Project Summary Depression, addiction, and disordered eating are common mental health disorders that affect millions of people worldwide, and all involve dysregulated reward circuitry leading to abnormally low, or abnormally high reward pursuit. While there are some effective treatments for these disorders, not all individuals respond well to these treatments and some experience significant side effects. Therefore, it is vital to develop new therapies that induce behavioral changes quickly and remain effective for extended periods. Recently, clinical trials using psychedelic drugs to treat these disorders and others have shown promising and long-lasting results, and trials are now underway using psilocybin to treat eating disorders such as anorexia nervosa and binge eating disorder. Although these findings are exciting, it remains a concern that little is known about the mechanisms by which psychedelics may have therapeutic effects, other than that their actions require agonism of the serotonin (5-HT) 2A receptor. Animal models are useful to study these mechanisms and establish their causal effects, but animal models of depression, and especially of psychedelic drug actions, are to say the least challenging in rodents. Here we capitalize on our well-validated, translationally relevant rat early-life adversity (ELA) model, which causes long-lasting and sex-dependent alteration in reward circuitry, such as anhedonia in males and excessive pursuit of rewards in females. Parallel findings emerge in our model and in men and women who experienced low socioeconomic status, trauma, or chaotic early-life environments, allowing us to interrogate in rodents the responsible brain mechanisms, and potential therapeutics. My project will examine the effects of psychedelic 5-HT2A agonist drugs DOI and psilocybin on ELA- induced alterations to food-seeking behavior and reward circuit function in rats. We acknowledge that these drugs may act differently in rats and humans, but nonetheless our preliminary data suggests that at least some ELA-induced changes in reward pursuit are persistently reversed by a single dosing of DOI when it’s administered in a familiar and reward-filled “set and setting.” The current proposal aims to replicate and extend these exciting findings, determining the effective DOI dose range, and determining whether DOI effects also occur with the more readily translatable 5-HT2A agonist psilocybin. Further, we investigate whole-brain regional activity associated with ELA-induced anhedonia/hyperhedonia, and of its reversal by psychedelics. These studies may help develop a new animal model of the therapeutic effects of 5-HT2A stimulation, leveraging established models of developmental adversity, multiple 5-HT2A agonist drugs, and behavioral procedures modeled to the extent possible on human treatment protocols. We hope these studies will contribute to the sorely-needed body of basic research on psychedelic drug effects, and provide new insig...