Nawata Yoko, Ooishi Rina, Nishioku Tsuyoshi, Yamaguchi Taku
Department of Pharmacology, Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan.
Department of Pharmacotherapeutics and Neuropsychopharmacology, Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan.
Behav Brain Res. 2024 Jan 5;456:114708. doi: 10.1016/j.bbr.2023.114708. Epub 2023 Oct 11.
Nalmefene, an analog to naltrexone, is an antagonist at the μ opioid receptor and a partial agonist at the κ opioid receptor. Both agents are approved for the treatment of alcohol use disorder and opioid addiction. Here, we evaluated the potential of nalmefene for treating psychostimulant dependence using a methamphetamine (METH) self-administration rat model. Rats were trained to press a lever for 0.02-mg intravenous METH infusions paired with drug-associated cues (light and tone) under a fixed ratio 1 schedule. After a 10-day METH self-administration acquisition phase, rats underwent extinction training. A reinstatement test was conducted after fulfilment of the extinction criterion under saline infusions. Re-exposure to METH-associated cues or a priming injection of METH (1.0 mg/kg, i.p.) significantly reinstated METH-seeking behaviors. Pretreatment with nalmefene (10 mg/kg, i.p.) immediately before reinstatement tests significantly attenuated the METH-seeking behaviors induced by both cues and METH priming injection. To investigate the mechanism of effect of nalmefene, we also tested the ability of a group II metabotropic glutamate receptors (mGluR2/3) antagonist, LY341495, to the ameliorating effects of nalmefene. Pretreatment with LY341495 (1.0 mg/kg, i.p.) before nalmefene administration antagonized the effect of nalmefene on reinstatement. LY341495 alone did not affect the reinstatement of lever pressing. We found that nalmefene attenuates METH-seeking behaviors during withdrawal, and this attenuation of reinstatement is mediated by the activation of mGluR2/3. The present findings suggest that nalmefene could decrease incentive motivation for drug use in psychostimulant dependence.
纳美芬是纳曲酮的类似物，是μ阿片受体拮抗剂和κ阿片受体部分激动剂。这两种药物均被批准用于治疗酒精使用障碍和阿片类药物成瘾。在此，我们使用甲基苯丙胺（METH）自我给药大鼠模型评估了纳美芬治疗精神兴奋剂依赖的潜力。大鼠经过训练，在固定比率1的时间表下，按压杠杆以静脉注射0.02毫克METH，并伴有与药物相关的线索（光和声）。在10天的METH自我给药获取阶段后，大鼠接受消退训练。在生理盐水注射下达到消退标准后进行复吸测试。重新暴露于与METH相关的线索或注射一次METH（1.0毫克/千克，腹腔注射）引发剂可显著恢复觅药行为。在复吸测试前立即腹腔注射纳美芬（10毫克/千克）可显著减弱线索和METH引发剂注射所诱导的觅药行为。为了研究纳美芬的作用机制，我们还测试了II组代谢型谷氨酸受体（mGluR2/3）拮抗剂LY341495对纳美芬改善作用的影响。在给予纳美芬之前腹腔注射LY341495（1.0毫克/千克）可拮抗纳美芬对复吸的作用。单独使用LY341495不影响杠杆按压的复吸。我们发现纳美芬在戒断期间减弱觅药行为，并且这种复吸减弱是由mGluR2/3的激活介导的。目前的研究结果表明，纳美芬可以降低精神兴奋剂依赖中药物使用的动机。
