Do steroid transporters regulate the effects of glucocorticoid hormones on the brain - in cells, in animals and humans?

Major depression is the most prevalent of all psychiatric disorders and the single most burdensome disease in the world among people in the middle years of life. Moreover, currently available antidepressant treatments are effective in only 50-70 % of patients, and research into antidepressants has not yet identified a definitive biochemical system that is responsible for the clinical effects of these drugs. Recent studies have suggested that one possible biological mechanism involved in depression is the abnormal effect of glucocorticoid hormones, like cortisol, on the brain. Moreover, our own research has shown that antidepressant treatment may regulate the effects of cortisol on the brain.

The aim of this study is to examine, both in the laboratory and in a clinical setting, the physiology of the glucocorticoid action on the brain and the mechanisms behind its regulation by antidepressants. Therefore, this project will improve our knowledge of the causes of major depression and will lead to the development of new ideas for a better treatment, which will be the ultimate implementation of our research findings into clinical practice.

My hypothesis is that membrane steroid transporters, on the blood-brain-barrier (BBB) and in neurones, regulate the effects of the glucocorticoids on brain function and are a target of antidepressant treatment.

My recent work has demonstrated that membrane steroid transporters, like the multidrug resistance (MDR) P-glycoprotein (Pgp), regulate the intracellular levels of glucocorticoids in fibroblasts and neurones. Moreover, I have shown that the transport of glucocorticoids across cell membranes in vitro, and across the BBB in guinea-pigs, occurs at physiological concentrations of hormones. Finally, I have found that antidepressants inhibit these transporters (Pariante et al. 2001a, 2001b, 2003a; 2003b, 2004).

In the course of this 5-year project, I will study the membrane transport of glucocorticoids and its inhibition by antidepressants.

In vitro: I will study the mechanisms of steroid membrane transport, and of its inhibition by antidepressants, using techniques assessing the function and the expression of these transporters in mouse fibroblasts, rat cortical neurones, and epithelial cells that have been used as in vitro models of the human BBB.

In animals: I will study the transport of cortisol and corticosterone into the brain and cerebrospinal fluid (CSF) of mice (FBV mice that are knockout for MDR1a and MDR1b Pgp genes, and FVB/Ntac control mice). Moreover, I will examine the effects of 21-day treatment with the antidepressants, clomipramine and citalopram, on the transport of glucocorticoids.

In humans: I will investigate the access of cortisol and corticosterone to the brain, and its regulation by citalopram, in healthy volunteers, using a cognitive task (executive function) together with event-related potential (ERP) recordings.

The in vitro work (at the Institute of Psychiatry) will be conducted with Professor R. Kerwin, Dr A. Makoff and Professor S. Lovestone. The animal experiments will take place in the laboratories of Dr S. Thomas, at Guy‘s, King‘s and St Thomas‘ School of Biosciences, and of Professor S. Lightman and Dr H. Reul, in the Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology at the University of Bristol. The research in humans will be conducted at the University of Newcastle, with Dr H. McAllister-Williams. Conclusions: