Levodopa reduces consumption of multiple classes of addictive substances in rats.

Dopamine transmission is implicated in aberrant behaviors associated with substance use disorders. Previous research revealed a causal link between excessive drug consumption and the loss of dopamine signaling to stimuli associated with psychostimulant use. The emerging change in dopamine signaling is specific to stimuli associated with the substance rather than the pharmacological properties of the drug itself. Because the change in dopamine signaling was specific to the associated stimuli and not the pharmacological properties of the substance, we examined if treatment with the dopamine precursor, l-DOPA, alters alcohol and opioid self-administration. Therefore, we trained rats to orally self-administer ethanol or the synthetic opioid fentanyl and found that treating animals with l-DOPA significantly reduced consumption of both alcohol and fentanyl. These data suggest dopamine signaling has a vital role in mediating the amount of drug animals will voluntarily take, across multiple classes of drugs. Importantly, these data are preclinical demonstrations of l-DOPA being utilized as a harm reducing treatment in substance use disorders.

The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder.

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.