Characterization of the behavioral profile of the non-peptide CRF receptor antagonist CP-154,526 in anxiety models in rodents Comparison with diazepam and buspirone

The present series of experiments compared the behavioral effects of the novel non-peptide CRF antagonist CP-154,526 with those of diazepam and the 5-HT_1A receptor partial agonist buspirone in classical animal models of anxiety including conflict tests (punished lever pressing and punished drinking tests in rats) and exploratory models (elevated plus-maze test in rats, light/dark choice and free-exploration tests in mice), and a recently developed mouse defense test battery (MDTB) which has been validated for the screening of anxiolytic drugs. Results from both conflict procedures showed that diazepam (2.5–10 mg/kg, IP) produced clear anxiolytic-like effects, whereas buspirone (2.5 mg/kg, IP) displayed anticonflict activity in the punished drinking test only. CP-154,526 (0.6–20 mg/kg) was devoid of significant activity in both procedures. In the elevated plus-maze, diazepam (2 mg/kg, IP) produced significant effects on traditional (i.e. spatio-temporal) and ethologically derived (i.e. risk assessment and directed exploration) indices of anxiety. Buspirone (1–4 mg/kg, IP) reduced risk assessment activities only, and CP-154,526 (0.6–20  mg/kg, IP) did not modify the indices of anxiety in the elevated plus-maze. In the light/dark test, diazepam (2.5–5 mg/kg, IP) and CP-154,526 (10–40 mg/kg, IP) affected all behavioral indices of anxiety, while buspirone reduced risk assessment activities at the highest doses only (10 and 15 mg/kg, IP). In the free-exploration test, diazepam (1 mg/kg, IP) reduced avoidance responses towards novelty, as indicated by the increase in exploratory activity in a novel compartment and the decrease in risk assessment. CP-154,526 failed to affect the former behavior and weakly reduced the latter (5 and 20 mg/kg, IP). Buspirone (1.25–5 mg/kg, IP) was inactive in this test. Finally, in the MDTB, diazepam (0.5–3 mg/kg, IP) attenuated all defensive reactions of mice confronted with a rat stimulus (i.e. flight, risk assessment and defensive attack) or with a situation associated with this threat (i.e. contextual defense). Buspirone (1.25–5 mg/kg, IP) reduced defensive attack and contextual defense, while CP-154,526 (5–20 mg/kg, IP) affected all defensive behaviors, with the exception of one risk assessment measure. The finding that CP-154,526 displayed positive effects in mice but not in rats may be due to increased sensitivity to environmental stress of the strains used (i.e. BALB/c, Swiss) and/or to the fact that animals were exposed to unavoidable stress stimuli which may lead to a significant activation of the CRF system. Although in mice the anxiety-reducing potential of CP-154,526 is superior to that of the atypical anxiolytic buspirone, it is smaller in terms of the magnitude of the effects and the number of indices of anxiety affected than that of diazepam. Received: 7 September 1997/Final version: 26 November 1997     

Antidepressant effects of citalopram and CRF receptor antagonist CP-154,526 in a rat model of depression

Due to the interest in the antidepressant potential of nonpeptide corticotropin-releasing factor (CRF)(1) receptor antagonists, the present investigation examined the antidepressant-like effects of the CRF(1) receptor antagonist CP-154,526 on the exaggerated swim test immobility in the Flinders Sensitive Line (FSL) rat, a genetic animal model of depression. Chronic treatment with CP-154,526 (10 mg/kg; 2x day) for 14 days increased swimming in the Flinders Sensitive Line rats. Citalopram (5 and 10 mg/kg; 2x day) and desipramine (5 mg/kg; 1x day) also significantly increased swimming in the Flinders Sensitive Line rats, as expected. However, neither CP-154,526 nor citalopram (10 mg/kg) altered swimming times in the control Flinders Resistant Line (FRL) rats. Citalopram (10 mg/kg) and CP-154,526 also increased the abnormally low level of social interaction behavior in the Flinders Sensitive Line rats. These findings indicate that citalopram and CP154,526, a CRF(1) receptor antagonist, have both antidepressant and anxiolytic effects that can be detected in an experimental model of depression only and not in "normal" control animals.     

AVP V1b selective antagonist SSR149415 blocks aggressive behaviors in hamsters

Arginine vasopressin (AVP) has been implicated in a variety of physiological and behavioral responses to stress. Synthesis of receptor-selective AVP agonist and antagonist compounds allows differential analysis of the specific roles of particular receptor subtypes with respect to these responses. Here, effects of the recently synthesized AVP V1b selective antagonist, SSR149415, were examined for offensive aggression in male Syrian hamsters, using a resident-intruder paradigm. Oral administration of vehicle or 1, 10, or 30 mg/kg of SSR149415 to resident hamsters was followed by evaluation of a range of aggression-related measures of residents confronted by intruders. The 10 and 30 mg/kg doses significantly reduced the duration of offensive sideways and chase behaviors, and the 30 mg/kg dose also reduced chase frequency. The 10 and 30 mg/kg dose also significantly reduced frequency and duration of olfactory investigation and duration of flank marking. These findings suggest a link between activity of the V1b receptor and the modulation of offensive aggression. These findings agree with previous research on V1b receptor effects in suggesting that antagonism of this receptor may be useful in modulating a range of emotional responses to highly stressful or threatening conditions.     

SSR149415, a non-peptide vasopressin V1b receptor antagonist, has long-lasting antidepressant effects in the olfactory bulbectomy-induced hyperactivity depression model

Olfactory bulbectomy (OBX) in rats causes several behavioral and neurochemical CNS changes, reminiscent of symptoms of human depression. Such depression-like behavior after OBX can be reversed with antidepressants. Recently, a connection between the vasopressin 1_b (V_1b) receptor and the development of depression has been suggested; therefore, a vasopressin V_1b receptor antagonist (SSR149415) was investigated in the OBX model. Male rats received olfactory bulbectomy or sham surgery. After recovery, animals received 14 consecutive daily doses of SSR149415 (10 or 30 mg/kg), imipramine (20 mg/kg), or vehicle (5% hydroxy-propyl methylcellulose). Animals were tested in an open field after acute treatment, on days 7 and 14 of treatment and 1 week after cessation of treatment. Similar to imipramine, repeated, but not acute, administration of SSR149415 completely reversed OBX-induced hyperactivity, leaving activity in shams unaffected. This reversal of OBX-induced hyperactivity in the SSR149415 treated rats was still present 7 days after cessation of treatment. Although the behavioral effects of treatment with SSR149415 were specific for the OBX animals, adrenal gland weights were reduced in both sham and OBX animals treated with 30 mg/kg SSR149415. Chronic but not acute administration of SSR149415 normalizes OBX-induced hyperactivity up to 1 week after cessation of treatment, suggesting that a V_1b receptor antagonist may have long-lasting antidepressant activity.     

Antidepressant-like effects of the vasopressin V1b receptor antagonist SSR149415 in the Flinders Sensitive Line rat

There is an increased interest in the potential of vasopressin receptor antagonists as antidepressants because of the involvement of vasopressin in stress-related behavioral changes. The present study sought to provide confirmatory evidence for the antidepressant-like effects of the selective vasopressin V1b receptor antagonist SSR149415, which had been previously demonstrated in a variety of animal models. The Flinders Sensitive Line (FSL) rat, a selectively bred animal model of depression, was chronically treated for 14 days with SSR149415 (1, 10, and 30 mg/kg), vehicle, or desipramine (5 mg/kg) as a positive control. Approximately 22-24 h after the last treatment, the rats were exposed to a single 5-min session in a cylinder containing 25 degrees C water and immobility was recorded. A control group of Flinders Resistant Line (FRL) rats was included as a reference group as well as one treated with 10 mg/kg SSR149415. Vehicle-treated FSL rats exhibited much more immobility than the FRL rats, and desipramine-treated FSL rats had much lower scores, as expected. Treatment with SSR149415 reduced immobility in the FSL rats at all doses, but only the higher doses reduced it such that they were no longer different from the FRL rats. In contrast, SSR149415 did not alter the lower immobility of the FRL rats. The social interaction test of anxiety was also examined in the FSL rats, at 20-22 h after the last of the 14 injections. Results showed that the 10 and 30 mg/kg doses of SSR149415 increased the time spent in social interaction in the FSL rats, suggesting anxiolytic effects. These findings confirm the antidepressant-like potential of SSR149415 and suggest that it may also have anxiolytic effects. It is likely that the strategy of testing selective vasopressin V1b receptor antagonists will be fruitful.     

CP-154,526, a CRF type-1 receptor antagonist,attenuates the cue-and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior in rats

Rationale Previous studies from our laboratory and others have indicated a role for the hypothalamo-pituitary-adrenal (HPA) axis in the extinction/reinstatement animal model of cocaine relapse Objective This present study was designed to investigate the potential role for the HPA axis in the cue- and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior by determining the effects of ketoconazole and the corticotropin-releasing hormone (CRF) type 1 receptor antagonist, CP-154,526, on these behaviors. Materials and methods Male Wistar rats were trained to self-administer methamphetamine (0.03 mg/kg/infusion). The delivery of methamphetamine was paired with the presentation of a tone and the illumination of a house light. Once stable responding was reached, the rats were placed into extinction. The effects of pretreatment with ketoconazole (25, 50, or 100 mg/kg, i.p.) or CP-154,526 (20 or 40 mg/kg, i.p.; 3 μg, i.c.v) on cue-induced reinstatement were then evaluated. Results Cue-induced reinstatement was not significantly attenuated by pretreatment with peripherally administered CP-154,526 or by pretreatment with ketoconazole. However, centrally administered CP-154,526 (3 μg, i.c.v.) significantly attenuated cue-induced reinstatement. In a separate group of rats, CP-154,526 (20 mg/kg, i.p.) attenuated methamphetamine-induced reinstatement (0.12 mg/kg priming infusion); whereas a higher dose (40 mg/kg) was necessary to attenuate reinstatement induced by a priming infusion of 0.24 mg/kg/infusion. Ketoconazole (50 mg/kg) did not affect reinstatement induced by a 0.12 mg/kg priming infusion and, therefore, was not tested at the higher methamphetamine priming dose. Conclusions These data suggest an important role for CRF in the cue- and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior.     

The corticotropin-releasing factor 1 receptor antagonist, SSR125543, and the vasopressin 1b receptor antagonist, SSR149415, prevent stress-induced cognitive impairment in mice

The vasopressin 1b receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, are orally active non-peptidic compounds with anxiolytic- and antidepressant-like activities in animals. In the present study, their effects on stress-induced deficit in cognitive performances as assessed in a modified object recognition test were investigated in mice. The object recognition task measures the ability of a mouse to remember an object it has previously explored in a learning trial. During this acquisition session, the mouse was stressed by the presence of a pair of rats under the grid floor of the apparatus. One hour later, it was placed again in the environment with the known and a novel object, but in the absence of the rats. While non-exposed mice spent more time exploring the new object, mice that had been exposed to the rats during acquisition failed to discriminate between the known and the new object during retrieval. This cognitive impairment in stressed mice was prevented by the administration of SSR149415 (10 mg/kg, ip), SSR125543 (10 mg/kg, ip) and the selective serotonin reuptake inhibitor, fluoxetine (10 mg/kg, ip). Under similar conditions, the cognitive enhancer donepezil (1 mg/kg, ip) failed to reverse object recognition deficit. These results indicate that the effects of SSR149415 and SSR125543 in the modified object recognition test, in stressed mice, involve the ability of mice to cope with stress rather than an effect on cognition per se. Together, these data suggest that SSR149415 and SSR125543 may be of interest to reduce the cognitive deficits following exposure to stress-related events, such as acute stress disorder.     

Differential roles of amygdaloid nuclei in the anxiolytic- and antidepressant-like effects of the V1b receptor antagonist, SSR149415, in rats

Rationale SSR149415 ((2S, 4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide), the first selective nonpeptide vasopressin V1b receptor antagonist has been shown to induce antidepressant—and anxiolytic-like effects following systemic administration, whereas intraseptal infusion of the drug engender antidepressant—but not anxiolytic-like effects.Objectives Based on recent evidence that V1b receptors are located within the amygdaloid complex, a structure which is well known for its modulatory role of emotional processes, the possible involvement of the different amygdaloid nuclei in the anxiolytic- and/or antidepressant-like effects of SSR149415 was examined.Methods Male Sprague-Dawley or Wistar rats were infused with SSR149415 into the central (CeA), the basolateral (BlA), or the medial (MeA) nucleus of the amygdala and tested 10 min after microinjection in the elevated plus-maze or the forced-swimming test, two models typically used for assessing the anxiolytic and antidepressant effects of drugs, respectively.Results Microinjection of SSR149415 into the BlA (1–10 ng), but not into the CeA or the MeA, increased the percentage of time spent in the open arms of the elevated plus-maze, indicating anxiolytic-like effects. Furthermore, in the forced-swimming test, microinjection of the drug into the CeA (1, 10, and 100 ng), BlA (1–10 ng), or MeA (100 ng) decreased immobility, an effect which is indicative of an antidepressant-like action. Together, these findings indicate that while the antidepressant-like effects of SSR149415 are mediated by different amygdaloid nuclei, its anxiolytic-like effects appear to involve only the basolateral nucleus of the amygdala. Moreover, these results add further evidence to the role of extrahypothalamic vasopressinergic systems in the control of emotional responses.     

Comparison of the effects of diazepam, the CRF1 antagonist CP-154,526 and the group II mGlu receptor agonist LY379268 on stress-evoked extracellular norepinephrine levels

The present study used an elevated platform procedure to investigate the effects of diazepam, a CRF1 antagonist CP-154,526 and a group II mGlu2/3 receptor agonist LY379268 on stress-evoked increase in extracellular norepinephrine (NE). Pretreatment with either diazepam (1 mg/kg, i.p.), CP-154,526 (20 mg/kg, i.p.) or LY379268 (1, 3 and 10 mg/kg, p.o.) significantly reduced platform stress-evoked NE. Interestingly, at the highest dose tested (10 mg/kg) LY379268 caused a marked increase in baseline NE levels. We tested whether this effect would diminish after repeated dosing. In contrast to acute administration, a challenge injection of LY379268 after repeated dosing (10 mg/kg x days) did not alter basal NE. Importantly, although less effective, LY379268 still significantly reduced stress-evoked NE. We further show that this increase in basal NE may involve mGlu2/3 receptor regulation of the GABAergic system. To this end, administration of the GABAB agonist, baclofen (4 mg/kg, i.p.), 2 h after dosing with LY379268, reversed the increase in baseline NE. These data suggest that, like diazepam and CP-154,526, group II mGlu2/3 receptor agonists can attenuate stress-evoked increase in extracellular NE in the rat prefrontal cortex. In addition they reveal a 'stress-like' increase in NE after high doses of LY379268 which may reflect mGlu3 receptor modulation of GABAergic transmission.     

Evidence that the lateral septum is involved in the antidepressant-like effects of the vasopressin V1b receptor antagonist, SSR149415.

Previous experiments with the first selective nonpeptide vasopressin V1b receptor antagonist SSR149415 ((2S, 4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide) have shown that the drug elicits anxiolytic- and antidepressant-like effects following systemic administration. Extrahypothalamic V1b receptors have been suggested to be involved in these effects as evidenced by the findings that hypophysectomized rats were still sensitive to the antistress action of SSR149415. The first objective of the present work aimed at locating V1b receptors in the rat limbic brain using anti-V1b receptor immunohistochemistry. The immunolabeling revealed high densities of V1b receptors in the lateral septum, the amygdala, the bed nucleus of the stria terminalis, the hippocampal formation, and in several cortical areas. Since the lateral septum is well known to participate in the modulation of emotional processes, the second objective of this study went on to evaluate the behavioral effects of an infusion of SSR149415 into the lateral septum and to determine whether its behavioral effects are mediated by this structure. Animals were tested in models classically used for the screening of anxiolytics (ie the punished drinking and elevated plus-maze tests) and antidepressants (ie the forced-swimming test). Bilateral intraseptal infusion of SSR149415 (10 and 100 ng) produced a decrease in immobility time in the forced-swimming test, indicating antidepressant-like effects. In contrast, the behavior of rats in the punished drinking procedure or in the elevated plus-maze test was not modified by intraseptal infusion of SSR149415. These findings suggest that V1b receptors located in the lateral septum participate in the antidepressant- but not the anxiolytic-like action of SSR149415 in rats.     

An overview of SSR149415, a selective nonpeptide vasopressin V(1b) receptor antagonist for the treatment of stress-related disorders

Vasopressin (AVP) and corticotropin-releasing factor (CRF) are key mediators in the organism's neuro-adaptive response to stress. Through pituitary and central vasopressin V(1b) receptors, AVP participates in the control of the hypothalamic-pituitary-adrenal axis (HPA) and is involved in various emotional processes. SSR149415 is the first selective, orally active vasopressin V(1b) receptor antagonist yet described. It is a competitive antagonist with nanomolar affinity for animal and human V(1b) receptors and displays a highly selective profile with regard to a large number of receptors or enzymes. In vitro, SSR149415 potently antagonizes functional cellular events associated with V(1b) receptor activation by AVP, such as intracellular Ca(2+) increase or proliferation in various cell systems. Pharmacological studies, performed by measuring ACTH secretion induced by various stimulants such as hormones (AVP or AVP + CRF) or physical stress (restraint or forced swimming stress and dehydration) in conscious rats or mice, confirm the antagonist profile of SSR149415 and its efficacy in normalizing ACTH secretion in vivo. SSR149415 is active by the oral route, at doses from 3 mg/kg, it potentiates CRF effect and displays a long-lasting oral effect in the different models. At 10 mg/kg p.o. its duration of action is longer than 4 h. This molecule also decreases anxiety and exerts marked antidepressant-like activity in several predictive animal models. The anxiolytic effects of SSR149415 have been demonstrated in various Generalized Anxiety Disorders (GAD) models (four-plate, punished drinking, elevated plus-maze, light dark, mouse defense test battery, fear-potentiated startle and social interaction tests). It is as effective as the benzodiazepine diazepam in the acute stress exposure test. SSR149415 has similar efficacy to the reference antidepressant drug, fluoxetine, in acute (forced-swimming) and chronic (chronic mild stress and subordination stress) situations in rodents. SSR149415 also reduces offensive aggression in the resident-intruder model in mice and hamsters. Depending on the model, the minimal effective doses are in the range of 1-10 mg/kg i.p. or 3-10 mg/kg p.o. SSR149415 is devoid of adverse effects on motor activity, sedation, memory or cognitive functions and produces no tachyphylaxis when administered repeatedly. It is well-tolerated in animals and humans and exhibits an adequate ADME profile. Thus, SSR149415 is a new dual anxiolytic/antidepressant compound, which appears to be free of the known side effects of classical anxiolytic/antidepressant drugs. Clinical trials are in progress, they will hopefully demonstrate its therapeutical potential for treating stress-related disorders.     

Antidepressant-like effects of the corticotropin-releasing factor 1 receptor antagonist, SSR125543, and the vasopressin 1b receptor antagonist, SSR149415, in a DRL-72 s schedule in the rat.

The vasopressin 1b receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, are orally active non-peptidic compounds with anxiolytic- and antidepressant-like activities in animal models. Presently, SSR149415 and SSR125543 were evaluated in a differential reinforcement of low-rate 72 s (DRL-72 s) schedule, a procedure known to respond differentially to antidepressants and anxiolytics. Male Wistar rats were trained to lever-press for food reinforcement, but only lever-presses occurring after a 72 s delay were reinforced; otherwise, presses were not rewarded, and the timer was reset to 0 s. The selective serotonin reuptake inhibitor, fluoxetine, and the benzodiazepine anxiolytic, diazepam, were tested in parallel. SSR149415 (10-30 mg/kg, i.p.) and SSR125543 (30 mg/kg, i.p.) increased the percentage of responses emitted in the inter-response time (IRT) bin (49-96 s), which resulted in a greater number of reinforced presses. Both compounds shifted the frequency distribution of responses toward longer IRT durations, with a preservation of the bell shape of the IRT distribution curve. Fluoxetine (10 mg/kg, i.p.) had an effect on DRL-72 s similar to that of SSR149415 and SSR125543. By contrast, diazepam increased the number of responses in IRT bin (0-12 s), and the IRT distribution curve was shifted toward shorter IRT durations and flattened. In summary, these results show that SSR149415 and SSR125543 displayed antidepressant-like activity in a DRL-72 s schedule in rat, confirming their therapeutic potential for the treatment of pathological states induced by chronic frustration such as depression.     

Selectivity of d[Cha4]AVP and SSR149415 at human vasopressin and oxytocin receptors: evidence that SSR149415 is a mixed vasopressin V1b/oxytocin receptor antagonist

1 A possible role of arginine vasopressin (AVP) V(1b) receptor subtype in stress-related disorders has been recently highlighted by the discovery of the agonist [1-deamino-4-cyclohexylalanine] AVP (d[Cha(4)]AVP) and the antagonist SSR149415. Both compounds have been proposed to target specifically V(1b) receptors, since the reported affinities for the related V(1a), V(2) and oxytocin receptors are in the micromolar or submicromolar range. In the present study, we further investigated the binding affinities of d[Cha(4)]AVP and SSR149415 at recombinant human vasopressin V(1b) (hV(1b)) and oxytocin (hOT) receptors expressed in Chinese hamster ovary (CHO) cells and functional properties of both compounds at hV(1b), hV(1a), hV(2) and hOT receptors. 2 d[Cha(4)]AVP bound to hV(1b) receptors and hOT receptors with pK(i) values of 9.68+/-0.06 and 7.68+/-0.09, respectively. SSR149415 showed pK(i) values of 9.34+/-0.06 at hV(1b) and 8.82+/-0.16 at hOT receptors. 3 d[Cha(4)]AVP stimulated [Ca(2+)](i) increase in hV(1b)-CHO cells with a pEC(50) value of 10.05+/-0.15. It showed pEC(50) values of 6.53+/-0.17 and 5.92+/-0.02 at hV(1a) and hV(2) receptors, respectively, and behaved as a weak antagonist at hOT receptors (pK(B)=6.31+/-0.12). SSR149415 inhibited the agonist-induced [Ca(2+)](i) increase with pK(B) values of 9.19+/-0.07 in hV(1b)-CHO and 8.72+/-0.15 in hOT-CHO cells. A functional pK(i) value of 7.23+/-0.10 was found for SSR1494151 at hV(1a) receptors, whereas it did not inhibit 20 nM AVP response at hV(2) receptors up to 3 microM. 4 Data obtained confirmed the high potency and selectivity of d[Cha(4)]AVP at hV(1b) receptors, but revealed that SSR149415, in addition to the high potency at hV(1b) receptors, displays a significant antagonism at hOT receptors.     

The pharmacology of CP-154,526, a non-peptide antagonist of the CRH1 receptor: a review

Since CRH has been shown to mediate stress-induced physiological and behavioral changes, it has been hypothesized that CRH receptor antagonists may have therapeutic potential in disorders that involve excessive CRH activity. CP-154,526 and its close analog antalarmin are potent, brain-penetrable, selective nonpeptide CRH1 receptor antagonists that were discovered in an effort to develop compounds with efficacy in CNS disorders precipitated by stress. Since its discovery many investigators have used CP-154,526 as a tool to study the pharmacology of CRH and its receptors and to evaluate its therapeutic potential in a variety of CNS and peripheral disorders. Systemically-administered CP-154,526 has been demonstrated to antagonize CRH- and stress-induced neuroendocrine, neurochemical, electrophysiological, and behavioral effects. These findings support the hypothesis that CRH1 receptor antagonists may have therapeutic utility in a number of neuropsychiatric disorders. CP-154,526, as well as other CRH1 receptor antagonists that have since been discovered, have also shown activity in several preclinical models of anxiety, depression, and substance abuse, while having little effect on locomotor activity and motor function. Although these effects are on occasion inconsistent among different laboratories, clinical evaluation of CRH1 antagonists appears justified on the basis of these and clinical data implicating the involvement of CRH in several CNS disorders. The effects of CRH1 antagonists on cognition, neurodegeneration, inflammation, and the gastrointestinal system have not been as extensively characterized and additional studies will be necessary to evaluate their therapeutic potential in these areas.     

Antidepressant-like effects of CRF1 receptor antagonist SSR125543 in an animal model of depression

Much interest has been expressed in the antidepressant potential of nonpeptide, orally active corticotropin-releasing factor (CRF) receptor antagonists in recent years. Therefore, the present investigation examined the antidepressant-like effects of the novel CRF(1) receptor antagonist SSR125543 on the exaggerated swim test immobility in the Flinders Sensitive Line rat, a genetic animal model of depression. Chronic treatment with SSR125543 (3, 10, 20, 30 mg/kg, i.p.) for 14 days significantly increased swimming in the Flinders Sensitive Line rats. The reference serotonin reuptake inhibitor fluoxetine (5 mg/kg, i.p.) and the tricyclic antidepressant desipramine (5 mg/kg, i.p.) also significantly increased swimming, as expected. The higher doses of SSR125543 (20 and 30 mg/kg) also significantly increased the abnormally low level of social interaction behavior in the Flinders Sensitive Line rats. Together, these findings indicate that the CRF(1) receptor antagonist SSR125543 has both antidepressant- and anxiolytic-like effects in the Flinders Sensitive Line rats.     

The pituitary mediates the anxiolytic-like effects of the vasopressin V1B receptor antagonist, SSR149415, in a social interaction test in rats

A vasopressin V(1B) receptor antagonist has been shown to exhibit anxiolytic effects in a variety of animal models of anxiety. In the present study, we examined the involvement of the pituitary in the anxiolytic effects of a vasopressin V(1B) receptor antagonist by conducting a social interaction test in rats. In the sham-operated rats, both the vasopressin V(1B) receptor antagonist SSR149415 and the benzodiazepine chlordiazepoxide significantly increased the social behavior of a pair of unfamiliar rats, and the blood adrenocorticotropic hormone levels were markedly increased during the social interaction test. Hypophysectomy also increased the length of time that the animals engaged in social behavior to the same extent as that observed after treatment of the sham-operated rats with anxiolytics. However, while chlordiazepoxide further increased the duration of social interaction in the hypophysectomized rats, the anxiolytic effects of SSR149415 was no longer observed in these animals. These results suggest that the anxiolytic effects of the vasopressin V(1B) receptor antagonist in the social interaction test are mediated through blockade of the vasopressin V(1B) receptor in the pituitary.     

Characterization of the V1a antagonist,JNJ-17308616, in rodent models of anxiety-like behavior

RATIONALE: Vasopressin (AVP) plays a role in regulating anxiety, which is thought to be partially mediated through the V1a receptor. Recently, JNJ-17308616 was identified as a V1a antagonist. OBJECTIVES: The purpose of this work was to assess V1a receptor affinity and selectivity of JNJ-17308616 and in vivo efficacy in animal models of anxiety-like behavior. MATERIALS AND METHODS: The affinity of JNJ-17308616 for the human and rat V1a, V1b, V2, and oxytocin receptors was determined. Central administration of AVP induces a scratching response mediated through the V1a receptor. Inhibition of scratching was used as a behavioral measure of in vivo potency. JNJ-17308616 was tested in five models of anxiety: rat elevated plus-maze (EPM), rat-elevated zero-maze (EZM), rat-conditioned lick suppression (CLS), rat pup separation-induced ultrasonic vocalizations (USV), and mouse marble burying (MMB). RESULTS: High affinity for the human V1a receptor (K (i) 5.0 nM) was confirmed. However, the rat V1a receptor affinity was more modest (K (i) 216 nM), and the compound was not selective over the rat V2 receptor (K (i) 276 nM). At 100 mg/kg, JNJ-17308616 significantly reduced anxiety-like behavior in EPM, USV, and MMB; at 30 mg/kg, it was effective in EZM and CLS. JNJ-17308616 neither impaired social recognition nor reduced locomotor activity. CONCLUSIONS: These results demonstrate the potential for V1a receptor antagonists as novel anxiolytics. Tool compounds that have greater V1a receptor selectivity than JNJ-17308616 are necessary to make precise conclusions about the role of the V1a receptor in affective disorders.     

Effects of the CRH receptor antagonist CP-154,526 on intravenous cocaine self-administration in rats.

The role for corticotropin-releasing hormone (CRH) receptors in the maintenance of intravenous cocaine self-administration in rats was investigated using the centrally active, small molecule CRH1 receptor antagonist CP-154,526. In these experiments, adult male Wistar rats were allowed alternating 15-min periods of access to food reinforcement and cocaine self-administration (0.125, 0.25 or 0. 5 mg/kg/infusion) during daily 2-h sessions. A 1-min timeout separated access to the two reinforcers. Pretreatment with CP-154, 526 produced dose-related decreases in cocaine self-administration without affecting food-reinforced responding, suggesting a specific effect of the antagonist on cocaine-maintained behavior. Drug intake was decreased across several doses of cocaine, with the dose-response curve for cocaine self-administration shifted downward and flattened, suggesting that CP-154,526 decreased cocaine reinforcement. Furthermore, responding on the cocaine lever following CP-154,526 pretreatment was significantly suppressed, even during the first 15 min of the session, a time when rats typically sample the cocaine lever during extinction, suggesting that CRH receptors may also be involved in some of the conditioned effects of cocaine as well. These data are discussed in terms of the role for CRH in the neurobehavioral effects of cocaine.     

Effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization anxiolytic test in rat pups

CRF(1) receptor antagonists have been proposed as novel pharmacological treatments for depression, anxiety and stress disorders. The primary goal of the present study was to evaluate the effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization (SIV) model of anxiety. Nine- to 11-day-old rat pups were separated from their litter and the effects of intraperitoneally administered test compounds on the elicited ultrasonic vocalizations were measured. Side-effect potential was assessed using a modified inclined plane test ('time on an inclined plane', or TIP), and using negative geotaxis. SIV was reduced by CP 154,526 at doses that did not affect TIP or negative geotaxis, a profile like that of the 5-HT(1A) partial agonist buspirone. The benzodiazepine anxiolytic, diazepam, decreased SIV but also produced significant side effects at one to three-fold higher doses. Additional pharmacological characterization of SIV demonstrated anxiolytic-like effects of the atypical antipsychotic, clozapine, but not the typical antipsychotic, haloperidol, and of the serotonin reuptake inhibitor, zimelidine, but not the norepinephrine reuptake inhibitor, desipramine. In summary, the data support the conclusion that selective CRF(1) receptor antagonists may have utility in anxiety and stress disorders. The data further support the use of separation-induced vocalizations for identifying mechanistically diverse compounds with anxiolytic actions in man.     

CP-154,526, a selective, non-peptide antagonist of the corticotropin-releasing factor1 receptor attenuates stress-induced relapse to drug seeking in cocaine- and heroin-trained rats

We have found that peptide antagonists of corticotropin-releasing factor (CRF) receptors attenuate reinstatement of heroin and cocaine seeking induced by footshock. Here we examined the effect of a non-peptide, selective CRF₁ receptor antagonist, CP-154,526, on reinstatement of heroin and cocaine seeking induced by footshock. Rats were trained to self-administer heroin or cocaine (0.1 and 1.0 mg/kg per infusion, IV, respectively) for 9–12 days. Extinction sessions were given for up to 14 days, during which saline was substituted for the drugs. Tests for reinstatement were then conducted after exposure to intermittent footshock (10 or 15 min, 0.5 mA). The footshock stressor reliably reinstated extinguished cocaine- and heroin-taking behavior. Pretreatment with CP-154,526 (15 and 30 mg/kg, SC) significantly attenuated the reinstatement effect of the stressor in both heroin- and cocaine-trained rats. CP-154,526, administered in the absence of the footshock stressor, did not affect extinguished drug seeking. In addition, in a separate experiment, CP-154,526 was shown not to alter high rates of lever pressing for a 10% sucrose solution, suggesting that the suppression of lever pressing in stress-induced reinstatement is not caused by a performance deficit. These results extend previous reports on the role of CRF in reinstatement of drug seeking induced by stressors. The present data also suggest that, to the extent that exposure to environmental stressors provoke relapse to drug use in humans, systemically effective CRF receptor antagonists may be of use in the treatment of relapse to drug use. Received: 12 July 1997/Final version: 20 October 1997