FUNCTIONAL IMPLICATIONS OF BRAIN CORTICOSTEROID RECEPTOR DIVERSITY

1. Corticosteroids readily enter the brain and control gene expression in nerve cells via binding to intracellular receptors, which act as g ene transcription factors. In the rat brain corticosterone binds to mi neralocorticoid receptors (MRs) with a 10-fold higher affinity than to glucocorticoid receptors (GRs). As a consequence, these MRs are exten sively occupied under basal resting conditions, while substantial GR o ccupation occurs at the circadian peak and following stress. Both rece ptors are colocalized in most, but not all, hippocampal neurons. In ad dition, some neurons contain aldosterone-selective MRs, if corticoster one is enzymatically inactivated. These aldosterone target neurons are presumably localized in the anterior hypothalamus, where they underli e central control of salt appetite and cardiovascular regulation. 2. T he data show that MR- and GR-mediated effects proceed in a coordinate and often antagonistic mode of action: (i) in hippocampus MR activatio n maintains excitability, while GR occupancy suppresses excitability, which is transiently raised by excitatory stimuli; (ii) central MRs pa rticipate in control of the sensitivity of the neuroendocrine stress r esponse system, while GRs are involved in termination of the stress re sponse; (iii) MRs in the hippocampus have a role in regulation of beha vioral reactivity and response selection. GR-mediated effects facilita te storage of information. 3. On the basis of these data, we propose t hat a relative deficiency or excess of MR- over GR-mediated neuronal e ffects may lead to a condition of enhanced or reduced responsiveness t o environmental influences, alter behavioral adaptation, and promote s usceptibility to stress. The findings may serve development of novel t herapeutic strategies for treatment of stress-related brain diseases.