Chronic obstructive pulmonary disease (COPD) is characterized by periodic episodes of worsening symptom (e.g., shortness of breath, irregular breathing, and worse coughing with increased phlegm production), also called pulmonary exacerbations. Inflammation is an important cause of reduced lung function as inflammation contributes to airflow obstruction in the small airways and lung parenchyma. Even in individuals with mild COPD, inflammation reduces lung function, accelerates decline in lung function overtime, and increases the risk for respiratory exacerbations. Agents that reduce systemic inflammation are hypothesized to decrease the inflammation in the lungs, resulting in improvements in lung function and a decrease in exacerbation frequency. We hypothesize that antidepressants have a beneficial effect on lung function. In addition to having anti-inflammatory properties, antidepressants act upon serotonin, which is integral in central breathing control. The combination of the anti-inflammatory and serotonergic effects may provide users of selective serotonin reuptake inhibitors with a lung function benefit while avoiding the side effects of steroids. This dissertation assesses whether selective serotonin reuptake inhibitors increase concurrent lung function and reduce the risk for respiratory exacerbations. It consists of three parts: a systematic literature review and two analytic papers using large prospective databases. The systematic review of the literature identified limitations concerning the effect of selective serotonin reuptake inhibitors on lung function. Overall, the analytic papers found no support for a beneficial association between selective serotonin reuptake inhibitors and spirometry, dyspnea or pulmonary exacerbations; indeed the association was in the opposite direction as hypothesized. In addition, there was no support for meaningful mediation by inflammatory markers. Further research is needed to determine if selective serotonin reuptake inhibitors have a harmful effect on lung function and pulmonary exacerbations.

Thesis (Ph. D)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 65-78).

Thesis (Ph. D.)--University of Texas at Austin, 1998. / Vita. Includes bibliographical references (leaves 193-206). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph.D.)--Virginia Commonwealth University, 2010. / Prepared for: Dept. of Pharmacology and Toxicology. Title from title-page of electronic thesis. Bibliography: leaves 98-107.

No description available.

For over half a century, the monoamine hypothesis has been the dominant theoretical framework guiding depression research and drug development. This hypothesis posits that depression arises from a deficiency in the monoaminergic neurotransmitters serotonin, norepinephrine, and possibly dopamine, and that antidepressants function by increasing extracellular availability of these monoamines in the brain, especially at the synaptic level. It is clear however, that the monoamine hypothesis cannot fully explain either the pathophysiology of depression nor the mechanisms of antidepressant action. Tianeptine is an atypical antidepressant used in Europe to treat patients who respond poorly to selective serotonin reuptake inhibitors (SSRIs). The recent discovery that tianeptine is a mu opioid receptor (MOR) and delta opioid receptor (DOR) agonist has provided a potential avenue for expanding our understanding of antidepressant treatment beyond the monoamine hypothesis. This dissertation aims to understand the neural circuits underlying tianeptine’s antidepressant effects. We first characterized the acute and chronic effects of tianeptine on depressive-like and other opioid-related behaviors in mice, and used genetic and pharmacological models to test whether these behavioral effects are mediated by MOR and/or DOR. We found that acute tianeptine administration produced an antidepressant-like reduction in immobility time in the forced swim test, as well as classic opioid-like effects including analgesia, hypophagia, hyperactivity, and conditioned place preference. These behavioral responses to tianeptine are abolished in MOR knockout (KO) mice and in mice that have been pretreated with an MOR antagonist. By contrast, all responses to tianeptine remained intact in DOR KO mice. Remarkably, unlike other classic opiates such as morphine, chronic tianeptine treatment did not produce tolerance to tianeptine’s analgesic effect, nor naloxone-precipitated withdrawal. The acute behavioral effects of tianeptine (excluding analgesic effects, which were present at 15 minutes, but not 1 hour) were established to occur at 1 hour post-injection and to be largely absent by 3 hours post-injection. Chronically, tianeptine produced an antidepressant effect in corticosterone-treated mice, and prevented the development of restraint-stress-induced depression-like behavior, both in an MOR-dependent manner. Interestingly, tianeptine’s chronic antidepressant-like effects were evident in mice after as little as one week of treatment, rather than several weeks as might be expected for SSRIs. Using tissue-specific MOR knockouts, we further showed that MOR expression on GABAergic cells, specifically somatostatin-positive neurons, is necessary for the acute and chronic antidepressant-like responses to tianeptine. By contrast, tianeptine’s behavioral effects did not require the expression MORs on D1- and parvalbumin-expressing cells, nor the expression of ß-arrestin 2. These experiments also revealed a dissociation between the antidepressant-like phenotype and other opioid-like phenotypes resulting from acute tianeptine administration such as analgesia, conditioned place preference, and hyperlocomotion. Critically, we found that tianeptine’s mechanism of action is distinct from fluoxetine in three important aspects: 1) tianeptine requires MORs but not DORs for its chronic antidepressant-like effect, while fluoxetine is the opposite, 2) unlike fluoxetine, tianeptine does not promote hippocampal neurogenesis, and 3) tianeptine’s effects appear to persist even after serotonin depletion. Taken together, these results suggest a novel entry point for understanding what circuit dysregulations may occur in depression, as well as possible targets for the development of new classes of antidepressant drugs.

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 4 uppsatser.

Serotonin (5-HT) is a neurotransmitter in the central nervous system. Decrease in the brain 5-HT level could induce depression, showing a state of low mood, aversion to motion and feeling of worthlessness. About 12 million adults in the United States have depression. Antidepressants, such as monoamine oxidase inhibitors and selective serotonin reuptake inhibitors, can alleviate the depressive mood by increasing the brain's 5-HT activity, however they can also induce a potentially life-threatening side effect, namely 5-HT syndrome. This syndrome is manifested by neuromuscular hyperactivities, mental disorders and autonomic dysfunctions. Clinical studies have demonstrated that 5-HT2A receptor antagonists could effectively block severe symptoms of patients with the 5-HT syndrome. To understand the underlying mechanisms, in this study we examined the activity of the 5-HT2A receptor in rats with the 5-HT syndrome evoked by a combined injection of clorgyline, a monoamine oxidase inhibitor , and paroxetine, a selective 5-HT reuptake inhibitor. The major findings from my study were that: (1) Chronic clorgyline treatment significantly exacerbated 5-HT2A receptor-mediated symptoms of the 5-HT syndrome animals; (2) The 5-HT2A receptor-mediated symptoms were also aggravated when the 5-HT syndrome animals were housed in warm (32 ÀC) ambient temperature; (3) Blocking 5-HT2A receptors in the medial prefrontal cortex alleviated the 5-HT syndrome through a circuit between raphe serotonergic neurons and medial prefrontal cortex glutamatergic neurons. Taken together, my data demonstrate that the activity of 5-HT2A receptors may be enhanced by chronic antidepressant treatment and warm environmental temperature. / The sensitized 5-HT2A receptor in the medial prefrontal cortex may exacerbate the syndrome through a positive-feedback circuit between medial prefrontal cortex and raphe nuclei, which would result in excessive 5-HT in the brain. This study casts a new light on the underlying mechanisms of the 5-HT syndrome. / by Gongliang Zhang. / Thesis (Ph.D.)--Florida Atlantic University, 2010. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2010. Mode of access: World Wide Web.

Title from title page of PDF (University of Missouri--St. Louis, viewed Mar. 3, 2010). Includes bibliographical references (p. 113-127).

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.