Genetically-selected alcohol preferring rats are particularly sensitive to suppression of alcohol drinking and relapse by NOPR agonists (Ciccocioppo et al., 2004; Ciccocioppo et al., 1999; Economidou et al., 2008). These rats exhibit high innate sensitivity to stress, and high measures of both anxiety- and depression-like behaviors that are ameliorated by alcohol consumption (Ciccocioppo et al., 2006; Ciccocioppo and Hyytia, 2006). Hence, the effects of N/OFQ are in part likely due to its ability to alleviate a negative emotional state that otherwise provides an incentive for negatively reinforced alcohol consumption. Notably, these rats appear to have an innate up-regulation of the N/OFQ / NOPR system in several brain regions, and there appears to be a partial uncoupling of the NOPR from G-protein-mediated signal transduction in the central amygdala that may lead to a regionally selective functional deficit of the N/OFQ system, which could contribute to high levels of alcohol drinking and anxiety-like behavior (Economidou et al., 2008). This hypothesis is corroborated by data showing that alcohol self-administration is reduced by site-specific injections of N/OFQ into the central amygdala (Economidou et al., 2008).
