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The PDE4 inhibitor apremilast modulates ethanol responses in Gabrb1 S409A knock-in mice via PKA-dependent and independent mechanisms

ABSTRACT: We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABAA 3 subunits partially blocked apremilast-mediated decreases in alcohol drinking. Here, we produced Gabrb1-S409A knock-in mice to render GABAA β1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in 1 subunit expression or phosphorylation at other residues. 1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits in the hippocampus or in behavioral characteristics. Apremilast prolonged recovery from ethanol ataxia to a greater extent in Gabrb1-S409A mice but prolonged recovery from zolpidem and propofol to a similar extent in both genotypes. Apremilast shortened recovery from diazepam ataxia in wild-type mice but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 completely prevented apremilast modulation of ataxia induced by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting either PKA or EPAC2 (an exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute functional tolerance to ethanol ataxia and increased acute sensitivity to ethanol in both genotypes. However, there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of β1-containing GABAA receptors is not required for apremilast’s effects on acute tolerance to ethanol or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we also identified EPAC2 as an additional cAMP-dependent signaling mechanism by which apremilast regulates responses to GABAergic drugs.

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ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Neuron

SUBMITTER: Joshua Smalley

LAB HEAD: Joshua Smalley

PROVIDER: PXD052839 | Pride | 2025-10-06

REPOSITORIES: Pride

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The PDE4 inhibitor apremilast modulates ethanol responses in Gabrb1-S409A knock-in mice via PKA-dependent and independent mechanisms.

Blednov Yuri A YA Shawlot William W Homanics Gregg E GE Osterndorff-Kahanek Elizabeth A EA Mason Sonia S Mayfield Jody J Smalley Joshua L JL Moss Stephen J SJ Messing Robert O RO

Neuropharmacology 20240613

We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABA<sub>A</sub> β3 subunits partially blocked apremilast-mediated decreases in drinking. Here, we produced Gabrb1-S409A mice to render GABA<sub>A</sub> β1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in β1 subunit expression or pho ...[more]

PMID: 38876310

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Project description:Despite recent extensive genomic and genetic studies on behavioral responses to ethanol, relatively few new therapeutic targets for the treatment of alcohol use disorder have been validated. Here we describe a cross-species genomic approach focused on identifying gene networks associated with chronic ethanol consumption. To identify brain mechanisms underlying a chronic ethanol consumption phenotype highly relevant to human alcohol use disorder, and to elucidate potential future therapeutic targets, we conducted a genomic study in a nonhuman primate model of chronic open-access ethanol consumption. Microarray analysis of RNA expression in anterior cingulate and subgenual cortices from rhesus macaques was performed across multiple cohorts of animals. Gene networks correlating with ethanol consumption or showing enrichment for ethanol-regulated genes were identified, as were major ethanol-related hub genes within these networks. A subsequent consensus module analysis was used to co-analyze monkey data with expression data from a chronic intermittent ethanol vapor-exposure and consumption model in C57BL/6J mice. Ethanol-related gene networks conserved between primates and rodents were enriched for genes involved discrete biological functions, including; myelination, synaptic transmission, chromatin modification, Golgi apparatus function, translation, cellular respiration, and RNA processing. The myelin-related network, in particular, showed strong correlations with ethanol consumption behavior and displayed marked network reorganization between control and ethanol-drinking animals. Further bioinformatics analysis revealed that these networks also showed highly significant overlap with other ethanol-regulated gene sets. Altogether, these studies provide robust primate and rodent cross-species validation of gene networks associated with chronic ethanol consumption. Our results also suggest potential novel focal points for future therapeutic interventions in alcohol use disorder.

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