SLEEP DEPRIVATION AND 5-HT AUTOREGULATORY PROCESSES

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DESCRIPTION (applicant's abstract): This Mentored Clinical Scientist Developmental Award application includes a program of career developmental and research training for the applicant, Faustino Lopez-Rodriguez, M.D, Ph.D. The ultimate goal of the applicant is to develop as an independent investigator in examining the neurobiology of antidepressant mechanisms of action. The career developmental and research plan are designed to allow the applicant to reach this goal. The applicant intends to supplement his background in electrophysiology with techniques in neurochemistry (microdialysis of biogenic monoamines in behaving animals and high performance liquid chromatography) and molecular biology, which he plans to acquire during the Award period. The applicant intends to apply his expertise in sleep physiology to study the neurobiological mechanisms underlying the antidepressant effects induced by sleep deprivation. In this proposal, and as a first step in an overall research program, the applicant will concentrate on the effects of sleep deprivation on serotonin (5-HT) activity. His specific aims are as follows. 1) Sleep deprivation induces changes in 5-HT release in forebrain structures and is accompanied by sustained high levels of 5-HT in the raphe. 2) Sleep deprivation changes the activity of 5-HT1A and 5-HT1B autoreceptors. The applicant hypothesizes that sleep deprivation blocks the effects of 5-HT1A and/or 5HT1B agonists on 5-HT release, as well as the amounts and synthesis of 5-HT1A and 5-HT1B autoreceptors. 3) Sleep deprivation modifies the synthesis of 5-HT. In addition to studying the overall effect on 5-HT synthesis, the applicant will determine the effect of sleep deprivation on brain tryptophan concentration, gene expression of tryptophan hydroxylase (TPH, the rate-limiting enzyme in the biosynthetic pathway), and TPH activity. A better understanding of these sleep deprivation-related changes has the potential to advance our knowledge, both in sleep physiology and antidepressant mechanisms of action.