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. 2020 Nov 1;178:108220. doi: 10.1016/j.neuropharm.2020.108220. Epub 2020 Jul 29.
Phosphodiesterase type 4 (PDE4) inhibitors prevent hydrolysis of cyclic adenosine monophosphate and increase protein kinase A (PKA)-mediated phosphorylation. PDE4 inhibitors also regulate responses to ethanol and GABAergic drugs. We investigated mechanisms by which the PDE4 inhibitor, apremilast, regulates acute effects of ethanol and GABAergic drugs in male and female mice. Apremilast prolonged the sedative-hypnotic effects of gaboxadol, zolpidem, and propofol but did not alter etomidate effects, and unexpectedly shortened the sedative-hypnotic effects of diazepam. Apremilast prolonged rotarod ataxia induced by zolpidem, propofol, and loreclezole, shortened recovery from diazepam, but had no effect on ataxia induced by gaboxadol or etomidate. The PKA inhibitor H-89 blocked apremilast's ability to prolong the sedative-hypnotic effects of ethanol, gaboxadol, and propofol and to prolong ethanol- and propofol-induced ataxia. H-89 also blocked apremilast's ability to shorten the sedative-hypnotic and ataxic effects of diazepam. The β1-specific antagonist, salicylidene salicylhydrazide (SCS), produced faster recovery from ethanol- and diazepam-induced ataxia, but did not alter propofol- or etomidate-induced ataxia. SCS shortened the sedative-hypnotic effects of ethanol and diazepam but not of propofol. In Xenopus oocytes, a phosphomimetic (aspartate) mutation at the PKA phosphorylation site in β1 subunits decreased the maximal GABA current in receptors containing α1 or α3, but not α2 subunits. In contrast, phosphomimetic mutations at PKA sites in β3 subunits increased the maximal GABA current in receptors containing α1 or α2, but not α3 subunits. The GABA potency and allosteric modulation by ethanol, propofol, etomidate, zolpidem, flunitrazepam, or diazepam were not altered by these mutations. We propose a model whereby apremilast increases PKA-mediated phosphorylation of β1-and β3-containing GABA receptors and selectively alters acute tolerance to ethanol and GABAergic drugs.
磷酸二酯酶 4（PDE4）抑制剂可防止环磷酸腺苷单磷酸的水解，并增加蛋白激酶 A（PKA）介导的磷酸化。PDE4 抑制剂还可调节乙醇和 GABA 能药物的反应。我们研究了 PDE4 抑制剂阿普司特在雄性和雌性小鼠中调节乙醇和 GABA 能药物急性作用的机制。阿普司特延长了加巴喷丁、唑吡坦和异丙酚的镇静催眠作用，但没有改变依托咪酯的作用，出人意料的是，它缩短了地西泮的镇静催眠作用。阿普司特延长了唑吡坦、异丙酚和洛雷佐尔引起的旋转棒共济失调，缩短了地西泮的恢复时间，但对加巴喷丁或依托咪酯引起的共济失调没有影响。PKA 抑制剂 H-89 阻断了阿普司特延长乙醇、加巴喷丁和异丙酚的镇静催眠作用以及延长乙醇和异丙酚引起的共济失调的能力。H-89 还阻断了阿普司特缩短地西泮的镇静催眠和共济失调作用的能力。β1 特异性拮抗剂水杨酰水杨醛腙（SCS）使乙醇和地西泮引起的共济失调恢复更快，但没有改变异丙酚或依托咪酯引起的共济失调。SCS 缩短了乙醇和地西泮的镇静催眠作用，但不缩短异丙酚的镇静催眠作用。在非洲爪蟾卵母细胞中，β1 亚基 PKA 磷酸化位点的磷酸模拟（天冬氨酸）突变降低了包含α1 或α3 但不包含α2 亚基的受体中的最大 GABA 电流。相比之下，β3 亚基 PKA 位点的磷酸模拟突变增加了包含α1 或α2 但不包含α3 亚基的受体中的最大 GABA 电流。这些突变并没有改变 GABA 的效力和乙醇、异丙酚、依托咪酯、唑吡坦、氟硝西泮或地西泮的变构调节。我们提出了一个模型，即阿普司特增加了β1-和β3-包含 GABA 受体的 PKA 介导的磷酸化，并选择性地改变了对乙醇和 GABA 能药物的急性耐受。
