Despite their acknowledged efficacy, currently available antidepressants still demonstrate undesirable side effects, shortfalls in effectiveness and a delayed onset of action. All these agents act via monoaminergic mechanisms, although recent studies have begun to note the potential role of the cholinergic system as well as the amino acid pathways in affective isorders. It has been suggested that glutamate NMDA receptor activation may be involved in hippocampal degeneration seen in patients with depression, as well as contributing as a molecular target for the antidepressant action of known antidepressant drugs. Glutamate either separately or via the release of nitric oxide, regulates the release of various transmitters in the brain critical for affective state, e.g. monoamines (noradrenaline, dopamine), indoleamines (5HT), y-aminobutyric acid (GABA) and acetylcholine. The aim of this study was to investigate N-methyl-D-aspartate (I\IMDA) and muscarinic M1 receptor characteristics and also GABA and acetylcholine levels in a genetic animal model of depression, the Flinders Sensitive Line (FSL) rat, with respect to its control, viz. Flinders Resistant Line (FRL) rat, thereby establishing a possible role for the amino acid and cholinergic pathways in the hippocampus and frontal cortex, two brain areas implicated in depression. In addition, anxietylike behaviours were assessed using the open field and social interaction tests. A sensitive liquid chromatography tandem mass spectrometer (LC/MS/MS) method was used in the quantification of acetylcholine as well as high performance liquid chromatography with electrochemical detection (HPLG-EGD) for the quantification of GABA in the above-mentioned brain areas of FSL and FRL rats. NMDA and muscarinic M1 receptor characteristics were expressed in terms of receptor denSity (Bmax) and affinity (Kd) values and were performed using [3H]-MK801 (27.5 Gi/mmol) and quinuclidinyl benzilate (52.0 Gilmmol) for NMDA and M1 receptors, respectively. In addition, to provide evidence for face validity, behavioural assessments were routinely performed using the open field test and social interaction test. Significantly elevated levels of acetylcholine were found in the frontal cortex but with significantly reduced levels in the hippocampus of FSL rats. Cortical and hippocampal muscarinic receptor binding characteristics remained unchanged, while no differences with regard to GABA levels and NMDA receptor binding characteristics were noted in these brain areas. In concordance with studies from the literature, aversive and locomotor behaviour as measured in the open field test, provided evidence of anxiogenic behaviour in the FSL rat, evinced by significantly less social interaction than their FRL counterparts. In addition, evidence for a lack in general activity of the FSL rat in the open field was also noted. Our data therefore suggest the presence of a cholinergic dysfunction in both the frontal cortex and hippocampus of the FSL rat, although this is not accompanied by simultaneous changes in muscarinic M1 receptor binding in key limbic brain regions. Although increased cholinergic drive is a recognised characteristic of FSL rats and is representative of the model's' construct validity, we suggest that the depressive phenotype of these animals is not related to altered cholinergic activity in a single brain region, but instead involves various limbic brain regions, possibly being more dependent on opposing cholinergic deficits in the cortex and hippocampus. / Thesis (M.Sc. (Pharmacology)--North-West University, Potchefstroom Campus, 2009.

Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Sydney, 2007. / Cotutelle thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Discipline of Pharmacology, Faculty of Medicine, University of Sydney and to the Doctoral School: Santé, Sciences et Technologies, University of Tours (France). Title from title screen (viewed Sept. 21, 2007). Includes bibliography. Also issued in print.

Thesis (M.S.) --University of Texas Graduate School of Biomedical Sciences at San Antonio, 2008. / Vita. Includes bibliographical references.

Thesis (Ph.D.)--Medical University of Ohio, 2005. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences." Major advisor: Joseph F. Margiotta. Includes abstract. Document formatted into pages: iii, 226 p. Title from title page of PDF document. Bibliography: pages 80-92,130-139,149-225.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 45-50).

Thesis (Ph.D.)--Uppsala Universitet, 2009. / This website links to the complete document in PDF format. Title from title screen (viewed on November 21, 2009). Includes bibliographical references.

Asthma is a chronic inflammatory lung disease characterized by recurrent wheezing, coughing and difficulties in breathing. Asthma affects 25.7 million people in the USA including 8 million children. Asthma is often associated with early-life exposure to environmental insults. However, mechanisms that link early-life insults to persistent airway dysfunction are unknown. Our previous studies in mice showed that early-life allergen exposure increases the levels of neurotrophin 4 (NT4) causing airway smooth muscle (ASM) hyper innervation and persistent airway hyper reactivity (AHR). I show that early-life allergen exposure selectively increases cholinergic innervation. Notably, cholinergic nerves release acetylcholine, a potent airway constrictor that signals through the M3 receptor in ASM. Building upon these findings, my thesis encompasses two components. Firstly, how is NT4 expression aberrantly up regulated following early-life allergen exposure? Secondly, what is the effect of enhanced cholinergic innervation on the neonatal ASM? I find that NT4 is selectively expressed by ASM and mast cells in mice, nonhuman primates and humans. We show in mice that while NT4 expression in ASM remains unchanged upon allergen exposure, mast cells expand in number and degranulate to release NT4 thereby increasing NT4 levels in the lung. Adoptive transfer of wild-type mast cells, but not NT4-/- mast cells restores ASM innervation and AHR in KitW-sh/W-sh mice following early-life insults. In an infant primate model of asthma, the increased ASM innervation is also associated with the expansion and degranulation of mast cells. Therefore, pulmonary mast cells are a key source of aberrant NT4 expression following early-life insults in both mice and possibly primates. Next, I speculated that an increased cholinergic output in the neonatal lung might lead to persistent AHR. Using recurrent methacholine exposure and M3 receptor blocker, 4-DAMP, I show that enhanced cholinergic signaling in neonatal mice leads to persistent AHR without inflammation. In contrast, methacholine exposure in adult mice has no prolonged effects on airway reactivity. Together, my findings support a model in which deregulated neural activities following early-life insults cause persistent ASM hyper contractility. Thus, early-life interventions to block mast cell degranulation and the cholinergic pathway may benefit children with recurrent wheezing. / 2016-12-15T00:00:00Z