Project summary Alcohol use disorders (AUD) cost the United States health system roughly $250 billion per year, and recent data suggests that alcohol use in the US is rising. Problematically, only three drugs have been FDA approved for treatment of AUD and less than 10% of patients are prescribed them. Increasingly, patients reach to the internet to find alternative treatment options for AUD without a necessary prescription. A pertinent example is Mitrayna speciosa (kratom), an opioid containing plant that is used extramedically to self-medicate chronic pain as well as opioid dependence. Unsurprisingly given the role of the opioid receptor system in alcohol use and craving, kratom is occasionally used to self-medicate AUD. However, currently no studies have investigated whether kratom or any of its major alkaloids effectively reduce alcohol use. Additionally, it is unknown if these alkaloids have rewarding properties in alcoholics. Kratom contains several alkaloids (including the main constituent mitragynine) that are known to bind to and activate opioid receptors. Interestingly, these opioids appear to act as so-called ?biased agonists? in vitro by activating only the G-protein signaling pathway of G protein-coupled receptors (GPCRs), such as the opioid receptor, but not those pathways associated with ?-arrestin proteins. We have recently found that G-protein biased agonists targeting ?-opioid receptor (?OR) can effectively reduce alcohol intake in mice. In this proposal, we hypothesize that those alkaloids in kratom that can activate ?ORs will contribute to reduced voluntary alcohol consumption in mice particularly by signaling in a G-protein biased manner. We further hypothesize that these alkaloids will not produce conditioned place preference, a measure of the rewarding properties of a drug, via ?ORs. To investigate our hypothesis we will identify six kratom-derived opioids with the strongest affinity for ?ORs. We will then assess whether kratom and these kratom-derived opioids can reduce alcohol use in a model of limited-access voluntary alcohol consumption in wild-type mice as well as in specific opioid receptor knockout animals. Thirdly, we will determine to what degree kratom and the kratom- derived opioids can induce a conditioned place preference response in nave and alcohol exposed wild-type mice and in ?OR knockout mice. The information that will be gathered by successful completion of this proposal can jumpstart clinical studies into the use of kratom and the kratom-derived opioids for AUD treatment as well as educate the general public about the risks and benefits of kratom use. The aims of this proposal fit the larger goal of my research program which is geared toward development of novel therapeutics to treat AUD. This is in line with the major initiative of the National Institute on Alcohol Abuse and Alcoholism to ?offer effective intervention for problem alcohol use at all ages?.