Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Mechanisms Underlying Stress-Induced Activation of Serotonergic Systems

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Evidence supports the hypothesis that genetic influences, together with adverse experience, either during early life or during adulthood, contribute to the vulnerability of individuals to stress-related neuropsychiatric disorders, including anxiety and depression. One mechanism through which these factors may influence vulnerability to these disorders is through effects on monoaminergic systems, including brainstem serotonergic systems that are thought to play an important role in the development and pathophysiology of stress-related psychiatric disorders. We propose to study how exposure to stress activates serotonergic systems. Such studies are a prerequisite for understanding how chronic stress leads to dysfunction of serotonergic systems and, ultimately, the mechanisms underlying dysregulation of serotonergic systems in patients with stress- related psychiatric disorders. The proposed studies are designed to lead to novel strategies for preventing the onset of stress-related mental disease. The overall hypothesis is that stress-induced increases in serotonergic activity depend on activation of projections from the central amygdaloid nucleus (CE) to the caudal dorsal raphe nucleus (DR). The CE is an important component of brain circuits regulating autonomic and behavioral responses to stress and fear-related stimuli, while the DR is the main source of serotonergic innervation of limbic forebrain structures regulating anxiety and mood. First, we will test the hypothesis that stress-induced activation of serotonergic systems depends on activation of CRF2 receptors within the caudal DR. Second, we will test the hypothesis that stress-induced activation of serotonergic systems is dependent on norepinephrine (NE) signaling in the CE. Third, we will test the hypothesis that the CE acts as a coincidence detector where stress-induced elevation of glucocorticoid hormones and stress-induced NE release within the CE act synergistically to increase mesolimbocortical serotonergic activity and TPH activity. We will also test the hypothesis that the mechanism underlying this coincidence detection is glucocorticoid-mediated blockade of NE clearance by the low-affinity, high-capacity, corticosterone-sensitive transporter, organic cation transporter 3 (OCT3). OCT3 is known to mediate uptake 2, an alternative uptake mechanism for monoamines recently characterized in rat brain. These hypotheses will be tested using site-specific activation and blockade of specific receptors, measurement of serotonergic activity using microdialysis, and measurement of in vivo tryptophan hydroxylase activity. These studies are designed to provide new and important information related to the neural mechanisms through which stressful experiences activate serotonergic systems. Understanding the mechanisms involved in stress-induced activation of brain serotonergic systems may allow attenuation or prevention of long-term detrimental consequences of stress in individuals that are believed to be vulnerable to stress-induced neuropsychiatric disorders, either by virtue of genetic susceptibility, adverse early life experience, or chronic or intermittent exposure to a stressful environment. Stress-related neuropsychiatric disorders including anxiety disorders and depression represent a significant public health problem. For example, unipolar depression is projected to rank second, behind ischemic heart disease, as a cause of disability adjusted life years (DALYs) by the year 2020. This projected outcome demands that we begin to explore mechanisms that precipitate the onset of stress-related disease, so that we can ultimately prevent mental disease in susceptible individuals. This proposal is designed to address this important need by investigating mechanisms through which stress activates serotonergic systems that are thought to be central to both the etiology and pathophysiology of stress-related mental disease.
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