Project Summary/Abstract: There were about 81,000 drug overdoses in the U.S. from June 2019 to May 2020 – the highest rate ever recorded. Synthetic opioids (i.e., fentanyl and its analogues) are the primary driver of the increase in deaths, despite availability of naloxone for treatment of opioid-induced respiratory depression. Ten Western states reported an over 98% increase in synthetic opioid-involved deaths (CDC). Recent scientific data indicate, “The rate of opioid use disorder among patients in the Veterans Health Administration (VHA) is 7 times higher than that of non-VHA enrollees.” (Ahonle et al., Fed Pract. 2020; PMID: 33029067 PMCID: PMC7535957). Generally and too frequently, drug abuse is a confounding problem that is co-morbid with post-traumatic stress disorder and other mental illnesses, including schizophrenia and depression. Psychiatric outpatients are the second largest group of patients serviced by the Department of Veterans Affairs, with psychotic disorders such as schizophrenia being one of the most frequent diagnoses. Because there are no etiology- (biologically-) based treatments, these patients experience recurrent admissions to V.A. hospitals, and treatment compliance and symptom improvement are variable. Nationally, the V.A. spends over $3 billion and the Portland V.A. spends over $25 million annually on mental health programs. In addition, the V.A. spends over $250 million on antipsychotic medications and the Portland V.A. alone spends over $2.5 million annually on antipsychotic medications. Thus, drug abuse and schizophrenia have had an overwhelming impact on medical and financial aspects of the V.A. patient care mission. Developing treatments and cures could profoundly and positively impact medical and financial facets of the V.A. Our laboratory’s overarching goals are to 1) discover and characterize genetic and neurochemical pre-determinants for both neuropsychiatric disorders and drug response, and 2) discover and develop new etiology-based pharmacotherapies for neuropsychiatric disorders, including addictions. Using engineered cells expressing recombinant proteins, the laboratory has developed and continues to develop medium throughput radioligand binding and second messenger/signal transduction system assays for about (currently) 15 human G protein coupled receptors or ion channels and their polymorphisms. Additionally, we quantify radioligand binding, neurotransmitter uptake and neurotransmitter release by recombinant human neurotransmitter transporters and the vesicular monoamine transporter. Similar assays are used to characterize receptors and transporters in animal models of human disease and in human tissue. Newly developed imaging reagents are used to identify the intracellular localization of proteins of interest, as well as their orientation within cells to aid in computational modeling for new pharmacotherapies. Currently, we are identifying disease and drug-induced changes in the miRNA cargo of extra...