Behavioral Effects of Central Administration of The Novel CRF Antagonist Astressin in Rats

Spina, Mariarosa; Basso, Ana M.; Zorrilla, Eric P.; Heyser, Charles J.; Rivier, Jean; Vale, Wylie; Merlo‐Pich, Emilio; Gf, Koob

doi:10.1016/s0893-133x(99)00108-6

Cited by 73 publications

(60 citation statements)

References 34 publications

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“…In addition to this role, CRF also acts as an extra-hypothalamic neuromodulator and neurotransmitter, mediating adaptive behavioral responses to stress, including increased arousal, suppression of appetitive and reproductive behaviors and an increase in defensive responding and avoidance behaviors (Brown and Fisher 1985;Dunn and Berridge 1990;Owens and Nemeroff 1993;Spina et al 1996;Spina et al 2000). These behavioral activating effects have been shown to be independent of HPA axis activation, and thus represent extra-hypothalamic actions of CRF in the CNS (Britton et al 1986;Eaves et al 1985).…”

Section: Introductionmentioning

confidence: 99%

Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

et al. 2008

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Rationale-Central administration of corticotropin-releasing factor (CRF) elicits a specific pattern of behavioral responses resembling a stress-like state, and is anxiogenic in rodent models of anxiety.Objectives-Specific behaviors evoked by the administration of CRF were measured. The roles of CRF receptor subtypes and that of serotonergic and noradrenergic systems in mediating these responses were studied.Methods-Burying, grooming and head shakes were quantified in rats following intracerebroventricular administration of CRF and urocortin II and after pretreatment with antagonists. The role of forebrain norepinephrine in the behavioral responses to CRF (0.3 μg) was examined following pretreatment with the neurotoxin DSP-4 and that of serotonin after depletion using systemic administration of para-chlorophenylalanine (p-CPA).Results-CRF at 0.3 and 3.0 μg caused robust increases in burying, grooming and head shakes, but urocortin II was ineffective. Pretreatment with either antalarmin or propranolol significantly attenuated the CRF-evoked behaviors. Destruction of forebrain NE pathways blocked spontaneous burying behavior elicited by CRF and conditioned burying directed towards an electrified shock probe. In contrast, depletion of 5-HT selectively attenuated CRF-evoked grooming.Conclusions-Overt behavioral responses produced by CRF, burying, grooming, and head shakes, appeared to be mediated through the CRF 1 receptor. Spontaneous burying behavior evoked by CRF or conditioned burying directed towards a shock probe were disrupted by lesion of the dorsal noradrenergic bundle and may represent anxiety-like behavior caused by CRF activation of the LC. In contrast, CRF-evoked increases in grooming were dependent on serotonin.

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Section: Introductionmentioning

confidence: 99%

Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

et al. 2008

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“…In vitro assays indicate that AST is more potent for both CRH 1 and CRH 2 receptors than is another common CRH antagonist, αHelCRH, yet does not have its partial agonist properties (Brauns et al, 2001). However, in vivo studies in rats suggest that AST may be somewhat less potent in preventing some CRHand stress-induced and anxiety-related behaviors (Spina et al, 2000). Thus, potentially lesser potency in combination with strain differences in the regulation of CRH (Blank et al, 2003) may have been in factor in our failure to observe significant effects of AST on wakefulness or sleep in C57BL/6J mice.…”

Section: Discussionmentioning

confidence: 94%

Mouse strain differences in the effects of corticotropin releasing hormone (CRH) on sleep and wakefulness

et al. 2008

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Corticotropin releasing hormone (CRH) plays a major role in central nervous system responses to stressors and has been implicated in stress-induced alterations in sleep. In the absence of stressors, CRH contributes to the regulation of spontaneous waking. We examined the effects of CRH and astressin (AST), a non-specific CRH antagonist, on wakefulness and sleep in two mouse strains with differential responsiveness to stress to determine whether CRH might also differentially affect undisturbed sleep and activity. Less reactive C57BL/6J (n=7) and high reactive BALB/cJ (n=7) male mice were implanted with a transmitter for determining sleep via telemetry and with a guide cannula aimed into a lateral ventricle. After recovery from surgery and habituation to handling, ICV microinjections of CRH (0.04, 0.2, and 0.4 μg), AST (0.1, 0.4, and 1.0 μg) or vehicle alone (pyrogenfree saline, 0.2 μl) were administered during the fourth h after lights on and sleep was recorded for the subsequent 8 h. Comparisons of wakefulness and sleep were conducted across conditions and across strains. In C57BL/6J mice, REM was significantly decreased after microinjections of CRH (0.2 μg) and CRH (0.4 μg), and NREM and total sleep were decreased after microinjections of CRH (0.4 μg ). CRH (0.4 μg) and AST did not significantly change wakefulness or sleep. In BALB/cJ mice, CRH (0.4 μg) increased wakefulness and decreased NREM, REM and total sleep. AST decreased active wakefulness and significantly increased REM at the low and high dosages. These findings demonstrate that CRH produces changes in arousal when given to otherwise undisturbed mice. Strain differences in the effects of CRH and AST may be linked to the relative responsiveness of C57BL/6J and BALB/cJ mice to stressors and to underlying differences in the CRH system.

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“…In rat, astressin is a potent antagonist of IV-CRF stimulation of ACTH when pre-administered IV and also when administered ICV at a high dose (Rivier et al, 1996;Turnbull et al, 1999). ICV Astressin also reverses the anxiogenic effect of ICV CRF on the elevated plus maze in rats (Spina et al, 2000). In the present study the effects of pre-treatment with ICV versus IP astressin on ICV CRF stimulation of ACTH and CORT blood levels were studied, as were the effects of ICV versus IP astressin on ICV CRF induced changes in locomotor activity.…”

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confidence: 99%

“…Behavioural studies in rat demonstrated that ICV CRF leads to, for example, increased locomotor activity in a familiar cage, decreased activity in a novel open field, and increased anxiety on an elevated plus maze (Koob et al, 1993;Sutton et al, 1982). These effects were antagonized by peptidergic CRF-R1/R2 antagonists (Spina et al, 2000). In mice, ICV CRF has been demonstrated to induce activation, as increased local cerebral glucose utilization, in hypothalamic, thalamic, cerebellar and hippocampal regions (Warnock et al, 2009).…”

mentioning

confidence: 99%

“…The second and related aim was to utilize the same preparation to investigate the effects of prior treatment with a CRF-R1/R2 antagonist on ICV CRF-induced changes in plasma ACTH-CORT levels and locomotor activity. The antagonist used was astressin [cyclo(30-33) (Spina et al, 2000). In rat, astressin is a potent antagonist of IV-CRF stimulation of ACTH when pre-administered IV and also when administered ICV at a high dose (Rivier et al, 1996;Turnbull et al, 1999).…”

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confidence: 99%

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

Pryce¹,

Siegl²,

Mayer³

et al. 2011

Neuropharmacology

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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...

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Behavioral Effects of Central Administration of The Novel CRF Antagonist Astressin in Rats

Cited by 73 publications

References 34 publications

Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

Mouse strain differences in the effects of corticotropin releasing hormone (CRH) on sleep and wakefulness

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

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