NPY, being a potent, endogenous anxiolytic, is of interest in finding novel treatment targets for alcohol abuse and alcoholism. In a ground-breaking study published in 1998, the authors demonstrated, using genetically modified mice, that NPY levels are inversely related to ethanol intake (Thiele et al., 1998). Since NPY is exerting its anxiolytic effect primarily via the Y1-receptor (Heilig 1995, Karlsson et al 2008) compounds modifying would be of great interest. However, creating specific agonists to the NPY-Y1 receptor is chemically difficult. Following the theory that antagonism at the pre-synaptic Y2-receptor would mimic Y1-agonism, we instead used an Y2 antagonist, BIIE0246, and demonstrated that BIIE0246 does indeed suppress alcohol intake in both naïve (Thorsell et al 2002) and post-dependent animals (Rimondini et al., 2005). Studies of NPY-Y2 receptor knockout mice have supported this idea (Redrobe et al., 2003; Tschennett et al., 2003) and it is consistent with the anxiogenic-like effects of intra-amygdala treatment of Y2-preferring agonists in the rat social interaction test (Sajdyk et al., 1999). A novel brain-penetrant Y2-antagonist has been examined, however the results were negative (unpublished data) while
