Biobehavioral Imaging and Molecular Neuropsychopharmacology of Substance Abuse Mechanisms

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

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 rodents. In addition, clinical relevance of mechanisms studied in rodents 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 rodent 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 related conditions. This past year we developed a novel chemogenetic technology that can be used to produce artificial opposing bran signaling processes between cocaine ingestion and cocaine reinforcement to suppress its intake. This neuromodulatory approach may be useful for the treatment of cocaine addiction. We also developed novel PSAM/PSEM PET tracers, and an improved opsin for theranostic optogenetic applications. In continuing our work on deciphering the pharmacology of ketamine's therapeutic effects, we published new research and a comprehensive review describing its bifunctional effects on mu opioid receptors and NMDA receptors. In regard to out efforts in developing novel PET tracers, this past year we developed a novel mu opioid receptor agonist PET radiotracer as well as novel selective mu opioid receptor agonists based on the nitazene scaffold that can produce analgesia with minimal adverse effects. We are continuing to work on elucidating the mechanistic pharmacology of FDA-approved and investigational drugs such as (S)-ketamine , ketamine's 2R,6R-hydroxynorketamine metabolite, and methadone enantiomers. Finally, we are continuing to work on elucidating the involvement of synaptic zinc on dopamine neurotransmission. Recent efforts include developing a cre recombinase-expressing zinc transporter 3 (ZnT3) rat and discovery of the first ZnT3 ligands.