There is abundant evidence that both genetic factors and various environmental influences control the development, and ultimately the level of activity, of the adult CNS serotonergic neural systems. There is also unequivocal evidence that both genetic and environmental factors contribute to the vulnerability to many psychiatric disorders, including depression. As noted in the introduction of this CCNMD application, childhood abuse/neglect has been-established as a major risk factor in adult depression These findings suggest that both genetic and environmental influences contribute to individual differences in serotonergic function, and that this impacts upon an individual's vulnerability or resistance to develop depression or other disorders associated with altered CNS 5-HT function. In this project, we investigate the effect of adverse early experience on the development and function of the 5-HT system, utilizing two different animal models. The rodent early life stress model utilizes rats exposed to 180 min of maternal separation on postnatal days 2 to 14 as described in detail in Core B. The primate model also represents an epigenetic model described in detail in Core C; the early life stress is a variable foraging demand (VFD) on the mother reducing the amount of time she has to attend to her infant. The maternal separation and VFD stressors cause persistent changes in the CNS of adult animals as well as documented behavioral alterations. Among the neurochemical consequences of this manipulation in rats are increased hippocampal 5- HT2A receptor density, increased stress-induced HPA axis responsiveness, increased regional CRF concentrations in the CNS, increased CRF mRNA expression, and decreased glucocorticoid receptor density in hippocampus and frontal cortex. The behavioral consequences of the maternal separation stress include increased fear/anxiety behaviors and a pronounced preference for alcohol. All of these neurochemical and behavioral manifestations of maternal separation in adult rats are reversed by chronic treatment with paroxetine, a specific serotonin reuptake inhibitor. VFD monkeys exhibit altered endocrine responses to serotonergic challenge, CSF 5-HIAA alterations, and increased CSF CRF concentrations. Therefore, we propose to characterize the serotonergic systems of both models in detail, including developmental ontogeny, directly testing the role of increased 5-HT2A receptor function in mediating the phenotype, and response to antidepressants. We also propose multiple interactions with the different components of the Center including both basic science and clinical projects as well as all of the Cores. Our pilot data supports the hypothesis that serotonergic dysfunction is a central feature of the phenotypes displayed by each proposed model; and that alterations in markers of serotonergic activity will also be found in the two clinical projects.
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