Current topicsCorticotropin-releasing factor type-1 receptor antagonists: The next class of antidepressants?
Introduction
For decades, antidepressants have been designed primarily to target serotonin and/or norepinephrine neurotransmitter systems. However, the currently marketed antidepressants are not effective in all patients with depression and have other limitations including a delayed onset of action of 3–6 weeks and adverse side effects, which reduce treatment compliance. Accordingly, a variety of targets outside of the serotonin and norepinephrine systems are currently being explored in the search for novel pharmacological therapeutics to treat depression. Among these possible new targets are neuropeptides implicated in stress-related functions including tachykinins (e.g. substance P and neurokinin A), vasopressin, neuropeptide Y, galanin, and corticotropin-releasing factor (CRF; for review, see Holmes et al., 2003). Accumulating evidence suggests that nonpeptide CRF1 receptor antagonists may be a promising pharmacotherapeutic strategy for the treatment of depression.
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CRF and depression
CRF, also known as corticotropin-releasing hormone (CRH) is a 41 amino acid peptide originally isolated by Rivier and colleagues (Vale et al., 1981). CRF mediates the regulation of the hypothalamic-pituitary-adrenal (HPA) axis as well as autonomic and behavioral responses to both acute and chronic stress (for review, see Owens and Nemeroff, 1991, Arborelius et al., 1999). While activation of the HPA axis, autonomic and behavioral arousal systems are essential to the ability to cope with
Nonpeptide CRF1 receptor antagonists and depression
Various nonpeptide CRF1 receptor antagonists have been synthesized (Table 1). Preclinical studies have primarily focused on evaluating the anxiolytic potential of CRF1 receptor antagonists and there are many reports of positive anxiolytic-like effects in animal models (for review, see Griebel, 1999, Takahashi, 2001, Kehne and De Lombaert, 2002, Holmes et al., 2003, Seymour et al., 2003, Zorrilla and Koob, 2004). Nonetheless, these compounds may also possess potential antidepressant efficacy.
Tail suspension and mouse forced swim tests
Two well-established paradigms that are frequently used to screen compounds for antidepressant-like activity are the tail suspension and mouse forced swim tests. These tests have been shown to discriminate antidepressants from neuroleptics and anxiolytics (Porsolt et al., 1977a, Steru et al., 1985, van der Heyden et al., 1987, Borsini and Meli, 1988, Porsolt, 2000) and many of the currently marketed clinically active antidepressants exhibit activity in either one or both of these tests (Porsolt
Rat forced swim test
In the rat forced swim test, unlike the mouse forced swim test, rats are exposed to a 15-min pretest swim session. This initial swim stressor increases the rat's immobility in the test session, which usually occurs 24 h later (Porsolt et al., 1977b). Swim stress equivalent to that used in the rat forced swim pretest session, has been shown to alter the sensitivity of locus coeruleus neurons to CRF 24 h later (Curtis et al., 1999). In a small number of studies, CRF1 receptor antagonists have
Learned helplessness
In the learned helplessness model, similar to the rat forced swim test, rats are exposed to an uncontrollable stressor, often inescapable shock, prior to the escapable test situation. It has been demonstrated that inescapable shock, equivalent to that used in the learned helplessness procedure, alters subsequent sensitivity to CRF in the locus coeruleus (Curtis et al., 1995). Moreover, increased fear conditioning and poor escape behaviors are observed 24 h after CRF is injected directly into
Chronic mild stress and olfactory bulbectomy
In the chronic mild stress model, animals are exposed to a variety of mild stressors that induce behaviors resembling human depressive symptoms such as decreased sexual and investigative behaviors, decreased responses to rewards, weight loss, disrupted sleep and activity patterns, and a decrease in physical state due to decreased grooming behaviors (for review, see Willner et al., 1992, Willner, 1997). While, chronic mild stress does not alter normal HPA axis activity, it has been shown to
Genetic models
The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression that was developed by selectively breeding for sensitivity to cholinergic agonists and shares many similarities to individuals with depression (for review, see Overstreet, 1993, Overstreet, 2002, Overstreet et al., 1995, Yadid et al., 2000). Similar to patients with clinical depression, FSL rats have serotonergic abnormalities that are corrected following antidepressant treatment (Zangen et al., 1997) and have
Clinical trial with the CRF1 receptor antagonist R121919
The most direct evidence supporting the use of nonpeptidic CRF1 receptor antagonists in the treatment of depression comes from an open-label clinical trial. R121919 reduced measures of anxiety and depression in patients with major depression, which then relapsed when drug administration was discontinued (Zobel et al., 2000). R121919 also improved sleep electroencephalogram (EEG) patterns in patients with depression (Held et al., 2004). Importantly, the normal function of the HPA axis was not
Conclusions
Various nonpeptide CRF1 receptor antagonists have been synthesized and while early preclinical studies focused on investigating the anxiolytic potential of these compounds, studies are increasingly examining these compounds for their antidepressant potential. There are numerous reports suggesting that CRF1 receptor antagonists have the potential to treat anxiety (for a recent review, see Zorrilla and Koob, 2004). Various therapeutics treat both anxiety and depression and many of the preclinical
Acknowledgments
The author is grateful to Dr. Lisa H. Gold for invaluable and helpful comments on this manuscript. The author was supported by NIH grant DA016184.
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