Differential regulation of behavioral, genomic, and neuroendocrine responses by CRF infusions in rats.
Studies suggest that behavioral, genomic, and endocrine functions mediated by central corticotropin-releasing factor (CRF)-containing circuits may be differentially regulated. However, this hypothesis has never been tested directly by simultaneous assessment of distinct CRF-mediated responses within the same animal. The present study addressed this issue by concurrently examining the effects of central CRF infusions on anxiety responses, plasma corticosterone release, and c-fos mRNA induction within limbic brain circuits. Bilateral intracerebroventricular (icv) infusions of CRF (0.1-10 microg total) dose-dependently reduced exploratory behavior in a novel open field, increased circulating corticosterone (CORT) levels and augmented c-fos mRNA expression in the central nucleus of the amygdala (CeA) and the hypothalamic paraventricular nucleus (PVN). Plasma CORT levels increased significantly after 0.1 microg CRF, whereas behavioral and genomic responses required at least 1 microg CRF, suggesting that the distinct responses mediated by CRF are differentially regulated. Further characterization of intracerebroventricular CRF at 1 microg also demonstrated a disruption of social interaction behavior. The majority of behavioral effects and the elevated c-fos mRNA expression were attenuated by 10 mg/kg DMP696, a CRF(1) antagonist. However, plasma CORT elevation required 30 mg/kg DMP696 for attenuation. Thus, our studies demonstrate a greater sensitivity of the hypothalamic-pituitary-adrenal axis to intracerebroventricular CRF compared with the induction of innate fear-like responses and associated genomic changes.
Pfizer Global Research & Development, Biology II/Neurobiology, Kalamazoo, MI 49007, USA.
B M
BM
Campbell
J L
JL
Morrison
E L
EL
Walker
K M
KM
Merchant
D000324:Adrenocorticotropic Hormone / Q000097:blood* / Q000235:genetics*; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects* / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000523:psychology; D007276:Injections, Intraventricular; D008297:Male; D009490:Neurosecretory Systems / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D012333:RNA, Messenger; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone