Steroids screening for reducing opioid self-administration and their possible depressogenic effects in adult zebrafish

Abstract

The US is currently facing a staggering epidemic of opioid use disorder (OUD). Opioids are among the most addictive drugs and the two main drugs currently approved for maintenance therapy and supportive care of patients with OUD, methadone and buprenorphine, are also opioid receptor agonists that can lead to abuse, dependence and potentially overdose. In vivo studies using zebrafish (Danio rerio) have been widely used in Toxicology and this animal can be used in behavioral studies in the larval and adult stages, as currently there are several cataloged and validated tests for behaviors associated with memory, anxiety, and conditioning. Recently, the Peterson lab developed a young adult zebrafish assay to promote the discovery of new drugs that can significantly reduce opioid self-administration. Screening of approximately 200 compounds showed that one of the most effective drugs to reduce opioid seeking in fish was finasteride (FIN). These assumptions point to FIN as a highly promising therapy for OUD; however, this drug has been linked to a higher risk of depressive symptoms and suicide. The depressogenic effects of FIN are likely supported by the depletion of the 5±R product allopregnanolone (AP), which has antidepressant properties. In contrast, the beneficial effects of FIN on opioid seeking may be based on the accumulation of two 5±R precursors, pregnenolone (PREG) and dehydroepiandrosterone (DHEA), since both steroids have similar effects as FIN on opioid seeking in fish, although they do not induce depression-like effects. Therefore, the simultaneous effect of FIN on opioid consumption and depression may result from the distinct effects of various steroids altered by FIN treatment. Based on this, the central hypothesis is that DHEA and PREG participate in the therapeutic effects of FIN, while the depressogenic properties of this drug are attributed to the reduction of AP levels. For all these reasons, it will be valuable to decipher which steroid derivatives of DHEA and PREG reduce opioid seeking and modulate depression-like behavior. Likewise, it will be equally informative to identify which steroids affected by FIN may be responsible for its depressogenic effects (besides AP). Thus, the objective of this work is to identify therapies that reduce the risk of opioid overdose, decreasing consumption without producing abstinence by tracking the behavioral effects of a panel of steroids using opioid seeking and depression-like responses in adult zebrafish. This problem will be addressed using a panel of steroid derivatives that are structurally similar but exert very different biological effects. Subtle structural changes result in very different neurological effects, presumably influencing specific sets of targeted receptors. By running the entire panel through a battery of zebrafish behavioral assays, it will be possible to identify which ones have opioid-reducing effects and which ones have depressogenic defects. (AU)