Endocrine and behavioural responses to acute central CRF challenge are antagonized in the periphery and CNS, respectively, in C57BL/6 mice

Abstract

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 pretreatment 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. (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 (0.001-1 µg) induced no further increase in plasma ACTH versus vehicle, and induced dose-dependent increased plasma CORT. 1 µg 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.Dear Ms. Yeates, Dear Prof. Markou, Thank you very much to you and the reviewers for the very constructive and helpful criticism of the manuscript. All of the comments have been taken into account and the manuscript has been revised accordingly. The details of the revisions undertaken are stated point-by-point below. The changes made in the revised manuscript relative to the original are highlighted in bold font in the revision.My co-authors and I look forward to your reply on the suitability of the revised manuscript for publication in Neuropharmacology in due course. Thank you and yours sincerely, Christopher PryceCover letter Responses to ReviewersEditor's comments:Both reviewers found your work mostly well conducted and of potential interest to the field. There are, however, some issues that the reviewers raised that need to be addressed with specific changes in the manuscript. For example, the limitation of dr...

Effects of repeated adolescent stress and serotonin transporter gene partial knockout in mice on behaviors and brain structures relevant to major depression

“…At PND 80–84, SBS was performed as described in (Pryce et al, 2011b). To ensure that corticosterone titers were at baseline at sampling onset, per brother-pair one mouse was sampled per day on two consecutive days.…”

Corticotropin-Releasing Factor in the Brain and Blocking Spinal Descending Signals Induce Hyperalgesia in the Latent Sensitization Model of Chronic Pain

“…injection of CRF induced bilateral hyperalgesia in the hind paws of rats that had undergone CFA-induced unilateral hyperalgesia, but not in control rats injected in the hind paw with saline instead of CFA. Therefore, it is unlikely that the effect of CRF was due to alterations in motor activity, anxiety or other effects unrelated to pain (Koob and Thatcher-Britton, 1985; Strome et al, 2002; Pryce et al, 2011). We have previously shown (Walwyn et al, 2016) that rats similarly injected with CFA in the hind paw are in a state known as latent sensitization (Marvizon et al, 2015), characterized by a pain hypersensitivity that is continuously suppressed by the activation of μ, δ and κ opioid receptors and α 2A adrenergic receptors.…”