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

Abstract

Significant progress has been made in the development of several nonpeptide antagonists of the type 1 receptor for corticotropin-releasing factor (CRF). The present review outlines the properties of this drug class that point to their potential as agents for depression and/or anxiety. Behavioral tests of CRF 1 receptor antagonists relevant to depression have been mixed. For example, most CRF 1 receptor antagonists did not lower swim test immobility in a subacute paradigm, where three injections of the drug are given in the 24 hrs between a 15-min pre-swim and a 5-min test swim. However, reliable effects in other tests of antidepressant action were observed in the chronic mild stress protocol or the Flinders Sensitive Line rat that exhibits innately high swim test immobility when the drugs were given chronically. Because these latter tests have a very good record of predicting antidepressant activity, CRF 1 receptor antagonists are good candidates for clinical trials for depression. Evidence indicates that the CRF 1 receptor antagonists do not exhibit changes in anxiety-like behavior under basal conditions. However, this drug class effectively blocks the anxiogenic states produced by withdrawal from chronic alcohol, by exposure to stress, or in rats selectively bred for high anxiety. CRF 1 receptor antagonists also prevent the anxiety associated with multiple ethanol withdrawals when given only during the earlier withdrawals. Thus, these agents may also have clinically relevant anxiolytic effects, not only in individuals with anxiety disorders but also in individuals who have anxiety episodes during alcohol or drug withdrawal. Drug Dev. Res. 65:191-204, 2005.

Corticotropin Releasing Factor (CRF) Receptor Signaling in the Central Nervous System: New Molecular Targets

“…Finally, future investigations should attempt to clarify why non-peptidic CRF 1 receptor antagonists are most effective in reducing rodent anxiety-like behavior when they are administered to animals bred for high "trait" anxiety-like behavior or previously exposed to stress [7,241,242,256,259]. Interestingly, CRF 1 receptor antagonists do not appear to have an anti-depressant effect when rodents are tested in the traditional or modified versions of the forced swim test, or in the tail suspension test [386]. However, three different CRF 1 receptor antagonists have been shown to significantly reduce immobility in the forced swim test when administered chronically to Flinders Sensitive Line (FSL) rats, a strain that has been bred to express high levels of immobility in this test [386].…”

“…Interestingly, CRF 1 receptor antagonists do not appear to have an anti-depressant effect when rodents are tested in the traditional or modified versions of the forced swim test, or in the tail suspension test [386]. However, three different CRF 1 receptor antagonists have been shown to significantly reduce immobility in the forced swim test when administered chronically to Flinders Sensitive Line (FSL) rats, a strain that has been bred to express high levels of immobility in this test [386]. Similarly, CRF 1 receptor antagonists counteracted some of the effects of chronic mild stress when administered chronically [386].…”

The CRF1 Receptor, a Novel Target for the Treatment of Depression, Anxiety, and Stress-Related Disorders

“…Animal models which have been of particular utility for evaluating compounds for potential antidepressant activity are the forced swim test, the learned helplessness test, and the chronic mild stress model. The profile of CRF 1 receptor antagonists in animal models of depression has been the focus of a recent review [117]. As noted in this review, the majority of evidence indicates that CRF 1 receptor antagonists, unlike standard antidepressant reuptake inhibitors, do not decrease immobility in a standard forced swim test in rodents in which the test agent is administered either acutely or subchronically.…”

“…For example, benzodiazepines which positively modulate GABA A receptor mediated transmission have been used to validate certain models, and therefore these models may be "tuned" to detect GABAergic agents but may be insensitive to agents such as CRF 1 receptor antagonists which require activated CRF pathways. A full discussion of how CRF 1 receptor antagonists profile in animal models is beyond the scope of the present manuscript, but is addressed in other reviews [85,117,118].…”

New drug targets for depression and anxiety: Is the peptides era arriving?

“…The current issue includes a few commentaries exemplifying the need for more sophisticated models. One model, the Flinders-sensitive line (FSL) rats, is used to show the antidepressant potential of CRF 1 antagonists [Overstreet et al, 2005]. In contrast, the same CRF 1 ligands had no effect in the Flindersresistant line (FRL) rats.…”