A NOVEL AND POWERFUL MEDICATIONS SCREEN FOR ALCOHOL USE DISORDERS

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Alcohol use disorders (AUDs) cause serious problems in society and few effective treatments are available. Basic research with invertebrates has provided ground-breaking discoveries in uncovering mechanisms that underlie behaviors as complex as learning and memory. Recent work indicates that the same basic types of behavior that define drug reward in mammals are also evident in invertebrates (crayfish, flies, C. elegans). C. elegans is an excellent model to study the neurobiological basis of human behavior with: a surprisingly conserved, fully tractable genome; and a short generation time with low maintenance costs for fast generation of data at a fraction of the cost of other organisms. We have shown that C. elegans display a conditioned preference for cues previously paired with cocaine or methamphetamine, analogous to findings in mammalian models of drug reward. We have also found that C. elegans demonstrate movement toward, and concentration-dependent self-exposure to various psychoactive drugs (i.e. cocaine, caffeine, and ethanol (EtOH)), which is deemed a “preference response”. The recent discovery of opioid receptors in C. elegans provided the impetus to test the hypothesis that C. elegans may be used as a medications screen to identify new treatments for AUDs. We tested the effects of naltrexone, an opioid antagonist and effective treatment for AUDs and other addictions, on EtOH preference in C. elegans. Naltrexone treatment blocked acute EtOH and cocaine preference, but had no effect on motor activity or attraction to food or benzaldehyde (a volatile attractant). Chronic EtOH exposure enhanced EtOH preference, induced treatment resistance and compulsive- like behavior as evidenced by sustained self-exposure to EtOH in the presence of an aversive stimulus (nonanone). Together these data indicate that C. elegans have potential to serve as a model system to identify compounds to treat AUDs and other addictive disorders. However, clear evidence is needed to fully characterize the model and confirm that the phenomena observed thus far are consistent with efficacy of treatments for AUDs. Thus, the objective of this application is to test compounds, previously shown to reduce EtOH drinking and/or seeking in vertebrate models, in the C. elegans EtOH preference test in acute and chronic models, and to characterize the selectivity of the response. The results are expected to show that drugs that inhibit EtOH consumption and relapse in humans will produce similar effects in C. elegans where the pharmacology and molecular systems mediating the response are similar between the two species. Follow- up studies will test mutant C. elegans to identify mechanisms involved for candidate compounds with positive treatment results. To enhance the validity and translation of the model, future projects will include creating transgenic C. elegans expressing human receptors and pharmacology. The establishment of an effective high throughput behavioral model using C. elegans to screen candidate agents to treat AUDs would be a transformational advancement in the field, and is the long-term goal of this project.