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Chronically elevated levels of corticotropin-releasing hormone (CRH) are implicated in human stress-related and affective disorders, including generalized anxiety disorder and major depression. To gain more insight into the relationship between hyperactivity of the CRH system and associated neuroendocrine, autonomic, physiological, and behavioral changes, we have developed a transgenic mouse model of CRH overproduction (CRHOE). In this study, we explored the behavioral consequences of chronic CRH overproduction in mice of the two available transgenic lines (CRH-OE2122 and CRH-OE2123) in paradigms measuring behavioral aspects of stress, anxiety, and depression. These paradigms include tasks based on free exploration of novel environments (unfamiliar homecage and unfamiliar open field), stress-induced hyperthermia, tests associated with anxiety- related behavior (elevated plus maze and light-dark box), and paradigms in which (anti-)depressant-like behaviors can be detected (tail suspension test and forced swim test). The only relatively consistent finding, although not always significant, was reduced locomotor activity in CRH-OE2122 mice, corresponding well with the known effects of CRH on locomotion. Contrary to our predictions, CRH-OE mice did not show an altered response to stress, and a phenotype indicative of increased anxiety and/or depression was not evident in CRH-OE mice.

Background: Both corticotropin-releasing factor (CRF) and glucocorticoid receptors (GR) are implicated in the psychotic symptoms of psychiatric disorders. Correspondingly, it is of interest to determine their respective involvement in the sensorimotor gating deficits displayed by transgenic mice overexpressing CRF. These mice reveal lifelong elevations of CRF and corticosterone levels. Methods: Effects of the GR antagonists ORG34517 (5–45 mg/kg by mouth [PO]) and mifepristone (5–45 mg/kg PO) and the CRF1 receptor antagonists CP154,526 (20–80 mg/kg intraperitoneally [IP]) and DMP695 (2.5–40.0 mg/kg IP) on prepulse inhibition (PPI) of the acoustic startle response were studied in mice overexpressing CRF and in their wild-type littermates. In addition, PPI was measured in both genotypes 2 weeks after adrenalectomy with or without exogenous corticosterone administration via subcutaneous pellet implant (20 mg corticosterone). Results: ORG34517 and mifepristone did not influence perturbation of PPI in mice overexpressing CRF; reducing corticosterone levels by adrenalectomy likewise did not improve PPI. Further, elevation in corticosterone levels by pellet implantation did not disrupt PPI in wild-type mice. Conversely, both CRF1 receptor antagonists, CP154,526 (40–80 mg/kg IP) and DMP695 (40 mg/kg IP), significantly restored PPI in CRF-overexpressing mice. Conclusions: Sustained overactivation of CRF1 receptors rather than excessive GR receptor stimulation underlies impaired sensorimotor gating in CRF-overexpressing mice. CRF1 receptors thus may play a role in the expression of psychotic features in stress-related psychiatric disorders. [Copyright &y& Elsevier]

Pharmacological experiments have implicated a role for serotonin (5-HT)1A receptors in the modulation of anxiety. More recent is the interest in corticotropin-releasing hormone (CRH) system as a potential target for the treatment of anxiety disorders. However, selective pharmacological tools for the CRH system are limited, hampering research in this field. Gene targeting is a relatively new approach to study mechanisms underlying anxiety disorders. 5-HT1A receptor knockout (1AKO) mice have been created on three different background strains, and two different lines of mice, overexpressing CRH (CRH-OE), have been generated. In the present review, behavioural and physiological findings reported for 1AKO mice and CRH-OE mice will be reviewed. As behavioural phenotyping is often limited to one or two approach avoidance paradigms, we extended these observations and also tested 1AKO and CRH-OE mice in a conditioned fear paradigm. This paradigm reflects essentially different aspect of anxiety than approach avoidance paradigms. 1AKO mice on a 129/Sv background strain showed similar freezing as wild-type (WT) mice. In CRH-OE mice, less freezing was observed than in the corresponding wild-type mice. The fact that the anxious phenotype of these genetically altered mice seems less clear than initially reported will be discussed. Rather than studying the direct consequences of alterations in the targeted gene, 1AKO and CRH-OE mice seem very valuable to study compensatory processes that seem to have taken place in reaction to life-long changes in gene expression. [Copyright &y& Elsevier]