The long-term objective of this research is to test the hypothesis that the development of delusions in major depression is due to the effects of patients' own HPA axis overactivity on central dopamine (DA) systems. Major Depression with psychotic features (PMD), a syndrome with marked morbidity, is characterized by both increased hypothalamic-pituitary - adrenal (HPA) axis activity and increased levels of plasma and cerebrospinal fluid (CSF) homovanillic acid (HVA). This research has major implications for understanding the pathogenesis of PMD, identifying potential genetic risk factors, and developing new, more effective and less toxic treatments.
The specific aims i nclude: l.) To characterize the circadian rhythm of plasma homovanillic acid (HVA) in healthy human subjects and its relationship to the circadian rhythm of plasma cortisol and adrenocorticotropic hormone (ACTh). 2.) To compare the circadian rhythms and relative amplitudes of plasma HVA in PMD patients, non psychotic major depressed (NPMD) patients and healthy volunteers; to assess the relationships between components of the HPA axis and HVA in PMD patients; and to more precisely characterize the HPA overactivity in PMD as compared to NPMD patients and healthy controls. 3.) To compare the effects of the administration of oCRH, ACTH, hydrocortisone and saline on plasma HVA levels over the 48 hours post-injection in healthy controls, PMD patients, and NPMD patients. 4.) Utilizing intact, hypophysectomized, and adrenalectomized rats to determine which components of the HPA axis independently increase central dopamine activity, particularly in the mesocortical and mesolimbic DA systems, and to explore the mechanisms underlying such increases. Forty PMD patients, 40 NPMD patients, and 40 controls will be studied in G-CRC settings. Subjects will have blood collected for determination of ACTH, cortisol and HVA on an hourly basis for 24 consecutive hours before they receive one of the following: saline, ACTH, oCRH or hydrocortisone. Bloods will then be collected hourly for the next 24 hours and bi-hourly for the following 24 hours. Comparisons among groups of subjects will be made on basal ACTh, cortisol and HVA levels as well as on changes in these measures in response to specific challenges. Similar experiments will be conducted in intact, hypophysectomized, and adrenalectomized rats. Rats will be sacrificed at multiple time points post-challenge. Monoamines and metabolites as well as mRNA activity and protein levels primarily for tyrosine hydoxylase will be measured in specific brain regions and the periphery by RNase protection assay, radioenzymatic assay and immunotitration respectively. Where differences are found in mRNA, activity, and protein, they will be further localized cellularly by in situ hybridization and immunohistochemistry.
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