EMERGING SYNTHETIC OPIOIDS AND A2-AGONISTS: TRANSLATIONAL INVESTIGATION OF RESPIRATORY AND BEHAVIORAL RISK - PROJECT SUMMARY/ABSTRACT EMERGING SYNTHETIC OPIOIDS, INCLUDING THE NITAZENE CLASS, ARE INCREASINGLY DETECTED IN THE ILLICIT DRUG SUPPLY AND ARE ASSOCIATED WITH RAPID-ONSET RESPIRATORY DEPRESSION AND FATAL OVERDOSE. RECENT DRUG-CHECKING AND TOXICOLOGY REPORTS INDICATE THAT A2-ADRENERGIC AGONISTS, SUCH AS MEDETOMIDINE, ARE NOW FREQUENTLY CO-PRESENT WITH SYNTHETIC OPIOIDS. ALTHOUGH A2-AGONISTS REDUCE SYMPATHETIC OUTFLOW AND CAN PRODUCE PROFOUND SEDATION AND HYPOVENTILATION, THERE IS LITTLE EMPIRICAL WORK CHARACTERIZING THEIR INTERACTION WITH HIGHLY POTENT SYNTHETIC OPIOIDS. THIS GAP HINDERS THE DEVELOPMENT OF EVIDENCE-BASED HARM-REDUCTION STRATEGIES, THE REFINEMENT OF OVERDOSE PREVENTION MESSAGING, AND REGULATORY AND PUBLIC HEALTH RESPONSES AIMED AT REDUCING OPIOID-INVOLVED MORBIDITY AND MORTALITY. THIS PROJECT HAS THREE AIMS: (1) EVALUATE THE REINFORCING EFFECTS OF ETONITAZENE USING AN ESTABLISHED OPERANT ORAL SELF-ADMINISTRATION MOUSE MODEL; (2) ASSESS THE ACUTE AND REPEATED RESPIRATORY EFFECTS OF ETONITAZENE ALONE AND EFFECTS OF MEDETOMIDINE ADULTERATION USING WHOLE-BODY PLETHYSMOGRAPHY; AND (3) CHARACTERIZE AWARENESS, PERCEIVED RISK, AND USE BEHAVIORS SURROUNDING NITAZENES AND A2-AGONIST ADULTERANTS AMONG PEOPLE WHO USE OPIOIDS (PWUO) TO INFORM EVIDENCE-BASED PUBLIC HEALTH MESSAGING AND INTERVENTION STRATEGIES. RESULTS FROM THE PRECLINICAL AIMS WILL INFORM MECHANISTIC UNDERSTANDING OF POLYSUBSTANCE OVERDOSE RISK, WHILE THE HUMAN SURVEY DATA WILL CHARACTERIZE REAL-WORLD KNOWLEDGE AND RISK PERCEPTIONS AMONG PWUO. TOGETHER, THESE FINDINGS WILL SUPPORT THE DEVELOPMENT OF TARGETED HARM-REDUCTION MESSAGING AND GUIDE FUTURE TRANSLATIONAL RESEARCH ON EMERGING OPIOIDS AND ADULTERANTS. THIS WORK ALIGNS WITH NIH'S MISSION TO REDUCE THE BURDEN OF SUBSTANCE USE DISORDERS AND PREVENT OPIOID-RELATED MORBIDITY AND MORTALITY.