Suppression of Conditioned Fear by Administration of CRF Receptor Antagonist CP-154,526

Abstract

In order to examine the involvement of corticotropin-releasing hormone (CRF) receptor in the formation of anxiety, we investigated whether CRF receptor antagonist CP-154,526 suppressed conditioned fear stress. First, rats were individually subjected to 30 min of footshock. Twenty-four hours after footshock, the rats were again placed in the chamber and observed for 5 min without shock. CP-154,526 was administered 30 min before placing the rats in the chamber again. After that, CP-154,526 was once more administered 30 min before applying footshock. Administration of CP-154,526 30 min both before conditioned fear stress (placing the rats inside the cage but not applying footshock) and before actual footshock significantly reduced freezing behavior. These results show that CP-154,526 blocked both the acquisition and expression of conditioned fear, thus suggesting that the CRF receptor might be related to anxiety.

Anxiolytic-Like Effects of the Corticotropin-Releasing Factor1 (CRF1) Antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] Administered Acutely or Chronically at Doses Occupying Central CRF1 Receptors in Rats

“…First, 1.0 nM plasma-free concentration (similar to the in vitro IC 50 value) is necessary for greater than 50% CRF 1 receptor occupancy with DMP904 and for anxiolytic-like effects in the defensive withdrawal test in rats (1.0 mg/kg administered p.o.). This finding is consistent with studies with other CRF 1 antagonists in this [DMP696 and R121919 (Heinrichs et al, 2002)] and other models of anxiety (Habib et al, 2000;Hikichi et al, 2000;Kehne et al, 2000). Plasma-free levels of 4.2 nM or higher do not produce a significantly greater level of estimated CRF 1 receptor occupancy or a significantly higher reduction in exit latency.…”

“…CP-154,526 reversed separation-induced increase in ultrasonic vocalization in rat pups (Kehne et al, 2000) and reduced expression of conditioned fear in rats (Hikichi et al, 2000). In addition, this compound also increased time spent in open arms of an elevated-plus maze in rats (Lundkvist et al, 1996), although this result was not repeated in another study (Griebel et al, 1998).…”

“…In a previous study, DMP696, unlike CDP, did not produce sedation or ataxia at doses 3-to 10-fold higher than the lowest effective anxiolyticlike doses (McElroy et al, 2002). Similarly, 526 showed anxiolytic-like effects in rats without sedation (Hikichi et al, 2000) or ataxia (Kehne et al, 2000). In addition, DMP696 did not substitute for the discriminative stimulus effects of CDP and could not be established as a discriminative stimulus in rats at doses 6-fold higher than the lowest anxiolytic-like dose, indicating that it may not share subjective effects with benzodiazepines (Lelas et al, 2003).…”

Can CRF1 receptor antagonists become antidepressant and/or anxiolytic agents?

“…In almost every case, there is a modification of the behavior by the CRF 1 receptor antagonist. For example, CP-154, 526 is effective in the plus maze with CRF pretreatment , blocks CRF-potentiated and fear-potentiated acoustic startle [Chen et al, 1996;Schulz et al, 1996], reduces fear-potentiated freezing [Hikichi et al, 2000], reverses swim stress-induced changes in light/dark exploration [Millan et al, 2001], and reduces fear-potentiated and maternal separationinduced vocalizations [Kehne et al, 2000;Kikusui et al, 2000]. Antalarmin and CRA1000 also counteract plus maze changes induced by CRF pretreatment Zorrilla et al, 2002].…”

Synthesis of [N‐methyl‐11C]‐3‐[(6‐dimethylamino)pyridin‐3‐yl]‐2,5‐dimethyl‐N, N‐dipropylpyrazolo[1,5‐a]pyrimidine‐7‐amine: A potential PET ligand for in vivo imaging of CRF1 receptors

“…The intraperitonial administration of this compound reduces anxiety-like behavior assessed on an elevated level and shows antidepressant-like effects. 14,15 Although the radiosynthesis of a number of fluorinated and iodinated analogues of CP-154526 and antalarmin have been developed, the details of the in vivo validations of these tracers are not reported.…”