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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]

Chronically elevated levels of corticotropin-releasing factor (CRF) in transgenic mice overexpressing CRF in the brain (CRF-OE) appear to be associated with alterations commonly associated with major depressive disorder, as well as with sensorimotor gating deficits commonly associated with schizophrenia. In the present study, we tested the hypothesis that antipsychotics may be effective in normalizing prepulse inhibition (PPI) of acoustic startle in CRF-OE mice, which display impaired sensorimotor gating compared to wild-type (WT) mice. The typical antipsychotic haloperidol and atypical antipsychotic risperidone improved PPI in the CRF-OE mice, but were ineffective in WT mice. The atypical antipsychotic clozapine did not influence PPI in CRF-OE mice, but reduced gating in WT mice. This effect of clozapine in the CRF-OE mice may thus be regarded as a relative improvement, consistent with the observed effect of haloperidol and risperidone. As expected, the anxiolytic, nonantipsychotic chlordiazepoxide was devoid of any effect. All four compounds dose-dependently reduced the acoustic startle response irrespective of genotype. These results indicate that antipsychotic drugs are effective in improving startle gating deficits in the CRF-OE mice. Hence, the CRF-OE mouse model may represent an animal model for certain aspects of psychotic depression, and could be a valuable tool for research addressing the impact of chronically elevated levels of CRF on information processing. [ABSTRACT FROM AUTHOR]

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 (CRH-OE). 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. [ABSTRACT FROM AUTHOR]

Abstract Rationale: Young rodents emit ultrasonic vocalizations (USVs) when separated from their dams and littermates. Pharmacological agents that act on GABA[sub A] and/or 5-HT receptors and that alleviate anxiety in humans reduce the emission of these calls. Objectives: 1) to investigate specific 5-HT[sub 1] receptor subtypes that modulate maternal separation-induced USVs in mice; 2) to assess the behavioral specificity of these effects; and 3) to compare 5-HT[sub 1] agonists with a positive neurosteroid modulator of the GABA[sub A] receptor complex. Methods: Seven-day old CFW mouse pups were isolated from their littermates and placed onto a 20 Celsius surface for 4 min. USVs between 30 and 80 kHz, grid crossing, and rectal temperature were measured in separate groups of mouse pups following subcutaneous administration of 5-HT[sub 1A] and 5-HT[sub 1B] receptor agonists and antagonists, the neurosteroid allopregnanolone, or the benzodiazepine midazolam. Results: The 5-HT[sub 1A] agonists (+)8-OH-DPAT (0.01-0.1 mg/kg) and flesinoxan (0.3-1.0 mg/kg), the selective 5-HT[sub 1B] agonist CP-94,253 (0.03-30.0 mg/kg), and the mixed 5-HT[sub 1B/2C] receptor agonist TFMPP (0.1-10.0 mg/kg) dose-dependently reduced USVs. These effects were reversed by the 5-HT[sub 1A] receptor antagonist WAY 100,635 (0.1 mg/kg) or the 5-HT[sub 1B/D] receptor antagonist GR 127935 (0.1 mg/kg). The effects of TFMPP were biphasic; low doses (i.e. 0.01 and 0.03 mg/kg) increased the rate of vocalization. Midazolam and allopregnanolone also reduced USVs. The highest doses of flesinoxan, (+)8-OH-DPAT, and allopregnanolone suppressed locomotion, whereas CP94, 253, TFMPP, and midazolam stimulated motor activity. Conclusions: These experiments confirm that agonists at the 5-HT[sub 1] receptors and a positive allosteric modulator of the GABA[sub A] receptor complex decrease... [ABSTRACT FROM AUTHOR]

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]