Characterization of the Effects of Reuptake and Hydrolysis Inhibition on Interstitial Endocannabinoid Levels in the Brain: An in Vivo Microdialysis Study
Characterization of the Effects of Reuptake and Hydrolysis Inhibition on Interstitial Endocannabinoid Levels in the Brain: An in Vivo Microdialysis Study
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DOI：
10.1021/cn300036b
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发表时间：
2012-05-01
影响因子：
5
通讯作者：
Parsons, Loren H.
中科院分区：
文献类型：
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作者：
Wiskerke, Joost;Irimia, Cristina;Parsons, Loren H.
本实验采用体内微透析来表征常用的内源性大麻素清除抑制剂对大鼠脑内延髓核间质内源性大麻素水平的基础和去极化诱导的改变的影响。比较了靶向假定的内源性大麻素转运蛋白和水解酶（FAAH和MAGL）的化合物。转运蛋白抑制剂AM404适度增强去极化诱导的2-花生四烯酰甘油（2-AG）水平的增加，但不改变N-花生四烯酰乙醇酰胺（花生四烯酰胺，AEA）的水平。转运抑制剂UCM 707没有改变透析液中内源性大麻素的水平。FAAH抑制剂URB 597和PF-3845在去极化期间稳健地增加AEA水平，而不改变2-AG水平。MAGL抑制剂URB 602显著增强去极化诱导的2-AG增加，但不改变AEA水平。相比之下，MAGL抑制剂JZL 184在任何测试条件下都不改变2-AG或AEA水平。最后，双重FAAH/MAGL抑制剂JZL 195显着增强AEA和2-AG水平的去极化诱导的增加。与目前在大鼠中的观察结果相反，先前在小鼠中的工作已经证明了JZL 184诱导的去极化诱导的透析液2-AG增加的稳健增强。因此，为了进一步研究种属差异，在小鼠中进行了JZL 184、PF-3845和JZL 195的额外试验。与先前的报道一致，JZL 184显著增强去极化诱导的2-AG增加而不改变AEA水平。PF-3845和JZL 195在小鼠透析液中产生的特征与在大鼠中观察到的特征相当。这些发现证实，内源性大麻素清除抑制剂可以选择性地操纵大脑中的间质内源性大麻素水平。虽然PF-3845和JZL 195在大鼠和小鼠中产生相似的作用，但JZL 184疗效的实质性种属差异是明显的，这与先前的研究一致。
The present experiments employed in vivo microdialysis to characterize the effects of commonly used endocannabinoid clearance inhibitors on basal and depolarization-induced alterations in interstitial endocannabinoid levels in the nucleus accumbens of rat brain. Compounds targeting the putative endocannabinoid transporter and hydrolytic enzymes (FAAH and MAGL) were compared. The transporter inhibitor AM404 modestly enhanced depolarization-induced increases in 2-arachidonoyl glycerol (2-AG) levels but did not alter levels of N-arachidonoyl-ethanolamide (anandamide, AEA). The transport inhibitor UCM707 did not alter dialysate levels of either endocannabinoid. The FAAH inhibitors URB597 and PF-3845 robustly increased AEA levels during depolarization without altering 2-AG levels. The MAGL inhibitor URB602 significantly enhanced depolarization-induced increases in 2-AG, but did not alter AEA levels. In contrast, the MAGL inhibitor JZL184 did not alter 2-AG or AEA levels under any condition tested. Finally, the dual FAAH/MAGL inhibitor JZL195 significantly enhanced depolarization-induced increases in both AEA and 2-AG levels. In contrast to the present observations in rats, prior work in mice has demonstrated a robust JZL184-induced enhancement of depolarization-induced increases in dialysate 2-AG. Thus, to further investigate species differences, additional tests with JZL184, PF-3845, and JZL195 were performed in mice. Consistent with prior reports, JZL184 significantly enhanced depolarization-induced increases in 2-AG without altering AEA levels. PF-3845 and JZL195 produced profiles in mouse dialysates comparable to those observed in rats. These findings confirm that interstitial endocannabinoid levels in the brain can be selectively manipulated by endocannabinoid clearance inhibitors. While PF-3845 and JZL195 produce similar effects in both rats and mice, substantial species differences in JZL184 efficacy are evident, which is consistent with previous studies.