modulate stress-related processes of importance for excessive alcohol use and relapse. To our knowledge, however, NK1 antagonism has not been examined in relation to alcoholism. In our recent studies we have therefore examined the role of the NK1 receptor system in the modulation of alcohol addiction. Specifically, we studied mice with disruption of the NK1 receptor gene, and found that these have markedly decreased voluntary alcohol consumption (p=0.000001; appr. 6 vs 10 g/kg/24 hrs at final alcohol concentration), and markedly higher alcohol sensitivity, shown as longer sleep-time following a sedative alcohol dose compared to wildtype littermates (186±14 min vs 104±16 min, p<0.001), despite unaltered alcohol metabolism. In anxious, recently detoxified alcoholic inpatients, a novel NK1 antagonist, LY686017, suppressed spontaneous cravings for alcohol (Alcohol Urge Questionnaire, AUQ 3; p<0.05) and improved overall well-being (Clinician Global Impression, CGI Severity 4; p=0.001) in the absence of effects on anxiety or depression. LY686017 also blunted craving induced by a combined social stress and alcohol cue challenge (p=0.002), and attenuated the concomitant cortisol response (p=0.010). Finally, brain fMRI BOLD responses to negative affective stimuli (IAPS) were attenuated in LY686017-treated subjects, while responses to positive stimuli were increased.
