Koek Wouter, Carter Lawrence P, Wu Huifang, Coop Andrew, France Charles P
Department of Psychiatry, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
Behav Pharmacol. 2006 May;17(3):239-47. doi: 10.1097/00008877-200605000-00005.
Pigeons trained to discriminate 0.1 mg/kg flumazenil, proposed as an in-vivo model to study interactions with diazepam-insensitive gamma-aminobutyric acid (GABA)A receptors, were tested with various GABAergic and non-GABAergic compounds. As a result of its pharmacological selectivity, the model was suitable for further examining previously reported flumazenil-like effects of gamma-hydroxybutyrate (GHB). Flumazenil and the GABAA negative modulator Ro 15-4513 produced 82-100% flumazenil-appropriate responding. Diazepam and the direct-acting GABAA agonists muscimol and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP) produced 38-64% flumazenil-appropriate responding. GHB, its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), and the GABAB agonists baclofen and SKF97541 produced 0-24% flumazenil-appropriate responding. Baclofen shifted the flumazenil dose-response curve to the right and down, possibly involving perceptual masking of the discriminative stimulus effects of flumazenil by agonist activity at GABAB receptors. These masking effects of baclofen were blocked by the GABAB antagonist CGP35348. When CGP35348 was given together with GHB to block its GABAB agonist effects, GHB did not produce flumazenil-appropriate responding. Conceivably, effects of GHB at non-GABAB receptors (e.g. diazepam-sensitive GABAA receptors and GHB receptors) may interfere with the expression of its flumazenil-like discriminative stimulus effects. The asymmetric substitution between GHB and flumazenil is consistent with the hypothesis that the discriminative stimulus effects of GHB consist of several components, not all of which are mimicked by flumazenil.
训练鸽子辨别0.1毫克/千克氟马西尼，该模型被提议作为一种体内模型来研究与地西泮不敏感的γ-氨基丁酸（GABA）A受体的相互作用，并使用各种GABA能和非GABA能化合物进行测试。由于其药理学选择性，该模型适合进一步研究先前报道的γ-羟基丁酸（GHB）的氟马西尼样效应。氟马西尼和GABAA负性调节剂Ro 15-4513产生了82%-100%与氟马西尼相符的反应。地西泮以及直接作用的GABAA激动剂蝇蕈醇和4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇（THIP）产生了38%-64%与氟马西尼相符的反应。GHB、其前体1,4-丁二醇（1,4-BD）和γ-丁内酯（GBL），以及GABAB激动剂巴氯芬和SKF97541产生了0%-24%与氟马西尼相符的反应。巴氯芬使氟马西尼剂量-反应曲线向右下方移动，可能是由于GABAB受体激动剂活性对氟马西尼辨别刺激效应的知觉掩盖。巴氯芬的这些掩盖效应被GABAB拮抗剂CGP35348阻断。当CGP35348与GHB一起给药以阻断其GABAB激动剂效应时，GHB未产生与氟马西尼相符的反应。可以想象，GHB在非GABAB受体（如对地西泮敏感的GABAA受体和GHB受体）上的作用可能会干扰其氟马西尼样辨别刺激效应的表达。GHB和氟马西尼之间的不对称替代与以下假设一致，即GHB的辨别刺激效应由几个成分组成，并非所有成分都能被氟马西尼模拟。
