In vivo evidence for ligand-specific receptor activation in the central CRF system, as measured by local cerebral glucose utilization.
Corticotropin-releasing factor (CRF) is well known for its role in the hypothalamic-pituitary-adrenocortical (HPA) axis and its involvement in stress and anxiety. CRF acts via two main receptor subtypes, CRF(1) and CRF(2). Other endogenous CRF-related peptide ligands are the Urocortins 1 and 2 and Stresscopin. While CRF is thought to mediate its anxiogenic-like properties through CRF(1), the role of CRF(2) and its endogenous ligands Urocortin 2 and Stresscopin are less clear, with a suggested role in mediating the delayed effects of stress. Measurement of local cerebral glucose utilization (LCGU) provides an estimate of neuronal activity, and is of potential use as a translational tool in comparison to FDG PET. We hypothesized that comparison of the patterns of metabolic changes induced by CRF-related peptides could provide further information on their role in the brain. The present studies examined the effects of CRF-related peptides on LCGU, and the role of CRF(1) and CRF(2) in the CRF-induced LCGU response. CRF induced increases in LCGU in hypothalamic, thalamic, cerebellar and hippocampal regions, and further studies using antagonists or mutant mice lacking a functional CRF(1) receptor clearly suggested a role for CRF(2) in this effect. Urocortin 1 increased LCGU in a dissected hindbrain region. However, central administration of the CRF(2)-selective agonists Urocortin 2 and Stresscopin failed to affect LCGU, which may suggest ligand-dependent receptor activation within the CRF system. The present data supports a role for CRF(2) in the regulation of neuronal glucose metabolism.
Dept. Psychiatry, RED Europe, Johnson & Johnson PRD, Beerse, Belgium. gwarnock@ulg.ac.be
Geoff
G
Warnock
Dieder
D
Moechars
Xavier
X
Langlois
Thomas
T
Steckler
D000311:Adrenal Glands / Q000502:physiology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000008:administration & dosage
D010446:Peptide Fragments; C116607:antisauvagine 30; D003346:Corticotropin-Releasing Hormone; D005947:Glucose; D003345:Corticosterone