Women suffer from anxiety disorders at twice the rate of men (Palanza, 2001; Pigott, 2003; Steiner et al., 2003). Ovarian hormones, such as estrogen, are thought to play a significant role in regulation of anxiety, perhaps by modulating the serotonin (5-HT) system emanating from the dorsal raphe nucleus (DRN). The DRN, a major source of serotonergic innervation in the forebrain, plays a critical role in stress responsiveness (Maes and Meltzer, 1995; Sandford et al., 2000). Although controversial, both estrogen and serotonin has been shown to be anxiolytic, as antidepressant drugs collectively known as selective serotonin reuptake inhibitors (SSRIs) commonly used to treat anxiety disorders target the serotonergic system and estrogen treatment can augment the effects of SSRls. Variety of animal studies also show that estrogen increase 5-HT neurotransmission at multiple regulatory points (Rubinow et al., 1998). These studies suggest a possible interaction between estrogen and the DRN 5-HT system in regulating anxiety.
The focus of this dissertation is to investigate the effects of this interaction between estrogen and serotonin on regulation of anxiety, with overarching hypothesis that estrogen-induced increase in 5-HT neurotransmission mediates the anxiolytic effects. To investigate this hypothesis, I examined the following questions: (1) In what circumstances is estrogen anxiolytic? (2) What are the effects of estrogen treatment on some of the key genes important for serotonergic activity? (3) Do these estrogen-induced alterations in the serotonergic gene expression mediate the anxiolytic effects?
The results from these studies suggest that chronic estrogen treatment increases the capacity of DRN to enhance 5-HT neurotransmission in a region specific manner and that this in turn mediates the anxiolytic effects, supporting the hypothesis that DRN 5-HT system plays a critical role in estrogen's anxiolytic actions. We also report that activation of another distict subregion of DRN via estrogen-independent stimuli may be anxiogenic, reiterating recent notion that multiple subregions of the DRN 5-HT system are able to respond to different stimuli in an appropriate manner, which may also explain why estrogen and serotonin can have such multifaceted effects on anxiety. We hope that this work will contribute to advancing the steps towards developing improved treatment for women with anxiety disorders by better understanding the mechanisms underlying the regulation of anxiety by estrogen and serotonin.
|Advisor:||Neumaier, John F.|
|School:||University of Washington|
|School Location:||United States -- Washington|
|Source:||DAI-B 69/06, Dissertation Abstracts International|
|Subjects:||Neurology, Psychobiology, Physiological psychology|
|Keywords:||Anxiety, Female, Ovarian hormone, Progesterone, Raphe nucleus, Tryptophan hydroxylase|
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