Carter Lawrence P, Wu Huifang, Chen Weibin, Cruz Christopher M, Lamb R J, Koek Wouter, Coop Andy, France Charles P
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
J Pharmacol Exp Ther. 2004 Jan;308(1):182-8. doi: 10.1124/jpet.103.058909. Epub 2003 Oct 20.
Gamma-hydroxybutyrate (GHB), a metabolite of gamma-aminobutyric acid (GABA), is an increasingly popular drug of abuse and was recently approved for the treatment of narcolepsy (Xyrem). GHB and GABA receptors have been implicated in mediating effects of GHB; however, the relative importance of each of these receptors is unclear. This study evaluated the effects of selective antagonists in combination with GHB and related compounds on schedule-controlled responding. Eight male Sprague-Dawley rats responded under a fixed-ratio schedule of food presentation. Cumulative dose-effect curves were generated and ED50 values calculated to evaluate the relative potency at decreasing responding. The rank-order potency was as follows: diazepam = baclofen > gamma-butyrolactone (GBL) > 1,4-butanediol (1,4-BDL) = GHB. All compounds decreased responding 20 min after administration. The duration of action of diazepam, GHB, and GBL was shorter than that of 1,4-BDL and baclofen. p-3-Aminopropyl-p-diethoxymethyl phosphinic acid (CGP 35348) antagonized the rate-decreasing effects of baclofen and not GHB; flumazenil antagonized the effects of diazepam and not GHB. The GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) did not attenuate the rate-decreasing effects of GHB, baclofen, or diazepam; larger doses of NCS-382 further decreased rate of responding when given in combination with each of these compounds. These studies show that GBL, 1,4-BDL, and GHB differ significantly in potency and duration of action. The ability of CGP 35348 to antagonize the rate-decreasing effects of baclofen may be limited by the involvement of multiple GABAB receptor subtypes and the lack of antagonism of GHB by NCS-382 may be due to its own GHB-like effects.
γ-羟基丁酸（GHB）是γ-氨基丁酸（GABA）的一种代谢产物，是一种越来越流行的滥用药物，最近被批准用于治疗发作性睡病（Xyrem）。GHB和GABA受体被认为介导了GHB的作用；然而，这些受体各自的相对重要性尚不清楚。本研究评估了选择性拮抗剂与GHB及相关化合物联合使用对按计划控制反应的影响。八只雄性Sprague-Dawley大鼠在固定比例的食物呈现计划下做出反应。生成累积剂量-效应曲线并计算ED50值，以评估降低反应时的相对效力。效力顺序如下：地西泮 = 巴氯芬 > γ-丁内酯（GBL）> 1,4-丁二醇（1,4-BDL）= GHB。所有化合物在给药后20分钟均降低了反应。地西泮、GHB和GBL的作用持续时间短于1,4-BDL和巴氯芬。p-3-氨丙基-p-二乙氧基甲基次膦酸（CGP 35348）拮抗巴氯芬的降低速率作用，而不拮抗GHB；氟马西尼拮抗地西泮的作用，而不拮抗GHB。GHB受体拮抗剂（2E）-（5-羟基-5,7,8,9-四氢-6H-苯并[a][7]环壬烯-6-亚基）乙酸（NCS-382）并未减弱GHB、巴氯芬或地西泮的降低速率作用；与这些化合物中的每一种联合使用时，较大剂量的NCS-382进一步降低了反应速率。这些研究表明，GBL、1,4-BDL和GHB在效力和作用持续时间上有显著差异。CGP 35348拮抗巴氯芬降低速率作用的能力可能受到多种GABAB受体亚型参与的限制，而NCS-382缺乏对GHB的拮抗作用可能是由于其自身类似GHB的作用。
