Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
Molecular Targets and Medications Discovery Program, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
Neuropharmacology. 2018 Mar 15;131:96-103. doi: 10.1016/j.neuropharm.2017.12.006. Epub 2017 Dec 5.
Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R-MOD and compounds that are derived from modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R-MOD and four novel modafinil-derived ligands with increased DAT affinity (JJC8-016, JJC8-088, JJC8-089, and JJC8-091) on intravenous (i.v.) METH self-administration in rats that were allowed short access (ShA; 1 h) or long access (LgA; 6 h) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA and LgA rats (in the 1st hour only). JJC8-091 and JJC8-016 decreased METH self-administration in both ShA and LgA rats. JJC8-089 decreased METH self-administration in LgA rats only, whereas JJC8-088 had no effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorders and suggest several novel compounds as candidate drugs.
甲基苯丙胺（METH）是一种高度成瘾的毒品，但目前尚无治疗 METH 使用障碍的药理学方法。与 METH 类似，促觉醒药物（R）-莫达非尼（R-MOD）与多巴胺转运体（DAT）结合。与 METH 不同，R-MOD 不是 DAT 转运的底物，滥用潜力低。我们假设非典型 DAT 抑制剂 R-MOD 和源自莫达非尼的化合物通过降低 METH 在 DAT 上的作用来减少 METH 的摄入。我们测试了系统注射 R-MOD 和四种新型高 DAT 亲和力的莫达非尼衍生配体（JJC8-016、JJC8-088、JJC8-089 和 JJC8-091）对允许短时间（ShA；1 小时）或长时间（LgA；6 小时）接触药物的大鼠静脉内（i.v.）METH 自我给药的影响。ShA 大鼠在各次试验中表现出稳定的 METH 摄入量，而 LgA 大鼠则表现出药物摄入量的增加。R-MOD 减少了 ShA 和 LgA 大鼠的 METH 自我给药（仅在第 1 小时）。JJC8-091 和 JJC8-016 减少了 ShA 和 LgA 大鼠的 METH 自我给药。JJC8-089 仅减少了 LgA 大鼠的 METH 自我给药，而 JJC8-088 对 ShA 或 LgA 大鼠的 METH 自我给药均无影响。这些发现支持非典型 DAT 抑制剂治疗 METH 使用障碍的潜力，并提示几种新型化合物作为候选药物。
