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.
Section snippets
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.
References (120)
- et al.
Comparison of the behavioral and endocrine response to forced swimming stress in five inbred strains of rats
Psychoneuroendocrinology
(1995) - et al.
Cerebrospinal fluid neuropeptides in mood disorder and dementia
Journal of Affective Disorders
(1992) Effects of sertraline on regional neuropeptide concentrations in olfactory bulbectomized rats
Pharmacology, Biochemistry, and Behavior
(2001)- et al.
The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications
Brain Research
(1992) - et al.
Plasma corticotropin-releasing factor in depressive disorders
Biological Psychiatry
(1998) - et al.
Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450
European Journal of Pharmacology
(2004) - et al.
Targeted mutations of the corticotrophin-releasing factor system: effects on physiology and behavior
Neuropeptides
(2002) - et al.
Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1
Brain Research
(1999) - et al.
Understanding corticotropin releasing factor neurobiology: contributions from mutant mice
Neuropeptides
(1999) - et al.
Previous stress alters corticotropin-releasing factor neurotransmission in the locus coeruleus
Neuroscience
(1995)
Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders
Psychoneuroendocrinology
Effects of the selective nonpeptide corticotropin-releasing factor receptor 1 antagonist antalarmin in the chronic mild stress model of depression in mice
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Chronic imipramine, l-sulpiride and mianserin decrease corticotropin releasing factor levels in the rat brain
Neuroscience Letters
Comparison of noradrenergic and serotonergic antidepressants in reducing immobility time in the tail suspension test
Japanese Journal of Pharmacology
Plasma corticotropin-releasing factor in depressed patients before and after the dexamethasone suppression test
Biological Psychiatry
Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders?
Pharmacology and Therapeutics
The effects of CRA 1000, a non-peptide antagonist of corticotropin-releasing factor receptor type 1, on adaptive behaviour in the rat
Neuropeptides
Corticotropin-releasing factor antagonist reduces emotionality in socially defeated rats via direct neurotropic action
Brain Research
Corticotropin-releasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior
Regulatory Peptides
Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist
Neuropsychopharmacology
Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression
Journal of Psychiatry Research
Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders
Trends in Pharmacological Sciences
The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety
Journal of Psychiatry Research
The corticosteroid receptor hypothesis of depression
Neuropsychopharmacology
The olfactory bulbectomized rat as a model of depression: an update
Pharmacology and Therapeutics
A role for corticotrophin releasing factor and urocortin in behavioral responses to stressors
Brain Research
Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects
Journal of Psychiatry Research
Brain corticotrophin-releasing factor immunoreactivity and receptors in five inbred rat strains: relationship to forced swimming behaviour
Brain Research
Chronic infusion of a CRH1 receptor antisense oligodeoxynucleotide into the central nucleus of the amygdala reduced anxiety-related behavior in socially defeated rats
Regulatory Peptides
Differential behavioural effects of chronic infusion of CRH 1 and CRH 2 receptor antisense oligonucleotides into the rat brain
Journal of Psychiatry Research
Genetic differences in the tail-suspension test and its relationship to imipramine response among 11 inbred strains of mice
Biological Psychiatry
Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test
Neuropsychopharmacology
A non peptidic corticotropin releasing factor receptor antagonist attenuates fever and exhibits anxiolytic-like activity
European Journal of Pharmacology
Effects of a non-peptide CRF antagonist (DMP696) on the behavioral and endocrine sequelae of maternal separation
Neuropsychopharmacology
Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist
European Journal of Pharmacology
A chronic treatment with fluoxetine decreases 5-HT(1A) receptors labeling in mice selected as a genetic model of helplessness
Brain Research
Antidepressant-like activity of corticotropin-releasing factor type-1 receptor antagonists in mice
European Journal of Pharmacology
The Flinders sensitive line rats: a genetic animal model of depression
Neuroscience and Biobehavioral Reviews
Antidepressant-like effects of CRF1 receptor antagonist SSR125543 in an animal model of depression
European Journal of Pharmacology
Stress-induced immobility in rats with cholinergic supersensitivity
Biological Psychiatry
Antidepressant effects of citalopram and CRF receptor antagonist CP-154,526 in a rat model of depression
European Journal of Pharmacology
Behavioural despair in rats: a new model sensitive to antidepressant treatments
European Journal of Pharmacology
“Behavioural despair” in rats and mice: strain differences and the effects of imipramine
European Journal of Pharmacology
Effect of chronic antidepressant treatment on responses to apomorphine in selectively bred rat strains
Brain Research Bulletin
Interferon-alpha and transforming growth factor-beta 1 regulate corticotropin-releasing factor release from the amygdala: comparison with the hypothalamic response
Neurochemistry International
Antidepressant-like effects in various mice strains in the tail suspension test
Behavioural Brain Research
Specificity of the learned helplessness model of depression
Pharmacology, Biochemistry, and Behavior
Corticotropin-releasing hormone receptor (type I) antisense targeting reduces anxiety
Neuroscience
Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development
Neuron
Increased corticotropin-releasing factor concentrations in the bed nucleus of the stria terminalis of anhedonic rats
European Journal of Pharmacology
Cited by (47)
Building better strategies to develop new medications in Alcohol Use Disorder: Learning from past success and failure to shape a brighter future
2019, Neuroscience and Biobehavioral ReviewsCitation Excerpt :For instance, it has been shown that brain expression and function of CRF and CRF1R may vary in species differing in parental care, maternal defense or social behavior in general (Hostetler and Ryabinin, 2013). Additionally the differences in preclinical and clinical studies may arise from divergences between human symptomology compared to animal behavior and dosage and bioavailability of the CRF1 antagonists (Binneman et al., 2008; Kehne and Cain, 2010)(Dong et al., 2018; Nielsen, 2006; Zorrilla and Koob, 2004). Despite the inconsistency between preclinical and clinical data the CRF system remains an interesting target for development of AUD medication and evidence of its role in modulating alcohol drinking continue to grow (de Guglielmo et al., 2019).
Corticotrophin releasing factor receptor 1 antagonists prevent chronic stress-induced behavioral changes and synapse loss in aged rats
2018, PsychoneuroendocrinologyCitation Excerpt :Overall, these results suggest that manipulating CRF/CRF1 signaling may help to mitigate stress-related effects on behavior and neural architecture in age animals. CRF1 antagonists have been used in clinical trials of mood disorders for many years, but with disappointing results (Nielsen, 2006; Zorrilla and Koob, 2004). The inconsistency of results of CRF1 antagonist administration between preclinical studies and clinical trials may due to many factors, including: 1) the doses used (Kehne and Cain, 2010), which may have failed to achieve necessary levels of CRF1 receptor occupancy in clinical trials, 2) differences in the symptoms experienced by patients and the behaviors assessed in rodents, and 3) differences in the involvement of different CRF1 receptor populations and/or different functional states of the CRF1 in patients versus animal subjects (Kehne and Cain, 2010).
Similar effect of CRF<inf>1</inf> and CRF<inf>2</inf> receptor in the basolateral or central nuclei of the amygdala on tonic immobility behavior
2018, Brain Research BulletinCitation Excerpt :In this way, while antagonist CRF1 receptors have pronounced effects in normalizing stress-induced anxiety when CRF is released, CRF2 receptors appear be involved in the expression of both stress-induced anxiety and spontaneous anxiety behavior (Takahashi, 2001). Moreover, although preclinical data using CRF1 receptor antagonists in experimental animal models were unclear concerning their antidepressant activity (Nielsen, 2006), this receptor is considered to be possible target for the treatment of psychiatric diseases (Arborelius et al., 1999; Heinrichs et al., 1997; Reul and Holsboer, 2002). Additionally, previous study has shown that the activation of neurons that express CRF2 in the lateral septum promotes persistent anxious behavior, as evaluated by the light-dark box test, the open field test and the novel object test in mice (Anthony et al., 2014).
Corticotropin releasing factor-1 receptor antagonism alters the biochemical, but not behavioral effects of repeated interleukin-1β administration
2012, NeuropharmacologyCitation Excerpt :Therapies that alter the regulation of the HPA axis have also been suggested as possible treatments (Schüle et al., 2009). Pharmacological agents that inhibit the activity of CRF; a hormone that regulates the activity of the HPA axis, like CRF receptor 1 (CRF1) antagonists, demonstrate antidepressant activity in human (Zobel et al., 2000; Valdez, 2006, 2009; Zorrilla and Koob, 2010) and animal (Nielsen, 2006) studies. Subsequent studies in humans, however, indicate that CRF1 antagonism may have limited efficacy as an antidepressant (e.g. Binneman et al., 2008).