Several studies suggest upregulation of serotonin2A (5-HT2A) receptors in the brain of suicide victims with or without depression and in platelets of depressed and suicidal patients. The significance and the mechanisms of this upregulation of 5-HT2A receptors and their functional consequences have not been explored. The investigator hypothesizes that the upregulation of 5-HT2A receptors in the brain and in platelets of depressed patients is caused by an abnormal HPA axis. The major objectives of the proposed studies are thus to examine the significance and the mechanisms of the upregulation of platelet 5-HT2A receptors and its relationship to the brain 5-HT2A receptors, which will be achieved by conducting a clinical and an animal study.
The specific aims of the investigator's clinical component are to study 5-HT2A receptor number and the 5-HT2A functional consequences as well as PKC, a key component in the 5-HT-linked PI signaling system, in platelets obtained from depressed patients and normal controls. The investigator will further examine the relationship of 5-HT and PKC measures with suicidal and impulsive/ aggressive behavior in depressed patients. To examine of 5-HT2A upregulation in depressed patients is related to abnormal HPA function, he will correlate 5-HT2A receptor measures with plasma cortisol and nonsuppression of the dexamethasone suppression test (DST). The objectives of the proposed animal studies are to examine if an abnormal HPA will modulate 5-HT2A receptors and PKC both in the brain and in platelets. This will be achieved by studying 5-HT2A receptor number, 5-HT2A mRNA levels in the brain, 5-HT2A receptor number in platelets, 5-HT- and phorbol myristate acetate (PMA)-induced PKC translocation, (3H)phorbol dibutyrate (PDBU) binding and PKC activity in the brain, and immunolabeling of PKC isozymes in the brain and in platelets obtained from rats treated with corticosterone (CORT), dexamethasone (DEX), or adrenocorticotropical hormone (ACTH), and from adrenalectomized (ADX) rats and in ADX rats treated with CORT. The investigator's study will thus not only clarify the role of 5-HT2A receptors and PKC in the pathophysiology of depression, but it will also elucidate the mechanisms by which 5-HT2A receptors are upregulated both in the brain and in platelets. These studies may thus increase our understanding of the pathophysiology of depression and may help identify depressed or suicide-prone patients.
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