(2R,6R)-Hydroxynorketamine as a Novel Treatment for Opioid Use Disorder - Project Summary: Psychoplastogens have emerged as potential treatments for psychiatric disorders, including substance use disorders. For example, recent studies have shown that low-dose ketamine may be an effective treatment for depression and opioid use disorder (OUD). Despite promising results, the use of ketamine remains limited due to its side effects and misuse potential. More recently, researchers have turned to (2R,6R)-Hydroxynorketamine (HNK), a ketamine metabolite that has exhibited therapeutic effects in preclinical models of depression and stress, but unlike ketamine, HNK lacks misuse potential and dissociative properties. Our lab recently found that HNK reduces oxycodone withdrawal symptoms and reinstatement of oxycodone conditioned place preference. To build on these exciting data and make advancements towards potential treatments for OUD, I propose to use a combination of behavioral and cell type-specific approaches to investigate the behavioral effects and cellular mechanisms of HNK in multiple OUD models. In Aim 1, I will identify brain regions and specific cell-types involved in the therapeutic response of HNK during oxycodone withdrawal. In Aim 2, I will determine the effects of HNK on extinction and reinstatement of oxycodone self-administration. To achieve these goals, I will receive advanced training in behavioral pharmacology, sophisticated animal models of SUD, cell type-specific analysis, and chemogenetics. Overall, this proposal will provide critical insights into the neural mechanisms underlying the therapeutic effects of HNK in opioid withdrawal, highlighting its potential as a novel treatment for OUD.
