Table 2.
Summary of effects of CRF1 receptor antagonists (CRAs) in various animal models. This table describes compounds that are efficacious (ACTIVE) or which lack efficacy (INACTIVE) in numerous animal models. Column 1 summarizes the therapeutic application or other attribute (side effect potential, physiological system, etc.) associated with activity in the model. In Column 2, models are listed by behavioral endpoint or common name, and, if applicable, any special test conditions or parameters, and/or species/strain used. Species is summarized in Column 3. As is evident from this table, the same behavioral endpoint can be incorporated into different paradigms which have different therapeutic applications or interpretations.
| Therapeutic Application/System |
Assay (endpoint, special test conditions, strains, etc.) |
Species | Active CRAs | Inactive CRAs |
|---|---|---|---|---|
| Anxiety | Burying, defensive | Rat | R121919 (Heinrichs, et al., 2002); MPZP (Richardson, et al., 2008); MJL-1-109-2 (Zhao, et al., 2007) | |
| Anxiety | Burying, marble | Mouse | CP-154,526 (Hodgson, et al., 2007) | |
| Anxiety | Defensive Withdrawal | Rat | R121919 (Gutman, et al., 2003; Heinrichs, et al., 2002); DMP696 (Lelas, et al., 2004; McElroy, et al., 2002); DMP 696 (chronic) (Lelas, et al., 2004); DMP 904 (Lelas, et al., 2004); DMP 904 (chronic) (Lelas, et al., 2004); antalarmin (Zorrilla, et al., 2002); CP-154,526 (chronic) (Arborelius, et al., 2000) | |
| Anxiety | Elevated Plus Maze | Mouse | CP-154,526 (Hodgson, et al., 2007) | |
| Anxiety | Elevated Plus Maze | Rat | DMP 904 (7); CP-154,526 (chronic) (Mallo, et al., 2004) | R121919 (Heinrichs, et al., 2002); CRA0450 (Chaki, et al., 2004); antalarmin (Zorrilla, et al., 2002); CP 154,526 (Millan, et al., 2001); DMP695 (Millan, et al., 2001); MTIP (Gehlert, et al., 2007) |
| Anxiety | Elevated Plus Maze (exogenous CRF icv) | Mice | CRA1000 (Okuyama, et al., 1999); CRA1001 (Okuyama, et al., 1999); CP-154,526 (Okuyama, et al., 1999) | |
| Anxiety | Elevated Plus Maze (with prior maternal separation stress) | Rat | DMP696 (Maciag, et al., 2002) | |
| Anxiety | Elevated Plus Maze (with prior stress) | Rat | R121919 (Heinrichs, et al., 2002); CRA0450 (Chaki, et al., 2004) | |
| Anxiety | Elevated Plus Maze | Rat | CP-154,526 (chronic) (Mallo, et al., 2004) | |
| Anxiety | Elevated Plus Maze (“Low Anxiety Behavior, LAB, strain) | Rat | R121919 (Keck, et al., 2001) | |
| Anxiety | Elevated Plus Maze (“High Anxiety Behavior, HAB, strain) | Rat | R121919 (Keck, et al., 2001) | |
| Anxiety | Elevated Plus Maze, (“Swim High-Active” inbred strain) | Rat | R121919 (Gutman, et al., 2008) | |
| Anxiety | Food Intake (footshock stressor-suppressed) | Rat | CRA1000 (Sekino, Ohata, Mano-Otagiri, Arai, & Shibasaki, 2004) | |
| Anxiety | Food Intake (novel environment-suppressed; unpredictable mild chronic stress model) | Mouse | SSR125543 (Surget, et al., 2008) | |
| Anxiety | Freezing, conditioned | Mouse | CP-154,526 (Blank, et al., 2003) | |
| Anxiety | Freezing, conditioned (acquisition) | Rat | CP-154,526 (Hikichi, et al., 2000); CP-154,526 (Rau & Fanselow, 2007) | DMP696 (Hubbard, et al., 2007); |
| Anxiety | Freezing, conditioned (consolidation) | Rat | CP-154,526 (Rau & Fanselow, 2007) | |
| Anxiety | Freezing, conditioned (retention) | Rat | CP-154,526 (Hikichi, et al., 2000); DMP904 (Ho, et al., 2001) | |
| Anxiety | Freezing, conditioned (acquisition, retention) | Rat | Antalarmin (Deak, et al., 1999) | |
| Anxiety | Freezing, conditioned (acquisition, retention), prior stress-enhanced | Rat | Antalarmin (Deak, et al., 1999) | |
| Anxiety | Freezing, conditioned (prior stress-induced deficit) | Mouse | CP-154,526 (Blank, et al., 2003) | |
| Anxiety | Lick Suppression (Conditioned) | Mouse | CP-154,526 (Hodgson, et al., 2007) | |
| Anxiety | Lick Suppression (Unconditioned) | Rat | CP-154,526 (Millan, et al., 2001); DMP695 (Millan, et al., 2001) | CRA450 (Chaki, et al., 2004) |
| Anxiety | Light-Dark Box | Mouse | CRA1000 (Okuyama, et al., 1999); CRA1001 (Okuyama, et al., 1999); CP-154,526 (Okuyama, et al., 1999) | |
| Anxiety | Light-Dark Box (with prior swim stress) | Mouse | CRA1000 (Okuyama, et al., 1999); CRA1001 (Okuyama, et al., 1999); CP-154,526 (Okuyama, et al., 1999) | |
| Anxiety | Locomotion (reduction induced by diurnal phase of dark cycle) | Rat | CRA1000 (Ohata, Arai, & Shibasaki, 2002) | |
| Anxiety | Social Interaction | Rat | CP 154,526 (Millan, et al., 2001); DMP 695 (Millan, et al., 2001) | NBI3b1996 (Gehlert, et al., 2005) |
| Anxiety | Social Interaction, Flinders Sensitive Line | Rat | CP-154,526 (chronic, 14 d) (Overstreet, Keeney, et al., 2004) SSR 125543 (chronic, 14 d) (Overstreet & Griebel, 2004) | |
| Anxiety | Social Interaction (with prior stress) | Rat | NBI3b1996(Gehlert, et al., 2005) | |
| Anxiety | Social Interaction (anxiety induced with multiple infusions of urocortin) | Rat | NBI3b1996 (Gehlert, et al., 2005) | |
| Anxiety | Splash Test (with prior stress -- unpredictable mild chronic stress model) | Mouse | SSR125543 (Surget, et al., 2008) | |
| Anxiety | Startle, fear conditioning-enhanced (contextual cue) | Mouse | R121919 (Risbrough, et al., 2008) | |
| Anxiety | Startle, fear conditioning-enhanced (contextual cue) | Rat | ||
| Anxiety | Startle, fear conditioning-enhanced (discrete cue) | Mouse | R121919 (Risbrough, et al., 2008) | |
| Anxiety | Startle, fear conditioning-enhanced, (discrete cue) | Rat | CP-154,526 (Schulz, et al., 1996); | GSK876008(D. Walker, et al., 2008) |
| Anxiety | Startle, footshock stressor-enhanced | Rat | GSK876008(D. Walker, et al., 2008) | |
| Anxiety | Startle, light stressor-enhanced | Rat | GSK876008(D. Walker, et al., 2008) | |
| Anxiety | Startle, predator stressor-enhanced (initiation or acquisition) | Mouse | CRA0450(Adamec, et al., 2010) | |
| Anxiety | Vocalization, audible – maternal separation induced in pup | Guinea pig | CP-154,526 (Hodgson, et al., 2007) | |
| Anxiety | Vocalization, ultrasonic – maternal separation stressor induced | Rat | CP-154,526 (Hodgson, et al., 2007; Iijima & Chaki, 2005; Kehne, et al., 2000); NBI27914 (Ise, et al., 2008) | |
| Anxiety | Vocalization, ultrasonic – systemic CRF induced in rat pup (37° C) | Rat | NBI27914 (Ise, et al., 2008) | |
| Anxiety | Vocalizations, ultrasonic (conditioned footshock stressor-elicited) | Rat | CP 154,526 (Millan, et al., 2001); DMP 695 (Millan, et al., 2001) | |
| Depression | Chronic Mild Stress Induced Debilitation (weight gain,, physical state)(BALB/c) | Mouse | Antalarmin (Ducottet, et al., 2003) | |
| Depression | Differential Rate of Low Reinforcement 72 sec (DRL72) | Rat | SSR125543 (Louis, et al., 2006) | CRA0450 (Chaki, et al., 2004) |
| Depression | Forced Swim Test | Mouse | CP-154,526 (Hodgson, et al., 2007) | |
| Depression | Forced Swim Test | Rat | CP-154,526 (Hodgson, et al., 2007); LWH234 (Jutkiewicz, et al., 2005) | Antalarmin (Jutkiewicz, et al., 2005); CRA0450 (Chaki, et al., 2004); CP-154,526 (Jutkiewicz, et al., 2005); R121919 (Jutkiewicz, et al., 2005) |
| Depression | Forced Swim Test, “Swim High-Active” Strain | Rat | R121919 (Gutman, et al., 2008) | |
| Depression | Forced Swim Test, Flinders Sensitive Line | Rat | CP-154,526 (chronic, 14 d) (Overstreet, Keeney, et al., 2004) SSR 125543 (chronic, 14 d) (Overstreet & Griebel, 2004) | |
| Depression | Olfactory Bulbectomy | Rat | CRA0450 (Chaki, et al., 2004); CRA1000 (Okuyama, et al., 1999); CRA1001 (Okuyama, et al., 1999) | |
| Depression | Olfactory Bulbectomy | Rat | CRA0450 (chronic, 10 d) (Chaki, et al., 2004); CRA1000 (chronic, 7d)(Okuyama, et al., 1999); CRA1001 (chronic, 7d) (Okuyama, et al., 1999) | |
| Depression | Operant avoidance, inescapable shock (expression) | Rat | CP-154,526 (Mansbach, et al., 1997) | |
| Depression | Shuttle box avoidance, inescapable shock (acquisition) | Rat | CRA0450 (Chaki, et al., 2004) | |
| Depression | Shuttle box avoidance, inescapable shock (acquisition, expression) | Rat | Antalarmin (Deak, et al., 1999) | |
| Depression | Shuttle box avoidance, inescapable shock (consolidation) | Rat | CRA1000 (Takamori, et al., 2001); CP-154,526 (Takamori, et al., 2001) | |
| Depression | Shuttle box avoidance, inescapable shock (expression) | Rat | CRA1000 (Takamori, et al., 2001); CP-154,526 (Takamori, et al., 2001) | |
| Depression | Shuttle box avoidance, inescapable shock avoidance (acquisition) | Rat | CRA0450 (chronic, 8d)(Chaki, et al., 2004); CRA1000 (chronic, 8d) (Takamori, et al., 2001); CP-154,526 (chronic, 8d) (Takamori, et al., 2001) | |
| Depression | Tail suspension | Mouse | CRA0450 (Chaki, et al., 2004); CP-154,526 (Hodgson, et al., 2007); | |
| Depression | Tail suspension | Mouse | R121919 (subchronic) (Nielsen, Carey, & Gold, 2004); DMP 696 (subchronic) (Nielsen, et al., 2004) | CRA0450 (Chaki, et al., 2004); CP-154,526 (Hodgson, et al., 2007); |
| Drug Abuse (Alcohol) | Alcohol Intake (non-dependent) | Rat | MPZP (Richardson, et al., 2008); MTIP (Gehlert, et al., 2007) | |
| Drug Abuse (Alcohol) | Alcohol Intake (dependent/withdrawal) | Rat | MPZP (Richardson, et al., 2008); MTIP (Gehlert, et al., 2007) | |
| Drug Abuse (Alcohol) | Alcohol Intake (withdrawal-induced/dependent), mSP alcohol preferring strain | Rat | MTIP (Gehlert, et al., 2007) | |
| Drug Abuse (Alcohol) | Alcohol Intake (reinstatement of stress induced alcohol seeking), post-dependent | Rat | MTIP (Gehlert, et al., 2007) | |
| Drug Abuse (Alcohol) | Alcohol Intake (reinstatement of stress induced alcohol seeking), mSP alcohol preferring strain | Rat | MTIP (Gehlert, et al., 2007) | |
| Drug Abuse (Alcohol) | Elevate Plus Maze (withdrawal) | Rat | MTIP (Gehlert, et al., 2007) | |
| Drug Abuse (Alcohol) | Lick Suppression (Unconditioned; chronic withdrawal) | Rat | MTIP (Sommer, et al., 2007) | |
| Drug Abuse (Alcohol) | Social Interaction (Deficits Induced by Single or Repeated Withdrawals from Alcohol) | Rat | CP-154,526 (Overstreet, Keeney, et al., 2004); CRA1000 (Knapp, Overstreet, Moy, & Breese, 2004; Overstreet, Knapp, & Breese, 2004) | |
| Drug Abuse (Cocaine) | Cocaine Seeking (Reinstatement by a Conditioned Reinforcer) | Rat | CP-154,526 (Goeders & Clampitt, 2002) | |
| Drug Abuse (Cocaine) | Locomotion (Cocaine-Stimulated) | Rat | CP-154,526 (Lu, Liu, Huang, & Zhang, 2003) | |
| Drug Abuse (Cocaine) | Place Preference (Cocaine-Induced) | Rat | CP-154,526 (Lu, et al., 2003) | |
| Exogenous CRF (functional) | Freezing (icv CRF-induced) | Mouse | NBI 27914 (Pelleymounter, et al., 2000) | |
| Exogenous CRF (functional) | Grooming (icv CRF-induced) | Rat | Antalarmin (Howard, et al., 2008) | |
| Exogenous CRF (functional) | Burying (icv CRF-stimulated) | Rat | Antalarmin (Howard, et al., 2008) | |
| Exogenous CRF (functional) | Elevated Plus Maze (icv CRF-induced reduction) | Rat | Antalarmin (Zorrilla, et al., 2002) | |
| Exogenous CRF (functional) | Food Intake (icv CRF-suppressed) | Mouse | NBI 27914 (Pelleymounter, et al., 2000) | |
| Exogenous CRF (functional) | Forepaw Treading (icv CRF-induced) | Gerbil | CRA0450 (Chaki, et al., 2004) | |
| Exogenous CRF (functional) | Locomotion (icv CRF-reduced) | Rat | DMP696 (Campbell, et al., 2004) | NBI 27914 (Pelleymounter, et al., 2000) |
| Exogenous CRF (functional) | Locomotion (icv CRF-stimulated) | Rat | R121919 (Heinrichs, et al., 2002); Antalarmin (Zorrilla, et al., 2002) | |
| Exogenous CRF (functional) | Startle, CRF-enhanced (icv), C57Bl/6J strain | Mouse | R121919 (Risbrough, Hauger, Pelleymounter, & Geyer, 2003) | |
| Exogenous CRF (functional) | Startle, CRF-enhanced (icv) | Rat | CP-154,526 (Schulz, et al., 1996); GSK876008 (D. Walker, et al., 2008) | |
| HPA Axis | ACTH, plasma (basal) | Rat | R121919 (Heinrichs, et al., 2002) | |
| HPA Axis | ACTH, plasma (icv CRF-stimulated) | Rat | CP-154,526 (Schulz, et al., 1996) | |
| HPA Axis | ACTH, plasma (iv CRF-stimulated) | Rat | CRA1000 (Okuyama, et al., 1999); CRA1001 (Okuyama, et al., 1999); CP-154,526 (Okuyama, et al., 1999) | |
| HPA Axis | ACTH, plasma (basal) | Mouse | ||
| HPA Axis | ACTH, plasma (stressor-stimulated) | Rat | R121919 (Gutman, et al., 2003; Heinrichs, et al., 2002) | CRA1000 (Okuyama, et al., 1999); CRA1001 (Okuyama, et al., 1999); CP-154,526 (Okuyama, et al., 1999) |
| HPA Axis | ACTH, plasma (iv CRF-stimulated), rhesus | Monkey | Antalarmin (Broadbear, Winger, Rivier, Rice, & Woods, 2004) | |
| HPA Axis | ACTH, plasma (stressor-stimulated; high anxiety behavior, HAB, strain) | Rat | R121919 (Keck, et al., 2001) | |
| HPA Axis | Corticosterone, plasma (acute stress-induced) | Rat | DMP 904 (Lelas, et al., 2004); CP-154,526 (chronic) (Arborelius, et al., 2000) | CRA1000 (Okuyama, et al., 1999); CRA1001 (Okuyama, et al., 1999); CP-154,526 (Okuyama, et al., 1999) |
| HPA Axis | Corticosterone, plasma (basal) | |||
| HPA Axis | Corticosterone, plasma (icv CRF stimulated) | Rat | DMP696 (Campbell, et al., 2004) | |
| HPA Axis | Corticosterone, plasma (iv CRF-stimulated) | Rat | CRA1000 (Okuyama, et al., 1999); CRA1001 (Okuyama, et al., 1999); CP-154,526 (Okuyama, et al., 1999) | |
| HPA Axis | Corticosterone, plasma (stressor-stimulated); high-anxiety behavior, HAB, strain | Rat | R121919 in high anxiety rats (Keck, et al., 2001) | |
| Physiology | Cardiovascular Parameters (stressor-stimulated) | Rabbit | CP-154,526 (Nalivaiko & Blessing, 2003, 2004) | |
| Physiology | CRF mRNA (decreased; periventricular nucleus) | Rat | CP-154,526 (chronic) (Arborelius, et al., 2000) | |
| Physiology | CRF mRNA decrease; Barrington’s nucleus) | Rat | CP-154,526 (chronic) (Arborelius, et al., 2000) | |
| Physiology | CRF1 receptor mRNA (basolateral amygdala) | Rat | CP-154,526 (chronic) (Arborelius, et al., 2000) | |
| Physiology | CRF1 receptor mRNA (cerebellum) | Rat | CP-154,526 (chronic) (Arborelius, et al., 2000) | |
| Physiology | CRF1 receptor mRNA (parietal cortex) | Rat | CP-154,526 (chronic) (Arborelius, et al., 2000) | |
| Physiology | CRF1 receptor occupancy | Rat | R121919 (Heinrichs, et al., 2002); DMP696 (Li, et al., 2003); (Lelas, et al., 2004); | |
| Physiology | Dopamine Release (prefrontal cortex) | Rat | CP-154,526 (Millan, et al., 2001); DMP 695 (Millan, et al., 2001) | |
| Physiology | Neurogenesis (chronic mild stressor-reduced; hippocampus dentate gyrus) | Mouse | SSR125543 (Alonso, et al., 2004) | |
| Physiology | Norepinephrine firing, locus coeruleus (icv CRF induced) | Rat | CRA1000 (Okuyama, et al., 1999); CRA1001 (Okuyama, et al., 1999); CP-154,526 (Okuyama, et al., 1999; Schulz, et al., 1996) | |
| Physiology | Norepinephrine release (frontal cortex) | Rat | CP-154,526 (Millan, et al., 2001); DMP 695 (Millan, et al., 2001) | |
| Physiology | Serotonin release (frontal cortex) | Rat | CP-154,526 (Millan, et al., 2001); DMP 695 (Millan, et al., 2001) | |
| Physiology | cFOS (icv CRF stimulated; central n. amygdala) | Rat | DMP 696 (Campbell, et al., 2004) | |
| Physiology | cFOS (icv CRF stimulated; periventricular nucleus of hypothalamus) | Rat | DMP 696 (Campbell, et al., 2004) | |
| Schizophrenia | Locomotion (amphetamine-stimulated) | Rat | Antalarmin (Zorrilla, et al., 2002) | |
| Side Effects | Hexobarbital anesthesia potentiation | Mouse | CRA0450 (Chaki, et al., 2004) | |
| Side Effects | Hexobarbital anesthesia potentiation | Rat | CRA0450 (Chaki, et al., 2004) | |
| Side Effects | Inclined Plane, 10 day old pup | Rat | CP-154,526 (Kehne, et al., 2000) | |
| Side Effects | Locomotion | Mouse | DMP 904 (Lelas, et al., 2004); CRA0450 (Chaki, et al., 2004) | |
| Side Effects | Locomotion (spontaneous; habituated or non-habituated) | Rat | CRA0450 (Chaki, et al., 2004); antalarmin (Zorrilla, et al., 2002) | |
| Side Effects | Locomotion (unpredictable chronic mild stress) | Mouse | SSR125543 (Surget, et al., 2008) | |
| Side Effects | Locomotion (“High Anxiety Behavior”, HAB, strain) | Rat | R121919 (Keck, et al., 2001) | |
| Side Effects | Negative Geotaxis, pup | Rat | CP-154,526 (Hodgson, et al., 2007) | |
| Side Effects | Passive avoidance | Rat | CRA1000 (Okuyama, et al., 1999); CRA1001 (Okuyama, et al., 1999)CP-154,526 (Okuyama, et al., 1999) | |
| Side Effects | Rotarod (ataxia) | Mouse | CRA0450 (Chaki, et al., 2004) | |
| Side Effects | Rotarod (ataxia) | Rat | DMP 904(Lelas, et al., 2004) | |
| Side Effects | Staircase Test | Mouse | CRA0450 (Chaki, et al., 2004) | |
| Side Effects | Startle | Mouse | R121919 (Risbrough et al., 2003) | |
| Side Effects | Startle | Rat | GSK876008 (D. Walker et al., 2008) | |
| Side Effects (abuse potential) | Drug Discriminative Cue | Rat | DMP 696 (Lelas, Zeller, Ward, & McElroy, 2003) | |
| Side Effects (abuse potential) | Drug Substitution, chlordiazepoxide | Rat | DMP 696 (Lelas, et al., 2003); DMP 904 (Lelas, et al., 2004) |