Project Summary Synthetic Psychoactive Drugs (SPDs) are substances designed to mimic the effects of controlled substances and other abused drugs. Although designer drugs are not a new phenomenon, the number and availability of SPDs is unprecedented and has increased dramatically over the last 5 years. Many hallucinogenic SPDs are structurally similar derivatives of known serotonergic hallucinogens, including drugs such as 25I-NBOMe (“25- I”, “N-Bomb”), 1-propionyl-LSD, and 5-MeO-DALT. The popularity and proliferation of hallucinogenic SPDs is causing a significant public health problem because they are often highly potent and pose greater risks of toxicity compared with older hallucinogens. Because very little is known about the mechanisms of action and behavioral effects of hallucinogenic SPDs, a NIDA program announcement (PAR-14-106) is soliciting research into “Synthetic Psychoactive Drugs and Strategic Approaches to Counteract Their Deleterious Effects.” This application seeks support for a project to investigate the specific pharmacological mechanisms, receptor targets, and signaling pathways that mediate the behavioral effects of hallucinogenic SPDs. The proposed research program is part of a larger collaborative effort to rapidly identify and characterize new SPDs, define their structure-activity relationships (SAR), and determine the mechanisms of their hallucinogenic and toxic actions. Hallucinogenic drug effects in rodents are assessed using two complementary behavioral paradigms: exploratory locomotor behavior, which has a direct counterpart in human studies; and the head twitch response (HTR), which is a hallucinogen-sensitive behavioral assay. Aim 1 will elucidate the mechanisms of action of SPD analogs of indoleamine hallucinogens, testing the hypothesis that these hallucinogenic SPDs (including tryptamines, benzofurans, and LSD analogs) act through 5-HT1A and 5-HT2A receptors. Studies will compare SPD effects with the known profiles of serotonergic hallucinogens and define the SAR of SPD analogs of indoleamine hallucinogens. Aim 2 will elucidate the structural features and second messenger systems mediating the behavioral effects of the highly potent N-benzylphenethylamine class of hallucinogenic SPDs, known as “NBOMes,” that are related to hallucinogens such as mescaline. Aim 2 studies are designed to assess (1) the link between specific structural features in NBOMes and their 5-HT2A affinities, and (2) the contributions of specific signaling pathways and 5-HT2A functional selectivity to the behavioral effects of these hallucinogenic SPDs. Aim 3 will assess the contributions of metabolites to the behavioral and toxicological effects of hallucinogenic SPDs. The idea that 1P-LSD acts as a pro-drug for LSD and the hypothesis that some SPD toxicity is due to O-demethylated metabolites will be tested. These studies address receptor interactions that have important implications for understanding the psychotomimetic effects of hallucinog...