Endocrine and behavioural responses to acute central CRF challenge are antagonized in the periphery and CNS, respectively, in C57BL/6 mice.
Corticotropin releasing factor (CRF) is a major mediator of central and peripheral responses to environmental stressors, and antagonism of its receptors (CRF-R1, -R2) is an active area of pharmacotherapeutic research for stress-related disorders. Stress responses include CRF activation of the hypothalamus-pituitary-adrenal axis and behavioural inhibition. Valid in vivo models for the study of these neuro-endocrine and -behavioural CRF pathways and their central-peripheral antagonism are important. The aims of this study in C57BL/6 mice were to describe the acute effects of intracerebroventricular (ICV) CRF using plasma ACTH-CORT titres and locomotor activity as readouts, and to study the impact on these readouts of central versus peripheral pre-treatment with the CRF-R1/2 antagonist, astressin. The following experiments were performed: Effects of (i) serial blood sampling (SBS) per se, (ii) physical confinement+SBS, (iii) ICV saline infusion+SBS, on plasma titres of ACTH-CORT. (iv) Effects of ICV or IP CRF infusion on plasma ACTH-CORT. (v) Effects of ICV CRF on plasma CRF. (vi) Effects of ICV or IP astressin on ICV or IP CRF-stimulated plasma CORT. (vii) Effects of ICV or IP astressin on ICV CRF-induced locomotor inactivity. Main findings were: (i)-(ii) Serial blood sampling per se and physical confinement+SBS led to similar, mild increases in plasma ACTH-CORT. (iii) ICV saline infusion led to a marked increase in plasma ACTH, possibly due to assay crossreactivity with "washed out" pituitary peptides, and a mild increase in plasma CORT. (iv) ICV CRF (0.001-1μg) induced no further increase in plasma ACTH versus vehicle, and induced dose-dependent increased plasma CORT. 1μg ICV CRF also reduced locomotor activity. (v) ICV CRF-induced dose-dependent increased plasma CRF. (vi) ICV astressin failed to block ICV CRF-induced increased plasma CORT, whereas IP astressin did do so. (vii) ICV CRF-induced locomotor inactivity was blocked by ICV astressin, but not by IP astressin. Therefore, ICV CRF-induced a dose-dependent increase in plasma CORT via a peripheral pathway and a reduction in locomotion via a central pathway, indicated by the double dissociation in the ability of astressin to antagonize these effects relative to its route of administration, IP or ICV, respectively. The preparation described here could be readily used to provide initial indications on the central and peripheral activity of CRF-R antagonists, including pharmacokinetics following peripheral administration.
Pryce
Christopher R
CR
Neuroscience Disease Area, Novartis Institutes for Biomedical Research, Novartis Pharma, Basel CH-4002, Switzerland. christopher.pryce@bli.uzh.ch
Siegl
Stephanie
S
Mayer
Roland
R
Rahmanzadeh
Gholamreza
G
McAllister
Kevin H
KH
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood*; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D013315:Stress, Psychological / Q000097:blood; D013997:Time Factors
D010446:Peptide Fragments; C104416:astressin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone