Regulation of corticotropin-releasing hormone receptor messenger ribonucleic acid in the rat brain and pituitary by glucocorticoids and stress.
Glucocorticoids and stress are known to influence the synthesis of corticotropin-releasing hormone (CRH) at a variety of sites in brain, including the hypothalamus and amygdala. The recent cloning of the CRH receptor (CRH-R) enabled us to determine whether glucocorticoids or stress influenced CRH action via regulation of CRH-R. We, therefore, used in situ hybridization to measure CRH-R messenger RNA (mRNA) levels in the hypothalamic paraventricular nucleus (PVN), anterior pituitary (AP), amygdala, and bed nucleus of the stria terminalis (BNST) under several conditions. Systemic corticosterone (CORT) treatment, both daily injection (5 mg/rat.day) up to 14 days and pellet implant (200 mg) for 14 days, decreased CRH-R mRNA in the PVN and lateral and basolateral nucleus of the amygdala (BLA). Corticosterone injection (10 mg/rat.day, for 7 days) decreased CRH-R mRNA in the AP. Adrenalectomy also decreased CRH-R mRNA in the PVN and AP, but did not alter it in the BLA. In both sham and adrenalectomized rats with CORT pellet replacement (39 mg; ADX+CORT rats), acute (2-h) and repeated (2 h daily for 14 days) immobilization stress (which produced a large increase in plasma CORT in sham rats) increased CRH-R mRNA in the PVN and decreased it in the AP, but did not affect CRH-R mRNA in the BLA. However, ADX+CORT rats consistently had higher levels of CRH-R mRNA in both the PVN and AP than sham rats after stress. Brain stem hemisection, which damaged all ascending catecholaminergic fibers with the exception of the locus ceruleus, attenuated immobilization stress-induced up-regulation of CRH-R mRNA ipsilaterally in the PVN. None of the treatments affected CRH-R mRNA levels in the central and medial nucleus of the amygdala or the BNST. These results suggest that high concentrations of CORT or CRH synergistically decrease CRH-R mRNA levels in the AP, and that at least high CORT has an inhibitory effect on PVN CRH-R mRNA levels. However, stress input can override such inhibitory effects and thus up-regulate CRH-R mRNA in the PVN. The extrahypothalamic regions, such as amygdala and BNST may have different sensitivities to CORT or CRH for the regulation of CRH-R mRNA.
Makino
S
S
Clinical Neuroendocrinology Branch, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
Schulkin
J
J
Smith
M A
MA
Pacák
K
K
Palkovits
M
M
Gold
P W
PW
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D013312:Stress, Physiological / Q000378:metabolism*
D005938:Glucocorticoids; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone