues of the CNS inhibitory transmitter, gamma - aminobutyric acid ( GABA ). In Chapter 1, the synthesis of N - alkyl and N - arylcaprolac - tams is described. In Chapter 2, the synthesis, by several methods, of simple 3 - alkylcaprolactams is investigated. Chapter 3 describes synthetic methods for the preparation of 4 - substituted caprolactams. Chapter 4 presents the preparation of 5 - alkyl and 7 - alkyl - caprolactams by the Schmidt reaction on 4 - alkyl and 2 - alkylcyclo - hexanones. Chapter 5 describes some investigations of possible syntheses of 6 - alkylcaprolactams. Chapter 6 contains the results of testing of some lactams and thiolactams as well as their structure - activity relationships. / Thesis (Ph.D.)--Department of Organic Chemistry, 1976.

Thesis (Ph.D.)--University of Adelaide, Department of Organic Chemistry, 1977. / Includes bibliographical references.

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Stress is an important risk factor for the development of clinical depression, yet little is known about the neurobiological mechanisms by which stress might promote depressive symptomatology. The brain is particularly susceptible to the negative effects of stress, as high levels of stress hormones result in decreased hippocampal neurogenesis, slowed cell maturation, and decreased cell complexity. Although we already know that these neurobiological changes are associated with significant impairments in important psychological functions such as learning, memory and motivation, we know little about the molecular details of this stress-induced remodeling and how it contributes to the development of depression. Currently, one candidate molecule of particular interest is reelin, an extracellular matrix protein responsible for regulating neuronal maturation and synaptic plasticity in the adult brain. Interestingly, recent post- mortem analyses indicate that reelin expression is decreased in depressed patients. Similarly, preclinical research has shown that repeated glucocorticoid administration significantly reduces reelin expression in the adult hippocampus. Combined, these results suggest that reelin may be an important protein to examine in regards to the pathogenesis of depression as well as a potential therapeutic target for the treatment of this disorder. The goal of this dissertation is to provide a comprehensive examination of the influence repeated glucocorticoid administration has on reelin expression in the rat hippocampus, and how this relates to the pathogenesis of depression. In chapter 2 we examined how co-treatment with the stress hormone corticosterone (CORT), and the antidepressant imipramine, influence reelin expression in the proliferative region of the hippocampus. In addition we determined whether changes in reelin expression are associated with alterations in neurogenesis and behavioral measures of depression. Results revealed that imipramine prevents CORT-induced downregulation of reelin in the hippocampus, and that these changes parallel improvements in FST behavior, increased neurogenesis and enhanced maturation of immature granule cells. Importantly, these data provide further evidence of reelin’s role in depression and establish this protein as a target of antidepressant treatment. In chapter 3 we examined the effect of CORT on a number of interneuron markers that co-localize with reelin throughout the hippocampus to determine whether the populations of neurons that express reelin are lost or are no longer expressing this protein. Results of this study indicate that CORT influences a number of interneuron markers in a region-specific manner in the hippocampus, but does not cause these cell populations to die, suggesting that CORT exploits an intracellular mechanism to regulate reelin expression in the hippocampus. Finally, in chapter 4, the influence of CORT on MeCP2 and DNMT1, two markers associated with DNA methylation, was examined in the hippocampus to elucidate a potential intracellular mechanism for CORT-induced reelin deficits. Results of this study indicate that CORT has no influence on global protein levels of these markers, but significantly increases the number of MeCP2-expressing cells in the proliferative subgranular zone of the hippocampus, suggesting that there is an increase in the number of methylated cells in this region. While it cannot be conclude from this study that increased methylation causes reelin deficits, the fact that an increase in MeCP2 is seen in the exact region where reelin deficits are most pronounced suggest it is possible. Moreover, these findings are novel, and suggest a role for MeCP2, and more generally, DNA methylation, in the neurobiology of depression. Collectively, the results of this dissertation enhance our understanding of the functional consequences of altered hippocampal neuroplasticity on the development of depressive symptomatology, and the role that reelin may play in this process. They also provide further support for reelin as a novel therapeutic target for the treatment of major depression.