Methamphetamine use disorder is associated with damage to regions of the brain that control cognitive and psychiatric function. One-third to one-half of adults with methamphetamine use disorder experience cognitive impairments and other psychiatric symptoms that significantly impact treatment outcomes (increased relapse and lower treatment retention rates). Mounting evidence demonstrates how immune factors can influence addictive behaviors and contribute to relapse. We have shown that recombinant T-cell receptor ligand (RTL) 1000 [a partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide (pDR2/MOG-35-55)] addresses the neuroimmune effects of methamphetamine addiction and offers a new strategy for the treatment of methamphetamine-induced central nervous system (CNS) injury. RTLs bind to and downregulate expression of the invariant chain CD74 - the primary receptor for macrophage migration inhibitory factor (MIF), a key inflammatory mediator in a number of diseases, including methamphetamine and alcohol use disorders. Preliminary data in rodent models demonstrate RTLâs therapeutic impact on cognitive function, drug seeking, and inflammation. A drawback of RTL1000 is that it can only be given to individuals that are DR2 positive. To overcome this limitation we have created DRα1-MOG which has the major advantage that it would be suitable to all people struggling with methamphetamine use disorder. The proposed application builds on our previous research by using complimentary rodent models that will allow us to rapidly move DRï¡1-MOG along the drug development pipeline toward readiness for clinical translation. The primary objective of this Phase I STTR project is to evaluate the efficacy of DRï¡1-MOG as a medication for methamphetamine use disorder and test whether DRï¡1-MOG can promote abstinent-like behavior by reducing drug seeking, improving cognitive function, and reducing anxious-like behavior. To accomplish this objective, we will evaluate the behavioral effects of DRα1-MOG on methamphetamine exposure in two rodent models that will assess self-administration behavior and the consequences of neurotoxic, binge-like drug exposure. Secondary objectives will investigate the effects of DRα1-MOG immunotherapy on methamphetamine-induced CNS inflammation by characterizing the effects of DRï¡1-MOG immunotherapy on the CD74/NF-ï«B inflammatory signaling cascade. Collectively, these objectives will establish the degree to which specific inflammatory signals contribute to methamphetamine relapse behaviors and methamphetamine-induced cognitive and affective dysfunction. We expect that following the completion of this one-year project, we will have substantial evidence to support a new treatment strategy for methamphetamine use disorder-âa strategy which addresses problems that are central to the underlying pathophysiology of methamphetamine addiction.
Public Health Relevance Statement: PROJECT NARRATIVE Discovery of a medication that could improve brain repair and recovery following methamphetamine addiction would represent a major scientific breakthrough that could broadly impact addiction treatment. This project will evaluate a novel medication for methamphetamine use disorder and test whether or not it can promote abstinent- like behavior by reducing relapse and improving cognitive and affective function. A major outcome of the proposed project will be moving closer to readiness for human clinical trials as a new medication to reduce relapse.
Project Terms: addiction; Addictive Behavior; Address; Adult; Affective; Alcohol or Other Drugs use; alcohol use disorder; Animals; Anxiety; anxious; Apoptosis; Area; associated symptom; Behavior; Behavioral; Binding; Biological; Brain; Brain region; brain repair; CCL2 gene; CD44 gene; Cell Survival; Cells; central nervous system injury; chemokine; clinical translation; Clinical Trials; Cognitive; cognitive control; Cognitive deficits; cognitive function; Complex; Corpus striatum structure; Cues; cytokine; Data; Development; Disease; Disease remission; Drug Addiction; drug development; Drug Exposure; efficacy testing; Electrophoresis; Evaluation; experience; Exposure to; Flow Cytometry; Functional disorder; Goals; Hippocampus (Brain); Histocompatibility Antigens Class II; Human; IL8RB gene; Immune response; Immunoblotting; Immunologic Factors; Immunoprecipitation; Immunotherapy; Impaired cognition; improved; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; invariant chain; Ligand Binding; Ligands; macrophage migration inhibitory factor receptor; Maintenance; Methamphetamine; Methamphetamine dependence; methamphetamine effect; methamphetamine exposure; methamphetamine use; MHC Class II Genes; migration; Migration Inhibitory Factor; monocyte; morris water maze; Mus; Myelin; Neuraxis; Neuroimmune; neuroinflammation; neuropsychiatric symptom; neurotoxic; Neurotransmitters; next generation; novel; Nuclear; Outcome; Peptides; Pharmaceutical Preparations; Phase; preclinical efficacy; Prefrontal Cortex; psychiatric symptom; Rattus; Readiness; receptor; receptor binding; Recombinants; Recording of previous events; Recovery; recruit; Relapse; Research; research clinical testing; retention rate; Rodent; Rodent Model; Self Administration; Signal Transduction; Small Business Technology Transfer Research; Specimen; Substance Use Disorder; success; System; T-Cell Receptor; Testing; Therapeutic; Therapeutic Effect; transcription factor; Treatment outcome; tr
