It has previously been postulated that the therapeutic effect of antidepressants, particularly selective serotonin re-uptake inhibitors (SSRIs), is mediated by a down-regulation of somatodendritic (presynaptic) 5-HT(1A) autoreceptors with chronic treatment. Animal studies have revealed that repeated administration of corticosteroids similarly down-regulate this receptor. However, it has previously been difficult to explore if this receptor is similarly modulated in man in vivo. The objective of this study was to explore the effect of repeated administration of cortisol to healthy volunteers utilising a novel putative index of somatodendritic 5-HT(1A) autoreceptor function. This method involves the administration of the 5-HT(1A) agonist buspirone and observing the subsequent negative shift in the frequency spectrum of the electroencephalogram (EEG). Healthy male volunteers were treated with cortisol 20 mg, or placebo, orally twice daily for 7 days in a double-blind random-order crossover study. After each treatment period volunteers were administered buspirone 30 mg orally prior to EEG recordings. Following a week's treatment with placebo, buspirone led to a negative shift in the EEG frequency spectrum as previously reported. However, following treatment with cortisol, the effect of buspirone was significantly attenuated. This is consistent with corticosteroids having a similar effect on somatodendritic 5-HT(1A) autoreceptors in man as seen in rodents.