Authors: Samantha R Spierling Eric P Zorrilla
Publish Date: 2017/03/07
Volume: 234, Issue: 9-10, Pages: 1467-1481
Abstract
Dr Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence Antagonists of corticotropinreleasing factor CRF receptors a target of interest to her have not reached the clinic despite strong preclinical rationale and sustained translational effortsPotential causes for negative outcomes include 1 poor safety and efficacy of initial drug candidates due to bad pharmacokinetic and physicochemical properties 2 specificity problems with preclinical screens 3 the acute nature of screens vs latepresenting patients 4 positive preclinical results limited to certain models and conditions with dynamic CRFCRF1 activation not homologous to tested patients 5 repeated CRF1 activationinduced plasticity that reduces the importance of ongoing CRF1 agonist stimulation and 6 therapeutic silencing which may need to address CRF2 receptor or CRFbinding protein molecules constitutive CRF1 activity or molecules that influence agonistindependent activity or to target structural regions other than the allosteric site bound by all drug candidates We describe potential markers of activation towards individualized treatment human genetic and functional data that still implicate CRF1 systems in emotional disturbance sex differences and suggestive clinical findings for CRF1 antagonists in food craving and CRFdriven HPAaxis overactivationThe authors thank Michael Arends for editorial assistance in the preparation of this manuscript Research reported in this publication was supported by the Pearson Center for Alcoholism and Addiction Research and the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under award number P60AA06420 The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health EP Zorrilla is an inventor on a patent for CRF1 antagonists US20100249138
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