Psychopharmacology (1998) 139 : 243250 ' Springer-Verlag 1998 ORIGINAL INVESTIGATION Richard J. Porter • R. Hamish McAllister-Williams Brian S. Lunn • Allan H. Young 5-Hydroxytryptamine receptor function in humans is reduced by acute administration of hydrocortisone Received : 6 October 1997 / Final version : 19 February 1998 Abstract 5-Hydroxytryptamine 1A (5-HT 1A ) receptors have been shown to be suppressed by corticosteroid hormones in a variety of animal experimental para- digms. It has been suggested that this e/ect may be cen- tral to the pathophysiology of severe clinical depressive illness, a condition in which 5-HT 1A receptor function is reduced and corticosteroid hormones are elevated. We report the e/ects of acute administration of hydro- cortisone in normal volunteers on a neuroendocrine model of 5-HT 1A receptor function. Fifteen healthy male volunteers took part in a random order, double blind, placebo controlled study, in which 100 mg hydro- cortisone or placebo was administered 11 h before infusion of L-tryptophan (L-TRP). Pre-treatment with hydrocortisone signiÞcantly reduced the growth hor- mone (GH), but not the prolactin (PRL) response to the infusion. These data are consistent with the view that acute administration of corticosteroid hormones signiÞcantly impairs 5-HT 1A receptor mediated func- tion in healthy human volunteers and are in line with animal studies of the e/ects of corticosteroid hormones on 5-HT 1A receptors. We propose that this Þnding is relevant to the pathophysiological processes which cause severe depressive illness. Key words L-Tryptophan • Hydrocortisone • Serotonin • Cortisol • Growth hormone • Prolactin • Human volunteer Introduction The 5-HT 1A receptor is a 450 amino acid polypeptide, with seven interconnected transmembrane segments, that is a member of the G-protein linked receptor super- family (Hartig 1989). Both binding sites and messen- ger ribonucleic acid (mRNA) for this receptor are located presynaptically on serotonin containing raphe neurones (somatodendritic autoreceptors) and postsy- naptically on cells throughout the cortex, especially in the hippocampus and Ammons Horn (Burnet et al. 1995; Azmitia et al. 1996; Pasqualetti et al. 1996). Animal investigations have suggested that treatments for depression, including a variety of di/erent classes of antidepressant drugs and electroconvulsive shocks, have speciÞc actions on the function of 5-HT 1A recep- tors (Goodwin et al. 1985) and that post-synaptic sero- tonergic transmission can be enhanced by increasing post-synaptic 5-HT 1A receptor sensitivity or attenuat- ing somatodendritic 5-HT 1A autoreceptors (Blier and de Montigny 1994). At present, there is little direct evidence to support this mechanism in humans, al- though early results suggest that pindolol, used in doses thought to cause blockade of somatodendritic 5-HT 1A autoreceptors, may be e/ective in accelerating antidepressant response (Perez et al 1997). Human studies using the technique of L-tryptophan (L-TRP) infusion have suggested that depressed patients have an impairment in post-synaptic 5-HT 1A receptor function (Heninger et al. 1984; Koyama and Meltzer 1986; Cowen and Charig 1987; Deakin et al. 1990; Price et al. 1991) and that this impairment is state depen- dant (Upadhyaya et al. 1991). It is therefore suggested that the functioning of 5-HT 1A receptors is central both to the pathology of depression and its treatment. An important but as yet unresolved question is why this possible impairment of 5-HT 1A function may arise in depressive illness. One possible cause might be the elevated levels of corticosteroid hormones which are found to be associated with depressive illness (Murphy R.J. Porter • R.H. McAllister-Williams B.S. Lunn • A.H. Young (*) Department of Neuroscience and Psychiatry, University of Newcastle, Royal Victoria InÞrmary, Newcastle NE1 4LP, UK e-mail: A.H.Young@ncl.ac.uk, Fax : +44-191-227-5108