This proposal is a part of an integrated project to test the efficacy of three candidate anxiolytics (two structurally unrelated CRr-^ receptor antagonists GSK008 and CRF-002, and a 5HTiA/iB/io receptor antagonist, GSK-1, provided by GlaxoSmithKline (GSK) as part of The Emory-MSSM-GSK-NIMH Collaborative Mood Disorders Initiative, using fear-potentiated startle. The anti-fear and anxiolytic activity of these compounds will be evaluated in healthy subjects using models of phasic (fear) and sustained (anxiety) aversive states derived from humans and from pre-clinical studies in rodents. Two experimental models will be implemented;one based on an instructed fear learning procedure and the other using Pavlovian cued and context conditioning in a computer-generated virtual reality environment, which will also enable us to examine behavioral avoidance. Both procedures are designed to distinguish between phasic fear and sustained anxiety, which according to pre-clinical studies (Dr. Davis, Project 1) are mediated by distinct neural systems. We will examine the potentiation of startle during anticipation of no-shock, predictable shock signaled by a discrete threat cue, and unpredictable shock. Fear-potentiated startle to the discrete threat cue will model phasic fear, whereas the potentiation of startle in the predictable and unpredictable shock conditions will model sustained contextual anxiety. A central goal of this project is to examine whether the GSK compounds are anxiolytic in these models, which have been shown to detect the anxiolytic activity of established anxiolytics (alprazolam, a benzodiazepine, and escitalopram an SSRI). Another goal is to identify different psychopharmacological profiles for phasic fear versus sustained anxiety. Given the prevalence of anxiety disorders in women compared to men, an exploratory aim will be to examine whether sex differences exist with respect to the sensitivity of our anxiety model to treatment with the GSK compounds. These same GSK compounds will also be evaluated in other laboratories (Projects 1 and 5) (separate applications), providing a translational approach to screening and evaluating the efficacy of new compounds. Dr. Davis'preclinical project (Project 1), which is particularly complementary to the present project, will use similar behavioral models in rodents based on startle as an operational measure of fear and anxiety. Drs. Rothbaum and Charney's project (Project 5) will test the clinical efficacy of GSK008 in posttraumatic stress disorder. These parallel projects will provide a test of the predictive validity of the human and animal models. It is hoped that this integrated effort will ultimately lead to development and validation of models for rapid evaluation of novel therapeutics.

Public Health Relevance

There is currently great dissatisfaction with the scientific process through which a drug is transformed from a discovery into a psychopharmacological treatment. The primary goal of this NCDDG Center is to accelerate the development of novel drugs for the treatment of depression and anxiety. The goal of this project (Project 4 of the Center) is to validate experimental models to test potential anxiolytics in healthy participants.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZMH1-ERB-S)
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Emory University
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Price, Matthew; Maples, Jessica L; Jovanovic, Tanja et al. (2015) An investigation of outcome expectancies as a predictor of treatment response for combat veterans with PTSD: comparison of clinician, self-report, and biological measures. Depress Anxiety 32:392-9
Stehouwer, Jeffrey S; Birnbaum, Matthew S; Voll, Ronald J et al. (2015) Synthesis, F-18 radiolabeling, and microPET evaluation of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines as ligands of the corticotropin-releasing factor type-1 (CRF1) receptor. Bioorg Med Chem 23:4286-302
Stehouwer, Jeffrey S; Goodman, Mark M (2015) Preparation of 1-Tosyloxy-4-Substituted-2-butenes Using Ag(I) Salts. Tetrahedron Lett 56:4480-4482
Ridgewell, Caitlin; Bray, Allison; Curtis, Kaylah et al. (2015) Enhanced Olfactory Cortex Connectivity in a Patient With PTSD With Olfactory Hallucinations. J Neuropsychiatry Clin Neurosci 27:e170-1
Grillon, Christian; Hale, Elizabeth; Lieberman, Lynne et al. (2015) The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle. Neuropsychopharmacology 40:1064-71
Stehouwer, Jeffrey S; Bourke, Chase H; Owens, Michael J et al. (2015) Synthesis, binding affinity, radiolabeling, and microPET evaluation of 4-(2-substituted-4-substituted)-8-(dialkylamino)-6-methyl-1-substituted-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-ones as ligands for brain corticotropin-releasing factor type-1 (CRF1) rec Bioorg Med Chem Lett 25:5111-4
Kilts, Clint D; Kennedy, Ashley; Elton, Amanda L et al. (2014) Individual differences in attentional bias associated with cocaine dependence are related to varying engagement of neural processing networks. Neuropsychopharmacology 39:1135-47
Dunlop, Boadie W; Rothbaum, Barbara O; Binder, Elisabeth B et al. (2014) Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial. Trials 15:240
Kaye, Joanna L; Dunlop, Boadie W; Iosifescu, Dan V et al. (2014) Cognition, functional capacity, and self-reported disability in women with posttraumatic stress disorder: examining the convergence of performance-based measures and self-reports. J Psychiatr Res 57:51-7
Miller, Andrew H; Haroon, Ebrahim; Raison, Charles L et al. (2013) Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30:297-306

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