Department of Pharmacology, Faculty of Pharmaceutical Science, Nagasaki International University, Nagasaki, Japan.
Int J Neuropsychopharmacol. 2019 Feb 1;22(2):165-172. doi: 10.1093/ijnp/pyy086.
Methamphetamine is a highly addictive psychostimulant with reinforcing properties. Our laboratory previously found that Δ8-tetrahydrocannabinol, an exogenous cannabinoid, suppressed the reinstatement of methamphetamine-seeking behavior. The purpose of this study was to determine whether the elevation of endocannabinoids modulates the reinstatement of methamphetamine-seeking behavior and emotional changes in methamphetamine self-administered rats.
Rats were tested for the reinstatement of methamphetamine-seeking behavior following methamphetamine self-administration and extinction. The elevated plus-maze test was performed in methamphetamine self-administered rats during withdrawal. We investigated the effects of JZL184 and URB597, 2 inhibitors of endocannabinoid hydrolysis, on the reinstatement of methamphetamine-seeking and anxiety-like behaviors.
JZL184 (32 and 40 mg/kg, i.p.), an inhibitor of monoacylglycerol lipase, significantly attenuated both the cue- and stress-induced reinstatement of methamphetamine-seeking behavior. Furthermore, URB597 (3.2 and 10 mg/kg, i.p.), an inhibitor of fatty acid amide hydrolase, attenuated only cue-induced reinstatement. AM251, a cannabinoid CB1 receptor antagonist, antagonized the attenuation of cue-induced reinstatement by JZL184 but not URB597. Neither JZL184 nor URB597 reinstated methamphetamine-seeking behavior when administered alone. In the elevated plus-maze test, rats that were in withdrawal from methamphetamine self-administration spent less time in the open arms. JZL184 ameliorated the decrease in time spent in the open arms.
We showed that JZL184 reduced both the cue- and stress-induced reinstatement of methamphetamine-seeking and anxiety-like behaviors in rats that had self-administered methamphetamine. It was suggested that a decrease in 2-arachidonoylglycerol in the brain could drive the reinstatement of methamphetamine-seeking and anxiety-like behaviors.
甲基苯丙胺是一种具有强化作用的高度成瘾性精神兴奋剂。我们实验室之前发现，外源性大麻素 Δ8-四氢大麻酚抑制了甲基苯丙胺觅药行为的复燃。本研究的目的是确定内源性大麻素的升高是否调节了甲基苯丙胺觅药行为的复燃和甲基苯丙胺自我给药大鼠的情绪变化。
在甲基苯丙胺自我给药和消退后，对大鼠进行了甲基苯丙胺觅药行为的复燃测试。在戒断期间，在甲基苯丙胺自我给药大鼠中进行高架十字迷宫测试。我们研究了 2 种内源性大麻素水解抑制剂 JZL184 和 URB597 对甲基苯丙胺觅药和焦虑样行为复燃的影响。
JZL184（32 和 40mg/kg，腹腔注射），一种单酰基甘油脂肪酶抑制剂，显著减弱了线索和应激诱导的甲基苯丙胺觅药行为的复燃。此外，URB597（3.2 和 10mg/kg，腹腔注射），一种脂肪酸酰胺水解酶抑制剂，仅减弱了线索诱导的复燃。大麻素 CB1 受体拮抗剂 AM251 拮抗了 JZL184 对线索诱导复燃的抑制作用，但不拮抗 URB597。JZL184 和 URB597 单独给药均未复燃甲基苯丙胺觅药行为。在高架十字迷宫测试中，戒断甲基苯丙胺自我给药的大鼠在开放臂中花费的时间更少。JZL184 改善了在开放臂中花费的时间减少。
我们表明，JZL184 减少了大鼠中甲基苯丙胺觅药和焦虑样行为的线索和应激诱导复燃。这表明大脑中 2-花生四烯酸甘油的减少可能导致了甲基苯丙胺觅药和焦虑样行为的复燃。
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