The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder
Gabriel D. Bosse, … , Marco Bortolato, Randall T. Peterson
Gabriel D. Bosse, … , Marco Bortolato, Randall T. Peterson
Published April 13, 2021
Citation Information: J Clin Invest. 2021;131(10):e143990. https://doi.org/10.1172/JCI143990.
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The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder

Abstract

Opioid use disorder (OUD) has become a leading cause of death in the United States, yet current therapeutic strategies remain highly inadequate. To identify potential treatments for OUD, we screened a targeted selection of over 100 drugs using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride reduced the physical signs associated with opioid withdrawal. In rat models of neuropathic pain, finasteride did not alter the antinociceptive effect of opioids and reduced withdrawal-induced hyperalgesia. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish in a fashion akin to the effects of finasteride. These results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new treatment option for this disorder.

Authors

Gabriel D. Bosse, Roberto Cadeddu, Gabriele Floris, Ryan D. Farero, Eva Vigato, Suhjung J. Lee, Tejia Zhang, Nilesh W. Gaikwad, Kristen A. Keefe, Paul E.M. Phillips, Marco Bortolato, Randall T. Peterson

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Figure 8

Specific neurosteroids also affect opioid self-administration.

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Specific neurosteroids also affect opioid self-administration. (A) Incub...
(A) Incubation with steroids upstream of 5αR, DHEA (10 μM) or pregnenolone (10 μM), reduced the number of triggering events at the active platform. P values were computed by Tukey’s HSD test on 1-way ANOVA; inactive platform [F(2, 21) = 2.18, P = 0.14] and active platform [F(2, 21) = 51.09, P = 8.57 × 10–9]. No significant difference was detected for the inactive platform compared with the DMSO control. DMSO: n = 12, pregnenolone: n = 8, and DHEA: n = 5. (B) Cotreatment with finasteride (10 μM) and a selection of steroids downstream of 5αR partially blocked the reduction in opioid self-administration induced by finasteride. P values were computed by Tukey’s HSD test on 1-way ANOVA; inactive platform [F(2, 16) = 1.58, P = 0.24] and active platform [F(2, 16) = 68.93, P = 1.37 × 10–8]. No significant difference was detected for the inactive platform. DMSO: n = 8, finasteride: n = 8, finasteride plus downstream steroids: n = 3. *P < 0.05, **P < 0.01. Each n value represents a group of 15 animals. These experiments were performed using a between-subjects design. All box plots were generated using R graphic programming and the ggplot module. The lower and upper hinges correspond to the first and third quartiles. The line indicates the median. The whiskers extend from the hinges to the maximum or minimum value, at most 1.5 times the IQR from the hinge. Data points beyond that are considered outliers.