Project Summary More annual causes have the than 16 million adults suffer from Alcohol Use Disorder (AUD) in the United States and the estimated economic burden of AUD is $249 billion. Approximately 88,000 Americans die from alcohol-related each year; untreated AUD is t he fourth most preventable cause of death in the US. Four medications been FDA-approved for treating AUD, but none of these medications have proven to be effective across heterogeneous groups of drinkers. Treating addiction more effectively is goal with national importance and accelerating drug development for AUD is one of the priorities for NIAAA. This proposal is intended to answer this call for accelerating drug development by exploring the potential of the histamine-3 (H-3) receptor inverse agonist/antagonist, pitolisant, as a candidate medication for the treatment of AUD. There is now substantial preclinical evidence that H-3 receptor antagonists and inverse agonists/antagonists can suppress behaviors that model both alcohol consumption and reward. These drugs have been shown to reduce alcohol consumption by rodents and attenuate alcohol-induced place preference. The administration of either an H-3 antagonist or of an antagonist/inverse agonist can block cue-induced reinstatement of responding for alcohol in mice. These findings are consistent with idea that alcohol seeking behaviors can be attenuated by agents that counteract the actions of H-3 receptor activation. There pitolisant intended agent AUD aims craving, days days method. order priming consume induced may This study may provide a rationale for phase II RCTs testing pitolisant with a treatment-seeking AUD population. These results may also help to spur further clinical investigation of the effects of pitolisant on the factors implicated in the regulation of alcohol consumption. . are no published clinical studies testing the effects of or any other H-3 receptor inverse agonist/antagonist on human alcohol consumption. This study is to accelerate medication development for AUD by testing a commercially-available and well-tolerated at a fraction of the cost of new drug discovery. None of the FDA-approved AUD medications or off-label medications target H-3 receptors, making pitolisant a promising compound for development. The specific of this study are to test the effects of pitolisant administration on 1) alcohol self-administration and 2) alcohol consumption and craving during a 5-day period of exposure, 3) sleep quality during the 5 of pitolisant administration, and, 4) the stimulant effects of a priming drink of alcohol. The effects of 5- of pitolisant or placebo will be evaluated in a human laboratory using an alcohol self-administration In this within-subjects crossover design study, 36 heavy drinkers will be randomized to exposure (pitolisant or placebo) prior to completing two alcohol self-administration trials. Subjects will receive a drink of alcohol and will have access to 8 drinks over a 2-hour period. We...