New Technologies for Accelerating the Discovery and Characterization of Neuroactives that Address Substance Use Disorders

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ABSTRACT Over the last decade, there has been a dramatic increase in deaths resulting from drug overdoses. Pharmacological interventions have proven to be transformative and life-saving in substance use disorders, particularly in opioid addictions and overdoses. Today, there is an increasing interest in having an armamentarium at clinician's disposal to address substance use disorders. There are three therapeutic classes of drugs that are highly sought: alternatives, attenuators, and antidotes. Having alternative therapeutic avenues for pain management other than opioids could help lower new addiction cases. For alternatives, we look to anesthetics that maintain analgesic effects at sub-anesthetic concentrations. For attenuators, we seek behavior-modifying drugs like ketamine and dizocilpine that have demonstrated reduced self-administration of drugs of abuse like cocaine, alcohol, methamphetamine, morphine, and nicotine in animal models. As a final line of defense, we endeavor to discover new drug overdose antidotes that reverse the toxicity of abused drugs. The discovery of novel chemical matter in these therapeutic classes could lead towards the development of new pharmacotherapies for treating addictions, but pharmacological modification of addictive behaviors in mammalian models is costly and challenging to evaluate. The objective of this proposal is to accelerate the discovery and characterization of novel small molecules affecting behavior using high-throughput screening of compounds in live animals guided by behavioral profiling as opposed to biochemical or cell-based assays. Our work exploits an automated technological platform in which the behaviors of hundreds of larval zebrafish under the influence of neuroactive compounds can be assessed and compared simultaneously. It enables the high-throughput screening of thousands of compounds for those that phenocopy neuroactive drugs of interest. The central premise of our approach is that pharmacological modulation by these therapeutic classes, their unique behavioral changes in larval zebrafish, and the identification of new related pharmacology are inter-connected. Accordingly, we predict that molecules that phenocopy anesthetics, ketamine, or the PQs ability to reverse benzodiazepine sedation will be new chemical matter for alternatives, attenuators, and antidotes of abused drugs. From this perspective, we can use the high-throughput behavioral assays in larval zebrafish as a primary screen of a structurally diverse set of >100,000 compounds. Importantly, from initial pilot screens we already have new chemical matter of all these classes in hand. We will perform mechanistic studies using state-of-the-art imaging of the zebrafish central nervous system to help further characterize new pharmacology. An essential part of the work is the translation of newly discovered neuroactives into rodent models of pain and substance use disorders.