Summary In 2020, 91,799 drug overdose deaths occurred in the United States , over a third of which were related to synthetic opioids. Opioid use disorder (OUD), like other substance use disorders (SUD), is characterized maladaptive behavioral allocation away from other rewarding aspects of life following prolonged use, as well as large rates of relapse. While pharmacotherapies exist for OUD, they tend to only target the opioid receptors rather than the underlying mechanisms behind the maladaptive behaviors. Serotonin (5-hydroxytryptamine; 5-HT) is involved in modulation of cravings and regulation of motivational reward-related behaviors, thought to be due to a top-down processing method of external and internal stimuli. Serotonin 2A receptors (5-HT2AR) are widespread throughout the brain and most densely populate layer V pyramidal neurons in the cortex. These cortical pyramidal neurons project to several subcortical regions, including the nucleus accumbens, which is associated with the neurobiology of addiction. 5- HT2ARs are the main target of classic psychedelics, which produce alterations in processes related to cognition, perception and sensory processing via activation of these receptors. These compounds may possess the ability to alter behaviors associated with reward-related behaviors, such as context-induced relapse, which plays a large part in substance use disorders. Moreover, these compounds are being studied in clinical trials for their ability to treat substance use disorders. The proposed study will investigate whether a psychedelic can alter drug-related behaviors and the role of cortical 5-HT2AR in modulation of these behaviors. This study will focus on tryptamine psychedelic, psilocybin, which has a chemotype very similar to serotonin that activates mainly 5-HT2AR and 5-HT1Rs. Throughout the proposed study, I will be assessing the role of the 5-HT2AR by utilizing cre-recombinase viral vector delivery which will allow me to assess specific loci of 5-HT2AR and how activation of these receptors modulates drug-context related behaviors. The success of this studies will identify important mechanisms behind this The success of this studies will identify important mechanisms behind this. The success of this studies will identify important mechanisms behind this powerful drug class, including circuitry that could be utilized to develop safe, non-addictive and non-hallucinogenic pharmacotherapies to treat OUD. The proposed will facilitate my training in molecular techniques and animal behavioral models as well as give me opportunities to advance my scientific writing, critical thinking and prepare me for a future as an independent research scientist.

Project Narrative Misuse of opioids alone is the greatest leading cause of accidental death in the U.S. Many available treatments against opioid use disorder have their own set of side effects, are costly and not effective for everyone. Psychedelic compounds have the ability to alter cognition and perception through serotonergic signaling in ways that may be useful in treatment of opioid use disorder. This proposal will characterize behavioral phenotypes, serotonin receptor involvement and molecular circuits involved in the effects of classical psychedelics in the context of drug- context interactions relevant to opioid use disorder.