For the last twelve years the investigator's laboratory has attempted to identify a specific and readily obtainable biological marker for depression. Platelet a2-adrenergic receptors (a2AR) were of theoretical interest because brain a2AR modulate monoamine output. In the wake of over 60 studies or the platelet a2AR in depression, the investigator noted a high degree of consistency only with an elevation in radioligand binding amongst those studies which utilized imidazolines (principally 3H-clonidine) in their """"""""a2 assays"""""""". After thoroughly characterizing the imidazoline-receptive sites on human platelets, the investigator concluded that platelets possess a nonadrenergic imidazoline receptor (IR1) binding site, in addition to an a2AR. In four studies of depression, and one of dysphoric PMS, the investigator has consistently observed an elevation of IR1 on platelet plasma membranes of depressed patients compared to matched controls, suggesting that the earlier literature might be explained by IR1 sites. The investigator also found that treatment of patients with either desipramine (DMI) or fluoxetine for 6 weeks leads to normalization (i.e., down regulation) of platelet IR1, suggesting that the platelet IR1 site might be a state marker for depression. These alterations were not correlated with changes in catecholamines. After transferring the grant from Case Western Reserve University the investigator replicated his findings in depressed patients with a demographically different population. Furthermore, he has developed a selective antibody assay for the IR1 protein, which is 100-fold more sensitive than the older IR1 radioligand binding assay. Using IR1-selective antiserum, depressed patients continue to display a marked elevation in the platelet IR1 density. The density of this single band (33 kDa), as detected on Western blots, is linearly correlated with the IR1 Bmax values of platelet samples. Recently the investigator has also observed an increase in 33 kDa/IR1 in hippocampi of depressed victims of suicide. Thus, in our search for an a2AR marker, he uncovered a novel nonadrenergic receptive protein which in five pre-treatment and 3 post-treatment studies of depression (and as assayed by two independent techniques) appears to be a marker for depression. The investigator's specific aims will determine: a) the extent to which IR1 elevation is observed throughout brain regions of depressed suicide victims, b) whether depressed patients also exhibit a functional IR1 alteration in hypothalamic growth hormone (GH) and prolactin responses to moxonidine infusions (as assessed under an a2AR mask), c) whether the potential platelet IR1 marker is sensitive to the severity of depressive illness, and d) whether the IR1 neurotransmitter candidate, agmatine, is also altered in depression.
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