Koek Wouter, Mercer Susan L, Coop Andrew, France Charles P
Department of Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 7792, San Antonio, TX 78229-3900, USA.
J Pharmacol Exp Ther. 2009 Sep;330(3):876-83. doi: 10.1124/jpet.109.151845. Epub 2009 Jun 29.
Gamma-hydroxybutyrate (GHB) is used therapeutically and recreationally. The mechanism by which GHB produces its therapeutic and recreational effects is not entirely clear, although GABA(B) receptors seem to play an important role. This role could be complex, because there are indications that different GABA(B) receptor mechanisms mediate the effects of GHB and the prototypical GABA(B) receptor agonist baclofen. To further explore possible differences in underlying GABA(B) receptor mechanisms, the present study examined the effects of GHB and baclofen on operant responding and their antagonism by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348). Pigeons were trained to peck a key for access to food during response periods that started at different times after the beginning of the session. In these pigeons, GHB, its precursor gamma-butyrolactone (GBL), and the GABA(B) receptor agonists baclofen and 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF97541) decreased the rate of responding in a dose- and time-dependent manner. CGP35348 shifted the dose-response curve of each agonist to the right, but the magnitude of the shift differed among the agonists. Schild analysis yielded a pA(2) value of CGP35348 to antagonize GHB and GBL [i.e., 3.9 (3.7-4.2)] that was different (P = 0.0011) from the pA(2) value to antagonize baclofen and SKF97541 [i.e., 4.5 (4.4-4.7)]. This finding is further evidence that the GABA(B) receptor mechanisms mediating the effects of GHB and prototypical GABA(B) receptor agonists are not identical. A better understanding of the similarities and differences between these mechanisms, and their involvement in the therapeutic effects of GHB and baclofen, could lead to more effective medications with fewer adverse effects.
γ-羟基丁酸（GHB）用于治疗和消遣。尽管γ-氨基丁酸B（GABA(B)）受体似乎起着重要作用，但GHB产生其治疗和消遣作用的机制尚不完全清楚。这个作用可能很复杂，因为有迹象表明不同的GABA(B)受体机制介导了GHB和典型的GABA(B)受体激动剂巴氯芬的作用。为了进一步探究潜在的GABA(B)受体机制的可能差异，本研究考察了GHB和巴氯芬对操作性反应的影响以及GABA(B)受体拮抗剂3-氨基丙基（二乙氧基甲基）次膦酸（CGP35348）对它们的拮抗作用。训练鸽子在会话开始后不同时间开始的反应期内啄击按键以获取食物。在这些鸽子中，GHB、其前体γ-丁内酯（GBL）以及GABA(B)受体激动剂巴氯芬和盐酸3-氨基丙基（甲基）次膦酸（SKF97541）以剂量和时间依赖性方式降低反应速率。CGP35348使每种激动剂的剂量-反应曲线右移，但各激动剂的右移幅度不同。Schild分析得出CGP35348拮抗GHB和GBL的pA(2)值[即3.9（3.7 - 4.2）]，与拮抗巴氯芬和SKF97541的pA(2)值[即4.5（4.4 - 4.7）]不同（P = 0.0011）。这一发现进一步证明介导GHB和典型GABA(B)受体激动剂作用的GABA(B)受体机制并不相同。更好地理解这些机制之间的异同，以及它们在GHB和巴氯芬治疗作用中的参与情况，可能会带来更有效且副作用更少的药物。
