Apremilast-induced increases in acute ethanol intoxication and decreases in ethanol drinking in mice involve PKA phosphorylation of GABAA β3 subunits. (1st December 2022)

• Record Type: Journal Article
• Authors: Blednov, Yuri A.; Da Costa, Adriana; Mason, Sonia; Mayfield, Jody; Moss, Stephen J.; Messing, Robert O.
• Is Part Of: Neuropharmacology. Volume 220(2022)
• Publication Date: 2022-12-01
• Subjects: PDE4 inhibitor apremilast -- β3 GABAA receptor subunit -- PKA phosphorylation -- Acute functional tolerance to ethanol -- Two-bottle choice ethanol consumption; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.109255
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: We previously showed that apremilast, an FDA-approved PDE4 inhibitor, selectively alters behavioral responses to ethanol and certain GABAergic drugs in a PKA-dependent manner in C57BL6/J mice. Here, we investigated if PKA phosphorylation of β3 GABAA receptor subunits is involved in apremilast regulation of ethanol, propofol, or diazepam responses. Apremilast prolonged rotarod ataxia and loss of the righting reflex by ethanol and propofol in wild-type mice, but not in β3-S408A/S409A knock-in mice. In contrast, apremilast hastened recovery from the ataxic and sedative effects of diazepam in both genotypes. These findings suggest that apremilast modulation of ethanol and propofol behaviors in wild-type mice is mediated by β3 subunit phosphorylation, whereas its actions on diazepam responses involve a different mechanism. The PKA inhibitor H-89 prevented apremilast modulation of ethanol-induced ataxia. Apremilast sensitized wild-type males to ethanol-induced ataxia and decreased acute functional tolerance (AFT) in females but had no effect in β3-S408A/S409A mice of either sex. These results could not be attributed to genotype differences in blood ethanol clearance. There were also no baseline genotype differences in ethanol consumption and preference in two different voluntary drinking procedures. However, the ability of apremilast to reduce ethanol consumption was diminished in β3-S408A/S409A mice. Our results provide strong evidence that PKA-dependent phosphorylation of β3 GABAA receptor subunits is an important mechanism by which apremilast increases acute sensitivity to alcohol, decreases AFT, and decreases ethanol drinking. Graphical abstract: Image 1 Highlights: The PDE4 inhibitor apremilast robustly decreases alcohol drinking in mice. Apremilast increases acute intoxication and decreases acute functional tolerance. Apremilast modulates these responses via PKA phosphorylation of β3 GABAA subunits. This mechanism is also important for the effects of propofol but not diazepam. Apremilast regulates alcohol responses via PKA-dependent GABAergic signaling.