McMahon Lance R, Coop Andrew, France Charles P, Winger Gail, Woolverton William L
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Eur J Pharmacol. 2003 Apr 11;466(1-2):113-20. doi: 10.1016/s0014-2999(03)01486-9.
Metabolic precursors and prodrugs of gamma-hydroxybutyrate (GHB), including 1,4-butanediol (BDL) and gamma-butyrolactone (GBL), have sedative and anesthetic effects and might have positive reinforcing effects. BDL and GBL were evaluated using behavioral procedures that measure positive reinforcing effects and discriminative stimulus effects of drugs that modulate gamma-aminobutyric acid (GABA) at the GABA(A) receptor complex. One group of rhesus monkeys could respond for saline or the barbiturate methohexital (i.v.) in a self-administration paradigm. Two other groups of monkeys discriminated the barbiturate pentobarbital (i.g.) or the benzodiazepine midazolam (s.c.) from saline in a drug discrimination paradigm; another group of monkeys was treated with the benzodiazepine diazepam (5.6 mg/kg/day, p.o.) and discriminated the benzodiazepine antagonist flumazenil (s.c.) from vehicle. In self-administration experiments, methohexital and not BDL (0.1-3.2 mg/kg/injection) or GBL (0.1-3.2 mg/kg/injection) reliably maintained responding above saline levels. BDL and GBL, up to doses that suppressed responding, did not substitute for pentobarbital, midazolam or flumazenil. The onset of action for both drugs to decrease response rate was delayed (90 min for GBL and 150 min for BDL). These results suggest that any abuse-related effects of BDL and GBL are qualitatively different from the abuse-related effects of GABA(A) receptor modulators and further indicate that BDL and GBL do not have positive reinforcing effects in rhesus monkeys experienced with self-administration of a short-acting sedative-hypnotic.
γ-羟基丁酸（GHB）的代谢前体和前体药物，包括1,4-丁二醇（BDL）和γ-丁内酯（GBL），具有镇静和麻醉作用，且可能具有正向强化作用。使用行为程序对BDL和GBL进行了评估，这些程序用于测量在GABA(A)受体复合物处调节γ-氨基丁酸（GABA）的药物的正向强化作用和辨别刺激作用。一组恒河猴可以在自我给药范式中选择生理盐水或静脉注射巴比妥类药物美索比妥。另外两组猴子在药物辨别范式中区分口服巴比妥类药物戊巴比妥或皮下注射苯二氮䓬类药物咪达唑仑与生理盐水；另一组猴子接受苯二氮䓬类药物地西泮（5.6毫克/千克/天，口服）治疗，并区分皮下注射苯二氮䓬类拮抗剂氟马西尼与赋形剂。在自我给药实验中，美索比妥而非BDL（0.1 - 3.2毫克/千克/注射）或GBL（0.1 - 3.2毫克/千克/注射）能可靠地使反应维持在高于生理盐水水平。BDL和GBL在达到抑制反应的剂量之前，都不能替代戊巴比妥、咪达唑仑或氟马西尼。两种药物降低反应率的起效时间均延迟（GBL为90分钟，BDL为150分钟）。这些结果表明，BDL和GBL的任何与滥用相关的作用在性质上与GABA(A)受体调节剂的与滥用相关的作用不同，进一步表明BDL和GBL在经历过短效镇静催眠药自我给药的恒河猴中不具有正向强化作用。
