Neurochemistry of Serotonin System in Suicide Victims

Janine E. Janosky, Ph.D. - Statistician

Various indices of serotonergic function have been reported to be altered in the central nervous system of depressed and suicidal individuals. A variety of postmortem brain studies and clinical investigations have provided evidence that serotonin neurotransmission is reduced in suicide victims, suicide attempters and depressed patients. While the clinical and postmortem studies have provided a valuable contribution towards understanding the role of serotonin in the pathophysiology of suicide and depression, an important question that remains: what neurochemical substrate or mechanism is responsible for the deficit in serotonin neurotransmission in depressed suicide victims?

The neurons that contain the biosynthetic machinery for synthesizing serotonin are located in the raphe nuclei of the brainstem. Surprisingly, very little information is known regarding the biosynthetic integrity of these serotonin neurons in suicide victims. We propose that a dysfunction exists in a selective population of brainstem serotonin neurons which leads to a reduction in the synthesis and release of serotonin in suicide victims with a history of major depression. We also propose that additional sites of alteration exist in serotonin neurons in depressed suicide victims which develop as adaptive or maladaptive responses to the deficit in serotonin biosynthesis. This proposal is intended to investigate the biosynthetic integrity of key neuronal substrates involved in regulating serotonin neurotransmission in postmortem brainstem raphe nuclei and in cortex of suicide victims with a confirmed diagnosis of major depression and matched non-psychiatric controls. The serotonergic neurochemical measurements will also be conducted in a group of subjects with major depression that died of natural or accidental causes and in cases of suicide victims without a diagnosis of major depression, but with depressive symptoms. The serotonergic neurochemical measurements conducted in these subject groups will determine whether serotonergic alterations exist in suicide victims with major depression, in non-suicide subjects with major depression or in suicide victims not classified as unipolar depressed but with depressive symptomatology. The specific aims of these studies will address the following questions:

• 1. Is the reduction in serotonin neurotransmission in depressed suicide victims the result of a deficiency in the biosynthesis of the rate-limiting enzyme, tryptophan hydroxylase (TPH), and are these changes restricted to specific subpopulations of brainstem serotonin neurons?

• 2. What adaptive or maladaptive neurochemical events occur in other serotonergic regulatory substrates in response to the deficit in serotonin biosynthesis in depressed suicide victims?

• 3. Is the deficiency in serotonin biosynthesis in dorsal raphe neurons in depressed suicide victims also evident at the terminal fields of these neurons?