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 corticotropin-releasing 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).

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