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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; Shawlot, William; Homanics, Gregg E; Osterndorff-Kahanek, Elizabeth A; Mason, Sonia; Mayfield, Jody; Smalley, Joshua L; Moss, Stephen J; Messing, Robert O.
Afiliação
  • Blednov YA; Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, 78712, USA.
  • Shawlot W; Center for Biomedical Research Support, Mouse Genetic Engineering Facility, The University of Texas at Austin, Austin, TX, 78712, USA.
  • Homanics GE; Departments of Anesthesiology & Perioperative Medicine, Neurobiology, and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
  • Osterndorff-Kahanek EA; Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, 78712, USA.
  • Mason S; Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, 78712, USA.
  • Mayfield J; Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, 78712, USA.
  • Smalley JL; Department of Neuroscience, Tufts University School of Medicine, Boston, MA, 02111, USA.
  • Moss SJ; Department of Neuroscience, Tufts University School of Medicine, Boston, MA, 02111, USA.
  • Messing RO; Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, 78712, USA; Department of Neuroscience, The University of Texas at Austin, Austin, TX, 78712, USA; Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, US
Neuropharmacology ; 257: 110035, 2024 Oct 01.
Article em En | MEDLINE | ID: mdl-38876310
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 ß3 subunits partially blocked apremilast-mediated decreases in drinking. Here, we produced Gabrb1-S409A mice to render GABAA ß1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in ß1 subunit expression or phosphorylation at other residues. ß1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits 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 but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 prevented apremilast modulation of ataxia by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting PKA or EPAC2 (exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute tolerance to ethanol ataxia in both genotypes, but there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of ß1-containing GABAA receptors is not required for apremilast's effects on acute tolerance or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we identified EPAC2 as an additional cAMP-dependent mechanism by which apremilast regulates responses to GABAergic drugs.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Talidomida / Proteínas Quinases Dependentes de AMP Cíclico / Receptores de GABA-A / Etanol / Inibidores da Fosfodiesterase 4 / Camundongos Endogâmicos C57BL Limite: Animals Idioma: En Revista: Neuropharmacology Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Talidomida / Proteínas Quinases Dependentes de AMP Cíclico / Receptores de GABA-A / Etanol / Inibidores da Fosfodiesterase 4 / Camundongos Endogâmicos C57BL Limite: Animals Idioma: En Revista: Neuropharmacology Ano de publicação: 2024 Tipo de documento: Article