Selective serotonin reuptake inhibitors (SSRIs) are among the most effective treatments for the pharmacological treatment of clinical anxiety. However, meaningful clinical improvements do not occur for several weeks in most patients and not at all in others. Moreover, a great deal of uncertainty exists as to how these compounds actually work. A significant obstacle to understanding the mechanism of clinical action, and to developing more efficacious and rapid-acting treatments, has been the lack of validated animal models of SSRI-sensitive anxiety. Over the last several years, we have obtained evidence that sustained increases in the amplitude of the acoustic startle response in response to long-duration threat stimuli are mediated by brain areas different from those which mediate shorter-duration phasic increases. The former type of response seems more akin to anxiety than to fear, and may be more suitable for detecting SSRImediated anxiolysis. Findings during the last grant period indicate that sustained startle increases are especially sensitive to corticotropin releasing factor type 1 receptor (CRF-R1) antagonists. In this application we will 1) compare the anxiolytic activity of two CRF-R1 receptor antagonists (GSK008 and CRF-002) in the sustained fear test;determine if sensitivity to CRF-R1 receptor blockade depends on conditioned fear stimulus duration during training or, alternatively, response duration during testing;and determine with greater precision the time-course over which potentiated startle becomes CRF-dependent, 2) Compare the efficacy and time-course of a mixed 5HTiA/iB/iD receptor antagonist (GSK-1) with that of the selective serotonin reuptake inhibitor (SSRI) escitalopram in disrupting phasic versus sustained fear, after acute versus chronic administration, 3) Evaluate the effect of acute versus chronic administration of GSK-1 and escitalopram in blocking CRF-enhanced startle and the effect of the CRF! receptor antagonist, GSK008, on the acute anxiogenic effects of escitalopram, 4) Evaluate over-expression of CRF in the central nucleus of the amygdala (CeA), using a CRF-producing lentiviral vector, as a novel model of anxiety in rats, and evaluate the effect of GSK008, CRF-002 and chronic administration of GSK-1 and escitalopram on measures of anxiety in these animals
Anxiety disorders affect 19 million people in the US alone yet often go untreated because of medication side effects or treatment failures. The primary goal of this Center is to accelerate the development of novel drugs for the treatment of depression and anxiety. The goals of Project 1 are to preclinically evaluate the anxiolytic potential of three novel compounds and to use these compounds as tools to further explore what appear to be dissociable neural substrates of fear- versus anxiety-like responses.
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