Regulation of 5‐HT Receptors and the Hypothalamic‐Pituitary‐Adrenal Axis

ABSTRACT: Disturbances in the serotonin (5‐HT) system is the neurobiological abnormality most consistently associated with suicide. Hyperactivity of the hypothalmic‐pituitary‐adrenal (HPA) axis is also described in suicide victims. The HPA axis is the classical neuroendocrine system that responds to stress and whose final product, corticosteroids, targets components of the limbic system, particularly the hippocampus. We will review resulsts from animal studies that point to the possibility that many of the 5‐HT receptor changes observed in suicide brains may be a result of, or may be worsened by, the HPA overactivity that may be present in some suicide victims. The results of these studies can be summarized as follows: (1) chronic unpredictable stress produces high corticosteroid levels in rats; (2) chronic stress also results in changes in specific 5‐HT receptors (increases in cortical 5‐HT2A and decreases in hipocampal 5‐HT1A and 5‐HT1B); (3) chronic antidepressant administration prevents many of the 5‐HT receptor changes observed after stress; and (4) chronic antidepressant administration reverses the overactivity of the HPA axis. If indeed 5‐HT receptors have a partial role in controlling affective states, then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood. These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance.