Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, 78712, USA.
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, USA.
Neuropharmacology. 2023 Jun 15;231:109508. doi: 10.1016/j.neuropharm.2023.109508. Epub 2023 Mar 18.
Apremilast is a phosphodiesterase (PDE) type 4 inhibitor that is nonselective at subtypes PDE4A-D. It modulates ethanol and GABAergic responses via protein kinase A (PKA) phosphorylation of specific GABA receptor subunits and has opposite effects on ethanol-induced ataxia in wild-type and GABA β3-S408/409A knock-in mice. We hypothesized that these different effects are due to preferential actions at different PDE4 subtypes. To test this hypothesis, we compared effects of selective PDE4 inhibitors on responses to ethanol and GABAergic drugs in male and female C57BL/6J mice. The PDE4B inhibitor A33 accelerated recovery from ataxia induced by ethanol and diazepam but did not alter ataxia induced by propofol. The PDE4D inhibitor D159687 accelerated recovery from diazepam-induced ataxia but prolonged recovery from ethanol- and propofol-induced ataxia. A33 shortened, while D159687 prolonged, the sedative-hypnotic effects of ethanol. Both drugs shortened diazepam's sedative-hypnotic effects. The modulatory effects of A33 and D159687 were completely prevented by the PKA inhibitor H89. Only D159687 prevented development of acute functional tolerance to ethanol-induced ataxia. D159687 transiently reduced two-bottle choice drinking in male and female mice that had consumed ethanol for 3 weeks and transiently reduced two-bottle choice, every-other-day drinking in male mice. A33 did not alter ethanol drinking in either procedure. Neither drug altered binge-like ethanol consumption or blood ethanol clearance. Thus, D159687 produced behavioral effects similar to apremilast, although it produced a more transient and smaller reduction in drinking. These results indicate that PDE4D inhibition contributes to apremilast's ability to reduce ethanol drinking, whereas PDE4B inhibition is not involved.
阿普米司特是一种磷酸二酯酶 (PDE) 4 型抑制剂，对 PDE4A-D 亚型无选择性。它通过蛋白激酶 A (PKA) 对特定 GABA 受体亚基的磷酸化调节乙醇和 GABA 能反应，并对野生型和 GABAβ3-S408/409A 敲入小鼠的乙醇诱导的共济失调有相反的影响。我们假设这些不同的影响是由于对不同 PDE4 亚型的优先作用。为了验证这一假设，我们比较了选择性 PDE4 抑制剂对雄性和雌性 C57BL/6J 小鼠对乙醇和 GABA 能药物反应的影响。PDE4B 抑制剂 A33 加速了乙醇和地西泮诱导的共济失调的恢复，但没有改变丙泊酚诱导的共济失调。PDE4D 抑制剂 D159687 加速了地西泮诱导的共济失调的恢复，但延长了乙醇和丙泊酚诱导的共济失调的恢复。A33 缩短了乙醇的镇静催眠作用，而 D159687 延长了。两种药物都缩短了地西泮的镇静催眠作用。A33 和 D159687 的调节作用完全被 PKA 抑制剂 H89 所阻止。只有 D159687 预防了急性功能性耐受乙醇诱导的共济失调的发展。D159687 短暂地减少了雄性和雌性小鼠在饮用 3 周乙醇后的双瓶选择饮酒，短暂地减少了雄性小鼠的双瓶选择，每隔一天饮酒。A33 没有改变这两种程序中的乙醇饮酒。两种药物都没有改变 binge-like 乙醇消耗或血液乙醇清除率。因此，尽管 D159687 产生的饮酒减少更为短暂和较小，但它产生了类似于阿普米司特的行为效应。这些结果表明，PDE4D 抑制有助于阿普米司特减少乙醇的摄入，而 PDE4B 抑制则没有参与。
