The 5-HT2A receptor mediates some of the key effects of serotonin in the central nervous system. In this Mentored Clinical Scientist Development Award, a program of research is outlined that will investigate the role of the 5-HT2A receptor in modulating stress and anxiety responses. Alterations in serotonergic transmission via the 5-HT2A receptor have been implicated in human disorders such as depression, schizophrenia, and anxiety. In animal models the 5-HT2A receptor exhibits opposite effects on anxiety and stress at different times during development. In adults, stimulation of the 5-HT2A receptor appears to increase stress hormone release, increase analgesia and temperature, and increase anxiety-driven behaviors, while blockade of the 5-HT2A receptor acts to reduce these responses. In contrast, during critical periods of early postnatal development, activation of the 5-HT2A receptor reduces stress and anxiety responses in adults via increased negative feedback of the HPA axis at the level of the hippocampus. As these mechanisms may play an important role in the development and expression of human stress and anxiety disorders, we propose to study this question with a genetic mouse model of 5-HT2A receptor dysfunction. This 5-HT2A receptor knockout mouse strain will be a useful tool to address the role of this receptor in the development, modulation, and integration of stress and anxiety responses. We propose a series of experiments that will examine the phenomenology and mechanisms of the behavioral and physiologic responses of 2A knockout mice during different stress paradigms. The career development of the candidate during this award will be provided by three outstanding mentors: Rene Hen (for transgenic expertise), Myron Hofer (for behavioral and phsyiological expertise), and Jack Gorman (to provide the candidate with clinical perspectives of anxiety and stress disorders). In addition, collaborative relationships with several experts has also been arranged with members of Dr. Hofer's Division and with Eric Kandel and Michael Meaney outside the Division. From the conduct of this research under their supervision, the candidate will expand his capabilities with advanced methods of transgenic technology, acquire new skills in behavioral and physiological analysis, and maintain an ongoing connection to reciprocal hypotheses that influence thinking in basic and clinical aspects of mental processes. The goal of this award is to generate new insights into the role of the 5-HT2A receptor in processes of stress and anxiety as well as provide the candidate with the continuity of support necessary to develop a program of funded research into basic genetic, neural, and behavioral mechanisms that are relevant for psychiatric disorders.
