Apremilast reduces co-occurring alcohol drinking and mechanical allodynia and regulates central amygdala GABAergic transmission
Valentina Vozella, … , Michal Bajo, Marisa Roberto
Valentina Vozella, … , Michal Bajo, Marisa Roberto
Published April 22, 2025
Citation Information: JCI Insight. 2025;10(8):e189732. https://doi.org/10.1172/jci.insight.189732.
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Research Article Neuroscience Public Health

Apremilast reduces co-occurring alcohol drinking and mechanical allodynia and regulates central amygdala GABAergic transmission

Abstract

The FDA-approved phosphodiesterase type 4 (PDE4) inhibitor, apremilast, has been recently investigated as a pharmacotherapy for alcohol use disorder (AUD) with promising efficacy in rodent models and humans. However, apremilast’s effects on mechanical allodynia associated with AUD as well as distinct responses of this drug between males and females are understudied. The present study examined the behavioral and electrophysiological effects of apremilast in Marchigian Sardinian alcohol-preferring (msP) rats and their Wistar counterparts. We used a 2–bottle choice (2-BC) alcohol drinking procedure and tested mechanical sensitivity across our drinking regimen. Spontaneous inhibitory GABA-mediated postsynaptic currents from the central nucleus of the amygdala (CeA) following apremilast application were tested in a subset of rats using ex vivo electrophysiology. Transcript levels for Pde4a or -4b subtypes were assessed for their modulation by alcohol. Apremilast reduced alcohol drinking in both strains of rats. Apremilast reduced mechanical allodynia immediately after drinking, persisting into early and late abstinence. Apremilast increased GABAergic transmission in CeA slices of alcohol-exposed Wistars but not msP rats, suggesting neuroadaptations in msPs by excessive drinking and mechanical allodynia. Pde4 subtype transcript levels were increased in CeA by alcohol. These results suggest that apremilast alleviates co-occurring excessive drinking and pain sensitivity, and they further confirm PDE4’s role in pain-associated AUD.

Authors

Valentina Vozella, Vittoria Borgonetti, Bryan Cruz, Celsey M. St. Onge, Ryan Bullard, Roman Vlkolinsky, Diego Gomez Ceballos, Angela R. Ozburn, Amanda J. Roberts, Roberto Ciccocioppo, Michal Bajo, Marisa Roberto

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Figure 3

Apremilast decreases mechanical allodynia across strain and sex immediately after alcohol exposure and into early abstinence.

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Apremilast decreases mechanical allodynia across strain and sex immediat...
(A–H) Effects of apremilast (10 or 20 mg/kg) on mechanical allodynia tested immediately after alcohol exposure (3 hours after injection, directly after 2-BC: left panel; 3–5 weeks into 2-BC) as well as during early abstinence (24 hours after injection: right panel; 5 weeks into 2-BC 24 hours after the last sessions) in Wistar (A–D) and msP (E–H) rats (n = 8–18 rats per group). (A) Wistar male mechanical threshold directly following 2-BC. Treatment F1.918,21.10 = 1.17, P = 0.32. Individual F11,22 = 1.58, P = 0.17. (B) Wistar female mechanical threshold directly following 2-BC. Treatment F1.988,32.80=7.99, P = 0.001. (C) Wistar male mechanical threshold in early abstinence; median (Mdn) = 0.0, Wilcoxon statistic (W) = 0.0, P > 0.000. (D) Wistar female mechanical threshold in early abstinence, Mdn = 16.0, W = 122.0, P = 0.002. (E) msP male mechanical threshold directly following 2-BC. Treatment F1.27,11.40 = 5.0, P = 0.04. (F) msP female mechanical threshold directly following 2-BC. Treatment F1.70,11.93 = 3.68, P = 0.06. (G) msP male mechanical threshold in early abstinence; Mdn = 11.0, W = 21.0, P = 0.03. (H) msP female mechanical threshold in early abstinence; Mdn = 16.0, W = 28.0, P = 0.01. Results are expressed as mean ± SEM and analyzed as a RM 1-way ANOVA or mixed-effects analysis as appropriate with Geisser-Greenhouse correction (A, B, E, F) followed by Dunnett’s multiple-comparison post hoc test and paired or unpaired t test (C, D, G, H). Significant difference relative to vehicle controls is denoted by *P < 0.05 and **P < 0.01.