PROJECT SUMMARY Stimulant use disorders and overdose deaths resulting from methamphetamine use are on the rise. Psychedelics, such as psilocybin, show therapeutic potential and efficacy against anxiety, depression, alcoholism, and nicotine dependence, after administration of a single dose, but serotonergic psychedelics exhibit polypharmacology and are not selective for the serotonin 5-HT2A receptor, which is necessary for psychoactive effects. In this proposal we aim to investigate the role of 5-HT2A receptor signaling in methamphetamine (METH) self-administration, neuroplasticity in vitro and in vivo, and on METH-induced amotivation. These innovative studies utilize several novel and recently identified 5-HT2A selective tool compounds with a range of G protein and β-arrestin recruitment efficacies designed to address the signaling mechanisms involved in each of the following aims. In aim 1, we will determine the role of 5-HT2 receptors and signaling pathways that lead to the suppression of reinforcing effects in a METH self-administration model. In aim 2, we will examine the role of neuroplasticity in the attenuation of METH effects induced by psychedelics and 5-HT2A selective agonists. In aim 3, we will determine the contribution of 5-HT2A and 5-HT2C receptors toward attenuation of METH-induced amotivation using progressive ratio breakpoint task (PRBT) and probabilistic reversal learning task (PRLT). Together, these studies will identify serotonin receptor signaling profiles as a clear mechanism for psychedelic-induced efficacy for stimulant use disorders, with the potential to identify neuroplastic and non-psychedelic signaling mechanisms for more effective treatments for drugs of misuse. 1