Department of Molecular Pharmacology and Experimental Therapeutics (S.-I.H., L.P., D.-S.C.), Neuroscience Program (D.-S.C.), and Department of Psychiatry and Psychology (D.-S.C.), Mayo Clinic College of Medicine, Rochester, Minnesota; and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (Y.C.).
Department of Molecular Pharmacology and Experimental Therapeutics (S.-I.H., L.P., D.-S.C.), Neuroscience Program (D.-S.C.), and Department of Psychiatry and Psychology (D.-S.C.), Mayo Clinic College of Medicine, Rochester, Minnesota; and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (Y.C.)
J Pharmacol Exp Ther. 2019 Nov;371(2):260-267. doi: 10.1124/jpet.119.261529. Epub 2019 Aug 13.
Adenosine signaling is associated with ethanol-related behaviors. We previously found that adenosine A receptor (AR) activation dampens ethanol drinking behaviors in equilibrative nucleoside transporter 1 (ENT1) knockout mice, and AR inhibition augments reward-seeking behavior in wild-type mice. The novel adenosine analog 6-(4-hydroxybenzyl)-adenosine (NHBA), which is isolated from the rhizomes of , activates AR and inhibits ENT1. Here, we examined the effects of NHBA on ethanol drinking in the two-bottle choice test and operant ethanol seeking behaviors. We selected mice exhibiting high ethanol drinking behavior in the two-bottle choice test. NHBA (0.1 mg/kg, i.p.) reduced ethanol drinking behavior in a limited-access 3-hour drinking session in high-consumption ethanol drinking mice, and NHBA (0.1 mg/kg, i.p.) did not alter locomotor activity in the open-field test. Operant conditioning with 10% ethanol and 10% sucrose (10E10S) reward increased zone entries and time spent in the ethanol zone, while NHBA (0.1 mg/kg, i.p.) dampened ethanol zone preference in the Y-maze. Furthermore, NHBA (0.1 mg/kg, i.p.) devalued 10E10S and 10% ethanol (10E) reward after operant conditioning with 10E10S and 10E. Taken together, NHBA through AR activation and ENT1 modulation may dampen ethanol drinking and seeking behaviors, suggesting that NHBA is a potential therapeutic agent for treating alcohol use disorder. SIGNIFICANCE STATEMENT: Our work highlights that AR activation and ENT1 inhibition by a novel adenosine analog isolated from , 6-(4-hydroxybenzyl)-adenosine, decreases ethanol drinking and seeking behaviors. We suggest that NHBA is a potential therapeutic agent to treat alcohol use disorder.
腺苷信号与乙醇相关行为有关。我们之前发现，腺苷 A 受体 (AR) 的激活可抑制平衡核苷转运蛋白 1 (ENT1) 敲除小鼠的乙醇饮用量，而 AR 的抑制可增强野生型小鼠的觅奖行为。新型腺苷类似物 6-(4-羟苄基)-腺苷 (NHBA) 从 根茎中分离出来，可激活 AR 并抑制 ENT1。在此，我们研究了 NHBA 对双瓶选择测试和操作性乙醇寻求行为中乙醇饮用量的影响。我们选择在双瓶选择测试中表现出高乙醇饮用量的小鼠。NHBA（0.1mg/kg，ip）可减少高消耗乙醇饮用量小鼠在限时 3 小时饮酒期间的乙醇饮用量，并且 NHBA（0.1mg/kg，ip）在旷场测试中不改变运动活性。10%乙醇和 10%蔗糖（10E10S）奖励的操作性条件作用增加了区域进入次数和在乙醇区域中花费的时间，而 NHBA（0.1mg/kg，ip）可减弱 Y 迷宫中的乙醇区域偏好。此外，NHBA（0.1mg/kg，ip）在 10E10S 和 10E 操作性条件作用后降低了 10E10S 和 10%乙醇（10E）的奖励价值。总之，NHBA 通过激活 AR 和调节 ENT1 可能会抑制乙醇饮用量和觅酒行为，这表明 NHBA 可能是治疗酒精使用障碍的潜在治疗剂。
我们的工作强调，新型腺苷类似物 6-(4-羟苄基)-腺苷从 根茎中分离出来，通过激活 AR 和抑制 ENT1，可减少乙醇饮用量和觅酒行为。我们认为 NHBA 是一种潜在的治疗酒精使用障碍的药物。
