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A central problem in treating drug addiction is the prevalence of relapse to drug use even after protracted intervals of forced or self-imposed abstinence. My laboratory is involved in programs that seek to identify new pharmacological targets for relapse prevention, a challenging factor in the treatment of post-dependent individuals. These projects investigate the neurobiological basis of chronic vulnerability to relapse, with an emphasis on identifying neural substrates that are responsible for the distinctly compulsive nature of drug (i.e., cocaine, alcohol, opioids, nicotine) seeking compared with behavior that is motivated by natural rewards that are essential for survival, well-being, and "healthy" hedonic pursuits. We use animal models of relapse and systematically compare drug vs. nondrug (usually a highly palatable food reward) in animals with and without a history of drug dependence. These models include cue-, stress-, and prime-induced drug-seeking behavior that are known factors that can induce intense craving and trigger relapse in abstinent individuals. Using a combination of original molecular techniques (i.e., AAV, DREADDs) and gold-standard animal models, this work has been a seminal contribution to the field in that the hypocretin (orexin) system is strongly engaged in drug-seeking behavior. In addition, this work made the key link showing that the hypocretin transmission in the paraventricular nucleus of the thalamus region not originally thought to be part of “drug addiction circuitry,” is implicated in modulating drug-directed behavior.