CP 154526

The CRF-1 receptor antagonist, CP-154,526, attenuates stress-induced increases in ethanol consumption by BALB/cJ mice.[Pubmed:18162074]

Alcohol Clin Exp Res. 2008 Feb;32(2):240-8.

BACKGROUND: Corticotropin-releasing factor (CRF) signaling modulates neurobiological responses to stress and ethanol, and may modulate observed increases in ethanol consumption following exposure to stressful events. The current experiment was conducted to further characterize the role of CRF1 receptor (CRF1R) signaling in stress-induced increases in ethanol consumption in BALB/cJ and C57BL/6N mice. METHODS: Male BALB/cJ and C57BL/6N mice were given continuous access to 8% (v/v) ethanol and water for the duration of the experiment. When a baseline of ethanol consumption was established, animals were exposed to 5 minutes of forced swim stress on each of 5 consecutive days. Thirty minutes before each forced swim session, animals were given an intraperitoneal injection of a 10 mg/kg dose of CP-154,526, a selective CRF1R antagonist, or an equal volume of vehicle. The effect of forced swim stress exposure on consumption of a 1% (w/v) sucrose solution was also investigated in an ethanol-naive group of BALB/cJ mice. RESULTS: Exposure to forced swim stress significantly increased ethanol consumption by the BALB/cJ, but not of the C57BL/6N, mice. Stress-induced increases in ethanol consumption were delayed and became evident approximately 3 weeks after the first stressor. Additionally, forced swim stress did not cause increases of food or water intake and did not promote delayed increases of sucrose consumption. Importantly, BALB/cJ mice pretreated with the CRF1R antagonist showed blunted stress-induced increases in ethanol intake, and the CRF1R antagonist did not influence the ethanol drinking of non-stressed mice. CONCLUSIONS: The present results provide evidence that CRF1R signaling modulates the delayed increase of ethanol consumption stemming from repeated exposure to a stressful event in BALB/cJ mice.

CP-154,526 Modifies CREB Phosphorylation and Thioredoxin-1 Expression in the Dentate Gyrus following Morphine-Induced Conditioned Place Preference.[Pubmed:26313266]

PLoS One. 2015 Aug 27;10(8):e0136164.

Corticotropin-releasing factor (CRF) acts as neuro-regulator of the behavioral and emotional integration of environmental and endogenous stimuli associated with drug dependence. Thioredoxin-1 (Trx-1) is a functional protein controlling the redox status of several proteins, which is involved in addictive processes. In the present study, we have evaluated the role of CRF1 receptor (CRF1R) in the rewarding properties of morphine by using the conditioned place preference (CPP) paradigm. We also investigate the effects of the CRF1R antagonist, CP-154,526, on the morphine CPP-induced activation of CRF neurons, CREB phosphorylation and Trx expression in paraventricular nucleus (PVN) and dentate gyrus (DG) of the mice brain. CP-154,526 abolished the acquisition of morphine CPP and the increase of CRF/pCREB positive neurons in PVN. Moreover, this CRF1R antagonist prevented morphine-induced CRF-immunoreactive fibers in DG, as well as the increase in pCREB expression in both the PVN and DG. In addition, morphine exposure induced an increase in Trx-1 expression in DG without any alterations in PVN. We also observed that the majority of pCREB positive neurons in DG co-expressed Trx-1, suggesting that Trx-1 could activate CREB in the DG, a brain region involved in memory consolidation. Altogether, these results support the idea that CRF1R antagonist blocked Trx-1 expression and pCREB/Trx-1 co-localization, indicating a critical role of CRF, through CRF1R, in molecular changes involved in morphine associated behaviors.

Corticotropin releasing factor-1 receptor antagonist, CP-154,526, blocks the expression of ethanol-induced behavioral sensitization in DBA/2J mice.[Pubmed:17919825]

Neuroscience. 2007 Nov 30;150(1):14-21.

RATIONALE: Manipulation of glucocorticoid receptor signaling has been shown to alter the acquisition and expression of ethanol-induced locomotor sensitization in mice. It is unknown if other components of the hypothalamic-pituitary-adrenal (HPA)-axis modulate locomotor sensitization resulting from repeated ethanol administration. In the present investigation, we determined if pretreatment with an i.p. injection of CP-154,526, a selective corticotropin releasing factor (CRF) type-1 receptor antagonist, would block the acquisition and/or expression of ethanol-induced locomotor sensitization in male DBA/2J mice. METHODS: To assess the role of the CRF1 receptor in the acquisition of behavioral sensitization, mice were pretreated with an i.p. injection of CP-154,526 30 min before each of 10 sensitizing i.p. injections of ethanol. To determine the role of the CRF1 receptor in modulating the expression of ethanol-induced sensitization, mice that had previously been sensitized to the locomotor stimulant effects of ethanol were pretreated with CP-154,526 30 min before an i.p. injection of ethanol on the test day. In a third study, ethanol-naive mice were pretreated with CP-154,526 30 min before an initial i.p. injection of ethanol to determine the combined effects of the CRF1 receptor antagonist and ethanol on locomotor activity. Blood ethanol concentrations were assessed at the termination of sensitization studies. RESULTS: Pretreatment with CP-154,526 blocked the expression of ethanol-induced locomotor sensitization in DBA/2J mice but did not prevent the acquisition of sensitization. The ability of CP-154,526 to block the expression of ethanol-induced locomotor sensitization was not attributable to alterations in blood ethanol levels or possible sedative effects produced by the combined administration of CP-154,526 and ethanol. CONCLUSIONS: These data provide novel evidence that CRF1 receptor signaling modulates the expression of ethanol-induced locomotor sensitization, and add to a growing literature suggesting a role for neurochemicals and hormones associated with the HPA-axis in behavioral sensitization resulting from repeated exposure to drugs of abuse.

Pretreatment with CP-154526 blocks the modifying effects of alarm pheromone on components of sexual behavior in male, but not in female, rats.[Pubmed:21502338]

Chem Senses. 2011 Sep;36(7):623-32.

We previously demonstrated that an alarm pheromone released from male donor Wistar rats evoked several physiological and behavioral responses in recipient rats. However, the pheromone effects on social behavior were not analyzed. In the present study, we examined whether the alarm pheromone affects sexual behavior in male or female rats. When a pair of male and female subjects was exposed to the alarm pheromone during sexual behavior, the ejaculation latency was elongated, the number of mounts was increased, and the hit rate (number of intromissions/number of mounts and intromissions) was decreased in the male subject. In contrast, female sexual behavior was not affected by the alarm pheromone. When we exposed only the male or female subject of the pair to the pheromone just before sexual behavior, the results were similar: the pheromone effects were evident in male, but not in female, subjects. In addition, when we pretreated with corticotropin-releasing factor (CRF) antagonist (CP-154526) before exposing the male subject to the alarm pheromone, the pheromone effects were attenuated in a dose-dependent manner. These results indicate that the alarm pheromone modifies male, but not female, components of sexual behavior and that CRF participates in the effects.

Comparison of the V1b antagonist, SSR149415, and the CRF1 antagonist, CP-154,526, in rodent models of anxiety and depression.[Pubmed:17291571]

Pharmacol Biochem Behav. 2007 Mar;86(3):431-40.

Vasopressin and corticotropin releasing factor (CRF) are both critical regulators of an animal's stress response and have been linked to anxiety and depression. As such, antagonists of the CRF1 and V1b receptor subtypes are being developed as potential treatments for affective disorders. The two most characterized V1b and CRF1 antagonists are SSR149415 and CP-154,526, respectively, and the present studies were designed to compare these two compounds in acute animal models of affective disorders. We employed five anxiety models: Separation-induced pup vocalizations (guinea pig and rat), elevated plus-maze (EPM), conditioned lick suppression (CLS), and marble burying (mouse); as well as three depression models: forced swim test (FST; mouse and rat) and tail suspension test (TST; mouse). SSR149415 (1-30 mg/kg) was active in the vocalization, EPM and CLS models, but inactive in marble burying. CP-154,526 (1-30 mg/kg) was active in vocalization models, but inactive in EPM, CLS, and marble burying. SSR149415 was inactive in all depression models; CP-154,526 was active in rat FST but inactive in mouse models. This work demonstrates the different profiles of V1b and CRF1 receptor antagonists and supports both approaches in the treatment of affective disorders.

A non peptidic corticotropin releasing factor receptor antagonist attenuates fever and exhibits anxiolytic-like activity.[Pubmed:8874139]

Eur J Pharmacol. 1996 Aug 8;309(2):195-200.

The multiple actions of corticotropin-releasing factor (CRF) on neuroendocrine and behavioural functions can now be examined using new, high affinity, non peptidic antagonists which exhibit central activity upon systemic application. We have shown that compound CP 154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine) displaces [125I][Tyr0]CRF from rat hippocampal CRF receptors (IC50 = 0.5 nM) and from pituitary CRF receptors (IC50 = 0.04 nM). The same compound inhibits in a concentration-dependent manner the ovine CRF (0.1 microM)-stimulated adenylate cyclase activity in membranes of a mouse pituitary adenoma cell line, AtT20, with an IC50 value of 50 nM. Systemic application of the CRF receptor antagonist (0.16 mg/kg i.p.) blocked recombinant human interleukin-1 beta 5 micrograms/kg i.p.) induced fever in rats. The CRF receptor antagonist CP 154,526 (1 mg/kg i.p.) also exhibited signs of anxiolytic-like activity in the elevated plus-maze test in rats.