Glutamate and N‐Methyl‐D‐Aspartate Stimulate Rat Hypothalamic Corticotropin‐Releasing Factor Secretion in vitro

Abstract

It is known that in vivo excitatory amino acids (EAA) stimulate the hypothalamo-pituitary-adrenal axis. However their site of action is not fully understood. We investigated the possibility of a direct action of 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 increase in CRF release induced by 5 x 10(-5) M NMDA or L-glutamate, respectively. Incubation with 1 x 10(-4) M kainate or 0.5 x 10(-4) M AMPA did not change basal CRF secretion. Incubation with 2 x 10(-4) M gamma-D-glutamylglycine (a specific antagonist of kainate and AMPA receptor) had no effect under basal conditions or during exposure to kainate or AMPA. Our data demonstrate that EAA could stimulate directly CRF secretion, by an action through NMDA and metabotropic receptors, but not kainate or AMPA receptors. These findings may be relevant to the regulation of the hypothalamo-pituitary adrenal axis, both under basal conditions and during exposure to stress.

Differential Mechanisms of CRF1 and CRF2 Receptor Functions in the Amygdala in Pain-Related Synaptic Facilitation and Behavior

“…Our antagonist data suggest tonic activation of CRF1 receptors in the arthritis pain model by an endogenous ligand that is continuously released, possibly as the consequence of plastic changes in presynaptic metabotropic glutamate receptor (mGluR) expression and function . mGluRs can regulate CRF release (Joanny et al, 1997). Reversal of PKA-mediated changes by a CRF1 receptor antagonist or a PKA inhibitor likely involves "net" dephosphorylation attributable to normal phosphatase activity in the absence of continued phosphorylation.…”

Neurotransmitter Regulation of Cellular Activation and Neuropeptide Gene Expression in the Paraventricular Nucleus of the Hypothalamus

“…The role of glutamate in the regulation of PVH mechanisms is unsettled, and its effects on parvocellular neurosecretory neurons have not been thoroughly characterized (Oliver et al, 1996;Herman and Cullinan, 1997). For example, in vitro studies report that hypothalamic CRF release may be increased (Joanny et al, 1997) decreased, or unaffected (Costa et al, 1992;Patchev et al, 1994) by excitatory amino acid administration. Another reports that glutamate alone has no effect on hypothalamic cultures but can potentiate the effects of forskolin (Yang et al, 1995).…”

Inhibition of glutamine synthetase during ammonia exposure in rainbow trout indicates a high reserve capacity to prevent brain ammonia toxicity

“…Glutamate can also stimulate the hypothalamic-pituitary-adrenal (HPA) stress axis in mammals and cause the release of corticotropinreleasing factor (CRF) from hypophysiotropic neurons (Joanny et al, 1997). CRF stimulates the secretion of adrenocorticotropin hormone from the pituitary, which in turn stimulates the synthesis and release of glucocorticoids from the adrenal cortex of mammals and the interrenal tissue of fish (Wenderlaar Bonga, 1997;Bernier et al, 2009).…”