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In this issue of NPP, Schwandt et al (2016) reported negative results from a comprehensive human translational medicine study in anxious alcohol-dependent women on the effect of the CRFR1 antagonist verucerfont on physiological and psychological stress responses, and subjective craving induced by alcohol-associated cues and stressors. The negative results on craving and stress responses are in agreement with recent work from the same group published in NPP last year (Kwako et al, 2015), using a different CRFR1 antagonist pexacerfont with a less favorable pharmacokinetic profile than verucerfont (Zorrilla et al, 2013). Indeed, the authors chose verucerfont for their second study because studies in rats suggest that the drug should have optimal pharmacokinetic and pharmacodynamic profile in humans due to its slower receptor dissociation rate (Fleck et al, 2012). The improved pharmacokinetic profile of verucerfont was confirmed in the Schwandt et al (2016) study, showing that the drug blocked both neuroendocrine responses to CRF and altered brain activity in response to stimuli with negative emotional valence in alcohol-dependent women. Below we provide a historical perspective for these two studies and discuss their implications for translational addiction research. In 1981 and 1983, Vale et al. published two papers that have had transformative influence on stress and psychiatry research. In the first study (Vale et al, 1981), they identified a 41-residue ovine hypothalamic peptide that stimulates the hypothalamic-pituitary adrenal axis, leading to the secretion of adrenal corticosterone (or cortisol in humans). In the second study (Swanson et al, 1983), they showed that the new stress-related peptide, termed corticotropinreleasing factor (CRF; the IUPHAR-recommended name; also termed corticotropin-releasing hormone), is expressed in extra-hypothalamic brain areas that control central stress responses (eg, central amygdala, bed nucleus of stria terminalis, prefrontal cortex). The next major advances over the next 20 years were the characterization of the hypothalamic and extra-hypothalamic CRF systems that include two major receptors (CRFR1 and CRFR2), a CRF binding protein, and the CRF-related peptides urocortin 1, 2, and 3 (Bale and Vale, 2004). In the psychiatry field, the discovery of the brain CRF systems has led to numerous studies that demonstrated a critical role of these systems in anxiety and depression, as assessed in rodent models (Holsboer and Ising, 2008). These studies have led to intense efforts by several pharmaceutical companies to develop small molecule CRFR antagonists. The first of them, a selective CRFR1 antagonist named CP-154,526 was characterized 20 years ago (Schulz et al, 1996). To date, however, several large clinical studies have failed to demonstrate an efficacy of CRFR1 antagonists in the treatment of anxiety and depression (see references in Schwandt et al (2016), Discussion section). In the addiction field, CRF was introduced by Koob et al. in a series of seminal studies in the 1980s on the behavioral effects of CRF (Koob and Bloom, 1985) and its role, first in psychostimulant sensitization (Cole et al, 1990), and subsequently in more relevant addiction-related behaviors in animal models: aversive stress-like drug withdrawal symptoms and escalation of drug self-administration (Koob, 2010), as well as stress-induced reinstatement of drug seeking (Mantsch et al, 2016; Shaham et al, 1997). A consistent finding in these studies is that across different drugs of abuse (alcohol, nicotine, cocaine, and heroin), CRFR1 antagonists effectively block aversive symptoms of drug withdrawal, escalation of drug self-administration under extended access conditions, and reinstatement induced by an intermittent footshock stressor, a standard stressor in reinstatement/relapse studies (Koob, 2010; Mantsch et al, 2016). Based on these consistent preclinical findings across drug classes in established animal addiction models, the negative findings from the two human studies with alcoholics are both disappointing and surprising. The main unresolved question is why what appears to be the most promising therapeutic target that has emerged from studies using animal models of addiction during the last 20 years did not show efficacy in humans? One set of issues to consider is the homology between the laboratory animal model and the human laboratory model *Correspondence: Dr Y Shaham or H de Wit, IRP-NIDA, Behavioral Neuroscience Branch, 251 Bayview Blvd, Baltimore, MD 21224, USA, Tel: +443 74

Lost in Translation: CRF1 Receptor Antagonists and Addiction Treatment