Diurnal effects of fluoxetine and naloxone on the human hypothalamic-pituitary-adrenal axis

1. Central serotonergic pathways are hypothesized to be involved in the stimulation of hypothalamic adrenocorticotropic hormone (ACTH) secretagogue release by both circadian- and stress-induced mechanisms, We aimed to investigate this hypothesis by measuring the effect of the highly specific serotonin re-uptake inhibitor fluoxetine (FX) on ACTH and cortisol release in the morning and in the afternoon in humans, both by itself and in combination with the opioid antagonist naloxone (Nal). Naloxone causes ACTH release in humans by removing an endogenous inhibitory opioid tone on central noradrenergic pathways stimulatory to hypothalamic corticotropin-releasing hormone (CRH) secretion, Serotonergic agents may act directly or indirectly through these central noradrenergic pathways and, if so, would be expected to be additive to or synergistic with Nd in causing ACTH and cortisol release