GLUTAMATE AND N-METHYL-D-ASPARTATE STIMULATE RAT HYPOTHALAMIC CORTICOTROPIN-RELEASING FACTOR SECRETION IN-VITRO

It is known that in vivo excitatory amino acids (EAA) stimulate the hy pothalamo-pituitary-adrenal axis. However their site of action is not fully understood. We investigated the possibility of a direct action o f EAA on the secretion of the major adrenocorticotropin hormone (ACTH) secretagogue: corticotropin-releasing factor (CRF) from incubated rat hypothalamic slices. N-methyl-D-aspartic acid (NMDA) or L-glutamate ( 1 x 10(-7) to 1 x 10(-3) M) stimulated in a dose-dependent fashion CRF release. The maximal effect was obtained at a concentration of 1 x 10 (-4) M for both drugs. The IC50 was 1.3 x 10(-5) M and 3.3 x 10(-5) M for NMDA and L-glutamate, respectively. incubation with 2.5 x 10(-4) M D-2-amino-5-phosphonovalerate (a NMDA receptor antagonist) or 2-amino -4-phosphonobutyrate (a metabotropic receptor antagonist) was without significant effect on basal CRF secretion and completely blocked the i ncrease in CRF release induced by 5 x 10(-5) M NMDA Or L-glutamate, re spectively. Incubation with 1 x 10(-4) M kainate or 0.5 x 10(-4) M AMP A did not change basal CRF secretion. Incubation with 2 x 10(-4) M gam ma-D-glutamylglycine (a specific antagonist of kainate and AMPA recept or) had no effect under basal conditions or during exposure to kainate or AMPA. Our data demonstrate that EAA could stimulate directly CRF s ecretion, by an action through NMDA and metabotropic receptors, but no t kainate or AMPA receptors. These findings may be relevant to the reg ulation of the hypothalamo-pituitary adrenal axis, both under basal co nditions and during exposure to stress.