MDMA Mechanisms of Prohedonic Efficacy: A Reverse Translational Approach - Project Summary/Abstract MDMA is a prototypical entactogen, a drug class defined by its prosocial and prohedonic effects in humans and laboratory animals. Although commonly known for its illicit use as the club drug Ecstasy, recent studies have documented its significant promise in the management of post-traumatic stress disorder (PTSD) and comorbid depression in treatment-resistant patients. These compelling findings led the FDA to grant MDMA the status of a breakthrough therapy in 2017 and, consequently, it currently is in Phase 3 clinical trials. It is important to note, however, that MDMA is also associated with several undesirable effects, including neurotoxicity and abuse liability. MDMA has a complex pharmacology which might lend itself to a neuropharmacological dissection of its beneficial and unwanted effects via rigorous examination of its stereoselective constituents and active metabolites. The major goal of this project will be to employ our recently developed platform that combines reverse-translated touchscreen assays of reward learning and concurrent electrophysiological recording in rats to identify the neurochemical drivers of MDMA’s prohedonic therapeutic efficacy. Indeed, anhedonia, the loss of pleasure derived from previously rewarding activities, is a behavioral phenotype implicated in several neuropsychiatric conditions, including PTSD and depression. Despite this transdiagnostic prevalence, and notwithstanding MDMA’s clinical trial successes, there are currently no approved mediations to abate anhedonic phenotypes. To advance our understanding and inform future medications development, the proposed studies will be conducted by associating electrophysiological biomarkers and task metrics following treatment with MDMA which, we hypothesize, will enhance reward learning and EEG delta wave alterations. Next, we will evaluate key neurochemical drivers of MDMA’s prohedonic outcomes via study of its enantiomers, primary metabolite constituents, and comparators that vary in relative dopaminergic or serotonergic activity. Racemic, S(+)-, R(-)-MDMA and -MDA, and compounds that vary in relative potency for dopamine/serotonin release will be studied to identify ratios of such activity and prohedonic efficacy. Then, we will Identify circuit engagement in which the kappa-opioid receptor (KOR) system and endogenous KOR ligand, dynorphin, regulates the behavioral and electrophysiological processes of enhanced (prohedonic) reward learning, given previous work highlighting its role in modulating symptoms of depression. Finally, in vivo microdialysis studies will be used to quantify dopaminergic and serotonergic efflux following MDMA and key drug comparators, both alone and following KOR circuit engagement to inform neurochemical mechanism. Ultimately, we expect the identification of the neurobiological and neurochemical drivers of MDMA’s therapeutic efficacy will inform subsequent development of candidate medications that improve upon its therapeutic profile for psychiatric conditions in which anhedonia is prevalent.
