Discussion
ADVERSE EFFECTS
We leveraged gene expression profiles of drinking to intoxication to identify compounds that might be repurposed to reduce excessive alcohol drinking characteristic of AUD. The FDA-approved PDE4 inhibitor apremilast was identified as the most promising target for repurposing, given a lower likelihood of severe PDE4 adverse effects associated with treatment discontinuation than earlier PDE4 inhibitors. We propose it is imperative to test potential therapeutics across multiple drinking paradigms, species, and strains to reduce the number of clinical study failures. The present work determined whether apremilast would reduce harmful alcohol drinking in male and female mice from 4 different strains with high risk for excessive drinking (i.e., selectively bred HDID-1 and 2, inbred HDID-1 mice, and C57BL/6J mice). Strikingly, we found that apremilast reduced excessive drinking across a spectrum of clinically relevant drinking models for binge-like, motivational, compulsive-like, and stress- and non–stress-induced facilitation of dependence-like drinking. Although follow-up testing suggests that apremilast acts through central means (i.e., the NAc), it is possible that either or both central and peripheral actions of apremilast are necessary for reducing harmful drinking. Therefore, future work should address the importance of such central and peripheral mechanisms. In a human POC study, we employed a double-blind, placebo-controlled study in non–treatment-seeking individuals with AUD and found that oral apremilast was robustly effective at reducing the number of daily drinks consumed. PDE4b, a target of apremilast, has been associated with both alcohol and nicotine dependence. We show that a gene identified from a genome-wide association study (Because apremilast works across a spectrum of models, in both sexes of 4 strains of mice (at multiple labs and universities) and importantly, in humans, we sought to determine the neural mechanisms by which PDE4 inhibition reduces harmful drinking. The NAc is a critical brain region for many behaviors and is well studied for its role in alcohol drinking. Structural and molecular changes in the NAc following both acute and chronic ethanol drinking are thought to play a role in further aberrant drinking patterns (The extent to which PDE4 inhibition, and in particular apremilast, alters input to, and output of, subpopulations of MSNs in the NAc helps to identify potential critical neurobiological mechanisms and may in part explain the observed reduction in harmful alcohol drinking across drinking models. Decreased alcohol drinking seen with chemogenetic manipulation of the NAc likely engages different signaling pathways that may be dependent on drinking paradigm, sex, and/or distinct cell types (The above double-blind, placebo-controlled POC study found a large effect of apremilast (90 mg/d) on decreasing drinking relative to placebo in 51 non–treatment-seeking men and women with severe AUD. The observed effect size for apremilast was more than double that reported in a comprehensive meta-analysis of randomized controlled trials of the FDA-approved treatments for AUD, acamprosate and naltrexone (This collaborative set of studies from 6 independent laboratories and universities highlights apremilast as a powerful AUD treatment option and further identifies mechanisms by which apremilast may reduce harmful alcohol drinking.