Induction of c-fos and CRF mRNA by MK-801 in the parvocellular paraventricular nucleus of the rat hypothalamus.
The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) stimulates the secretion of adrenocorticotropin hormone (ACTH). As corticotropin-releasing factor (CRF) represents the primary modulator of this secretion, we tested the hypothesis that the ability of MK-801 to activate the hypothalamic-pituitary-adrenal (HPA) axis was modulated through actions at the hypothalamic level that modulate the secretion of CRF. Induction of the immediate-early gene c-fos, as well as of CRF mRNA within the paraventricular nucleus (PVN) of the rat hypothalamus, was examined following the intraperitoneally administration of MK-801 (1 mg/kg). MK-801 markedly increased the expression of Fos-like protein in parvocellular nerve cells of the PVN within 60 min of systemic treatment, and double labeling immunocytochemistry indicated that Fos was primarily localized in CRF-containing neurons of the PVN. MK-801 also significantly increased CRF biosynthesis as detected by in situ hybridization, thus suggesting that c-fos could be involved in the regulation of CRF genes. Taken together, these results suggest that MK-801 stimulates the rat HPA axis probably through the neuronal gene expression of PVN CRF. The significance of these data is discussed in terms of hypothalamic NMDA receptor blockade and subsequent transcriptional regulation of CRF by immediate-early genes.
Clayton Foundation Laboratory for Peptide Biology, Salk Institute, La Jolla, CA 92031.
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D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D010913:Pituitary-Adrenal System / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016291:Dizocilpine Maleate; D003346:Corticotropin-Releasing Hormone