Safe and well tolerated non-peptide, orally available, and brain penetrant NK1R antagonists are available, and have allowed initial translation of the laboratory animal findings in a human patient population (George et al., 2008). The preclinical findings have been supported by these initial human data, in which administration of an NK1R antagonist to treatment-seeking, alcohol-dependent inpatients decreased alcohol craving during early abstinence. This effect was seen both under unprovoked conditions and in response to a challenge that combined exposure to a social stressor and alcohol associated cues. This study also demonstrated a suppression of cortisol release by the NK1R antagonist during cue/stress exposure, suggesting a role of the NK1R in regulation of stress-induced HPA axis function, as mentioned above. Finally, these findings were complemented by neuroimaging data, which showed that NK1R antagonist administration potently blocked activation of stress-responsive neurocircuitry following presentation of strongly aversive visual stimuli. Subsequent genetic analyses have suggested an association of specific haplotypes within the TacR1 locus, which encodes the NK1R, with increased risk for alcohol dependence (Seneviratne et al., 2009). Genetically-defined subgroups of patients may therefore be particularly responsive to NK1R antagonism.
