Initial subjective reward: single-exposure conditioned place preference to alcohol in mice.

Most adults consume alcohol with relative impunity, but about 10-20% of users persist (or progress) in their consumption, despite mounting and serious repercussions. Identifying at-risk individuals before neuroadaptative changes associated with chronic use become well ingrained is thus a key step in mitigating and preventing the end stage disease and its devastating impacts. Explaining liability has been impeded, in part, by the absence of animal models for assessing initial sensitivity to the drug's reinforcing properties, an important endophenotype in the trajectory toward excessive drinking. Here we assess the initial rewarding effects of the drug in a novel application of the conditioned place preference paradigm. In contrast to previous studies that have all employed repeated drug administration, we demonstrated a robust preference for a context paired with a single exposure to 1.5 g/kg EtOH in male and female subjects of three strains. This model validates an assay of initial sensitivity to the subjective rewarding effects of alcohol, a widely used drug with multifarious impacts on both brain and society, and provides a new tool for theory-driven endophenotypic pharmacogenetic approaches to understanding and treating addiction.

ß-endorphin modulates the effect of stress on novelty-suppressed feeding.

Although stress is implicated in the pathophysiology of mood and anxiety disorders, not all individuals who suffer stressful life events develop psychopathology. Differential susceptibility to stress may be influenced by genetically mediated differences in hypothalamic-pituitary-adrenal (HPA) axis activity and moderation of the stress response by the opioid peptide ß-endorphin (ß-E). The present study investigated genetic contributions to coping behavior by examining anxious behavior of transgenic mice with varying capacities to synthesize ß-E [B6.129S2-Pomc (tm1Low) /J; regulated by insertion of a premature stop codon into one or both copies of the proopiomelanocortin (POMC) gene], both under normal conditions and following 3 min of forced swim (FS). Ten minutes after this stress exposure or a control manipulation, acutely food-deprived female and male transgenic mice were subjected to a novelty-suppressed feeding (NSF) test, during which their interaction with an almond slice located in the center of an open field box was measured. There was an interaction between genotype and stress for latency to approach the almond and whether or not the almond was approached, such that mice with low or absent ß-E displayed a stronger aversion to novelty-feeding after stress exposure than did mice with normal levels. These data provide evidence for a moderating effect of ß-E on the behavioral response to stress. Genotypic differences in anxious behavior emerged when mice were stressed prior to behavioral assessment, suggesting that ß-E plays a role in coping behavior. These findings indicate that genetic variability in sensitivity of the ß-E system to stress may contribute, at least in part, to heritable differences in stress reactivity as well as vulnerability to stress-related psychopathology.