Carai Mauro A M, Lobina Carla, Maccioni Paola, Cabras Claudia, Colombo Giancarlo, Gessa Gian Luigi
CNR Institute of Neuroscience, Cagliari, Italy.
J Pharmacol Sci. 2008 Feb;106(2):199-207. doi: 10.1254/jphs.fp0071487. Epub 2008 Feb 9.
The endogenous brain constituent, gamma-hydroxybutyric acid (GHB), as well as its prodrug, gamma-butyrolactone (GBL), have recently gained interest in the drug addiction field due to their abuse potential and fatalities caused by overdose. It is known that GHB has two sites of actions: the gamma-aminobutyric acid(B) (GABA(B)) receptor and a specific-GHB binding site. The present study was designed to extend to GBL the investigations on the contribution of the GABA(B) receptor and the specific-GHB binding site to its in vivo effects. To this aim, DBA mice were pretreated either with GABA(B)-receptor antagonists, (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) and (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), or a putative antagonist of the specific-GHB binding site, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382), prior to the administration of doses of GBL that induced hypothermia, motor-incoordination (measured as motor-impairment at the Rota-Rod task), and sedation/hypnosis. The capability of SCH 50911 and NCS-382 to protect against GBL-induced lethality was also investigated. Pretreatment with either GABA(B)-receptor antagonist completely prevented GBL-induced hypothermia, motor-incoordination, and sedation /hypnosis. SCH 50911 also provided complete protection against GBL-associated lethality. Vice versa, NCS-382 failed to exert any antagonistic or protective effect. These results suggest that the in vivo GBL effects tested in the present study are mediated by activation of the GABA(B) receptor.
内源性脑成分γ-羟基丁酸（GHB）及其前体药物γ-丁内酯（GBL），由于其滥用潜力和过量使用导致的死亡事件，最近在药物成瘾领域引起了关注。已知GHB有两个作用位点：γ-氨基丁酸B（GABA(B)）受体和一个特异性GHB结合位点。本研究旨在将关于GABA(B)受体和特异性GHB结合位点对其体内效应的贡献的研究扩展到GBL。为此，在给予诱导体温过低、运动不协调（通过转棒试验测量运动障碍）和镇静/催眠的GBL剂量之前，用GABA(B)受体拮抗剂（3-氨丙基）（二乙氧基甲基）次膦酸（CGP 35348）和（2S）（+）-5,5-二甲基-2-吗啉乙酸（SCH 50911）或特异性GHB结合位点的假定拮抗剂6,7,8,9-四氢-5-羟基-5H-苯并环庚-6-亚基乙酸（NCS-382）预处理DBA小鼠。还研究了SCH 50911和NCS-382预防GBL诱导的致死性的能力。用任何一种GABA(B)受体拮抗剂预处理均可完全预防GBL诱导的体温过低、运动不协调和镇静/催眠。SCH 50911还提供了针对GBL相关致死性的完全保护。反之，NCS-382未能发挥任何拮抗或保护作用。这些结果表明，本研究中测试的GBL体内效应是由GABA(B)受体的激活介导的。
