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A major focus of Butelman’s work is the behavioral and neurobiological impact of the κ-opioid receptor (KOPr) system, and of the endogenous agonists that activate it, the dynorphins. The KOPr system is thought to be involved in several neuropsychiatric disorders, including anxiety, depression, and specific addictive diseases. His long-term goal is to open the door for the development of new pharmacotherapeutic approaches for these neuropsychiatric disorders, and for opiate and cocaine addiction, based on a better understanding of their etiology and their interaction with the KOPr–dynorphin system.

Butelman has also focused on characterizing the pharmacology of salvinorin A, a powerful hallucinogenic compound from the plant Salvia divinorum. This plant, originally used in ethnomedical practice, has more recently become widely available and abused, especially in adolescents and young adults. Butelman and his colleagues confirmed in vivo that salvinorin A is a KOPr agonist, by showing that its discriminative (subjective-like) effects are shared with known synthetic KOPr agonists. He further showed that KOPr blockade could both prevent and reverse behavioral effects of salvinorin A. Furthermore, a classic serotonergic hallucinogen did not share the discriminative effects of salvinorin A. Overall, these findings indicate that the behavioral and hallucinogenic effects of salvinorin A are thus completely separate from those of known “classic” hallucinogens, and implicates the KOPr–dynorphin system as a powerful mechanism underlying higher functions.