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Principal Investigator: Michael Michaelides
Organization: NATIONAL INSTITUTE ON DRUG ABUSE
Fiscal Year: 2022
Award: $1,981,761
Funding agency: National Institute on Drug Abuse
The societal and economic burden of substance use disorders is vast and ever-increasing. To address this requires developing innovative therapeutics, an approach necessitating a deep understanding of behavior and its neurobiological basis. Fortunately, the last decade has witnessed a surge of breakthrough technologies with significant promise for advancing the understanding of the neurobiological basis of normal and pathological behavior. Our goal is to leverage the unique NIH intramural environment to perform pioneering, collaborative, and translational research aimed to advance biological knowledge and treatment of substance use disorders. Our program implements state-of-the-art biobehavioral molecular imaging approaches integrated alongside cutting-edge neuromodulatory (e.g. chemogenetic, optogenetic), molecular, pharmacological, transgenic, and bioinformatic methods for identifying behaviorally-relevant neurobiological mechanisms associated with substance use disorders and related comorbid diseases/disorders. Special emphasis is placed on reverse-translating findings from clinical research to animals. In addition, clinical relevance of mechanisms studied in animals is determined in humans via bioinformatic, genetic and/or postmortem tissue examination.
One of the labs core areas of focus has been on development and application of novel molecular imaging strategies for assessment of whole-brain and cellular-level molecular dynamics simultaneously with behavior in animal models of substance use disorders. Another major core focus involves development of novel theranostic neuromodulation technologies that can be used for clinical treatment of addiction and other disease states. We have developed novel and highly potent chemogenetic technologies (DREADD agonists/PET tracers, PSAM/PSEM PET tracers), and the first PET ligand for optogenetics. We also developed a novel precursor and synthesis for 18F-fluoroethydiprenorphine and showed that this PET tracer, originally thought to be non-selective for all opioid receptors, is selective for binding to the mu opioid receptor in vivo. In addition, we have been working on elucidating the mechanistic pharmacology of FDA-approved and investigational drugs such as oliceridine, ketamine enantiomers, ketamine's 2R,6R-hydroxynorketamine metabolite, and methadone enantiomers. Finally, we are also working on elucidating the involvement of synaptic zinc on dopamine neurotransmission and recently showed that zinc modulates cocaine potency, cocaine reinforcement, and the function of the dopamine transporter in vivo.
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