Publisher Summary This chapter describes the serotonin (5-HT) and pituitary-adrenal function. The effects of altering 5-HT synthesis on the diurnal rhythm of plasma corticosterone and on the pituitary adrenal response to stress were studied in rats and man. The hypothesis is proposed that 5-HT mediates the corticosteroid negative feedback mechanism that regulates corticotrophin (ACTH) secretion and that the primary site of this feedback is extra hypothalamic. In contrast, pretreatment with I-tryptophan, 5-HTP alone or 5-HTP and MK 486 reduced slightly the stress response in intact rats and 5-HTP with MK 486 reduced 24 h urinary 17-hydroxycorticosteroids (17-OHCS) excretion in humans. On the other hand corticosterone administration or stress increased the activity of tryptophan hydroxylase in the midbrain and the conversion of tryptophan to 5-HT. In addition, there appears to be a correlation between the daily rhythm of 5-HT content in the limbic system and that of circulating corticosterone. It is reported that treatment with parachlorophenylalanine (PCPA) abolished the diurnal variation of plasma corticosterone at an intermediate level in the rat, affect the metabolism or action of 5-HT abolished the daily rise in plasma 17-OHCS in the cat but did not block the response to stress.