Tietz E I, Chiu T H, Rosenberg H C
Department of Pharmacology, Medical College of Ohio, Toledo 43699.
Eur J Pharmacol. 1989 Aug 11;167(1):57-65. doi: 10.1016/0014-2999(89)90747-4.
GABA/benzodiazepine coupling was evaluated in 8 regions of rat brain by the ability of GABA to stimulate 0.5 nM [3H]flunitrazepam binding. Rats were treated acutely with diazepam (p.o) or chronically with flurazepam, offered in the drinking water for 4 weeks, and compared to a pair-handled vehicle-treated control group. Regional variations in GABA/benzodiazepine coupling were found in control membranes. GABA increased benzodiazepine binding maximally (40%) in cerebellum and medulla, and least (25%) in olfactory bulb. A significant decrease in the effect of GABA was found in cortex of chronically treated rats immediately after, but not 2 days following treatment. The Emax for GABA stimulation of [3H]flunitrazepam binding was significantly increased in medulla after acute treatment but was not altered after acute or chronic treatment in other brain areas evaluated. Treatment had no effect on the ability of bicuculline to inhibit [3H]flunitrazepam binding in cortex. Benzodiazepine/Cl- coupling in cortex or hippocampus of acutely and chronically treated rats, evaluated by the ability of Cl- to stimulate specific [3H]flunitrazepam binding, was not changed. The results support the hypothesis that a functional uncoupling of the benzodiazepine recognition site from the GABA receptor in cortex, but not from the anion recognition site, may play a role in tolerance development.
通过γ-氨基丁酸（GABA）刺激0.5 nM [³H]氟硝西泮结合的能力，在大鼠脑的8个区域评估了GABA/苯二氮䓬偶联。大鼠急性给予地西泮（口服）或慢性给予氟西泮（在饮用水中给予4周），并与成对处理的溶剂对照组进行比较。在对照膜中发现了GABA/苯二氮䓬偶联的区域差异。GABA使小脑和延髓中的苯二氮䓬结合增加最多（40%），而在嗅球中增加最少（25%）。在长期治疗的大鼠中，治疗后立即在皮质中发现GABA的作用显著降低，但治疗后2天未降低。急性治疗后，延髓中GABA刺激[³H]氟硝西泮结合的最大效应（Emax）显著增加，但在评估的其他脑区，急性或慢性治疗后均未改变。治疗对荷包牡丹碱抑制皮质中[³H]氟硝西泮结合的能力没有影响。通过氯离子刺激特异性[³H]氟硝西泮结合的能力评估，急性和慢性治疗大鼠的皮质或海马中的苯二氮䓬/氯离子偶联没有变化。这些结果支持这样的假设，即皮质中苯二氮䓬识别位点与GABA受体的功能性解偶联，但不是与阴离子识别位点的解偶联，可能在耐受性发展中起作用。
