M. Magarinos, B. S. McEwen, R Pevet, unpublished data). Below we consider mechanisms involved in structural remodeling. The role of adrenal steroids in the structural remodeling described above reflects may interactions with neurochemical systems in the hippocampus, including serotonin, γ-aminobutyric
acid (GABA), and excitatory amino acids (Figure 5). 2 Probably the most important interactions are those with excitatory amino acids such as glutamate. Excitatory amino acids released by the mossy fiber pathway play a key role in the remodeling of the CA3 region of the hippocampus, and regulation of glutamate release by adrenal steroids Inhibitors,research,lifescience,medical may play an important role.54-57 We have found that the glutamate transporter, Glt-1, is elevated by CRS in hippocampus, particularly in the CA3 region, providing another indication that elevated glutamate levels arc an important component of structural plasticity. We previously showed that NMDA receptor blockade and the Na/Ca channel blocker, phenytoin,
both block Inhibitors,research,lifescience,medical CRS- and glucocorticoid-induced remodeling of dendrites in CA3.58-60 Recent evidence indicates that presynaptic receptors containing kainate receptor subunits such as GluR6 are important for the feed-forward actions of glutamate on mossy fiber terminals,61 and one study showed that a number of kainate receptor subunit mRNAs are regulated biphasically by adrenal steroids.57 In particular, Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical preferential mineralocorticoid receptor (MR) occupancy by low corticosterone (CORT) levels enhanced mRNA levels for KAR2, GluR6, and GluR7.57 This agrees with our finding that MR activation by aldosterone in adrenalectomized (ADX) rats restored levels of [3H]kainate binding in the mossy fiber region of CA3.56 However, further studies are needed. Figure 5. Glucocorticoids increase glutamate levels, N-methyl-D-aspartate (NMDA) receptors, calcium currents, 5-hydroxytryptamine (5-HT) turnover, and 5-HT2 receptors, decrease 5-HT1A receptors,
and alter subunit expression of GABAa receptors. A. Cross-section … Rapamycin nmr Because excitatory amino acids play a key role along with circulating glucocorticoids, Inhibitors,research,lifescience,medical the activation of the CREB (cyclic adenosine monophosphate response Megestrol Acetate element–binding protein) system is a likely candidate mediator, and recent evidence indicates that phosphorylation of CREB is chronically activated in rats subjected to CRS. CREB has been linked to regulation of synaptic plasticity and particularly neurogenesis.62 It is possible that CREB is involved in activity-dependent synapse formation, which is evident as a result of long-term potentiation.63,64 However, the role of glucocorticoids in activation of the CREB system has not been thoroughly investigated. Nevertheless, treatment with the mood stabilizer lithium prevented CRS-induced structural remodeling of the stress-induced elevation of Glt-1 and CREB phosphorylation (G. E.