Central Nervous System (CNS) delivery of glucocorticoids is fine-tuned by saturable transporters at the blood-CNS barriers and nonbarrier regions

Proper functioning of the hypothalamic-pituitary-adrenal axis depends on the ability of glucocorticoids (GCs), mainly cortisol in humans and corticosterone in rodents, to access brain targets and regulate their own secretion. Being highly lipophilic, GCs have been assumed to passively diffuse through the cell membrane. However, the access of these GCs to the brain may be a more complicated process, because the free movement of molecules into the central nervous system (CNS) is restricted by the presence of the blood-brain and blood-cerebrospinal fluid barriers. GCs do interact with some transporter systems, including the efflux transporter, P-glycoprotein, and members of the organic anion transporter polypeptide (oatp) family, both of which have been found at the blood-CNS barriers. Using an in situ brain/choroid plexus perfusion, P-glycoprotein was shown to not majorly regulate the access of [ ³H]cortisol and [³H]corticosterone to the choroid plexus or pituitary gland. Interactions of [³H]cortisol and [ ³H]corticosterone with saturable influx transporters were detected at the hypothalamus, cerebellum, choroid plexus, and pituitary gland. Oatp2 seems to have some role in the influx of [³H]cortisol and [ ³H]corticosterone to the choroid plexus and the pituitary gland and other transporters, unlikely to be oatp2, may play a very minor role in the access of [³H]cortisol and [³H]corticosterone to the brain, as well as having a significant effect on [³H]glucocorticoid receptor accumulation in the pituitary gland. Overall, these data suggest that the majority of cortisol and corticosterone present in the plasma diffuse into the CNS and that transporters do not play a major role in the accumulation of these GCs in the brain.