Gianutsos G, Suzdak P D
Naunyn Schmiedebergs Arch Pharmacol. 1984 Nov;328(1):62-8. doi: 10.1007/BF00496108.
Long-term oral administration (12 weeks) of gamma-butyrolactone (GBL) to mice resulted in pharmacological and neurochemical changes which may be interpreted as a decrease in GABA-mediated synaptic activity. The depression in motor activity produced by the GABA-mimetic muscimol was reduced following long-term GBL. The binding of GABA to its putative receptor was reduced in the GBL group as evidenced by a decrease in the Bmax in the cerebral cortex, cerebellum, and striatum, but not in the hippocampus. No difference in the concentration of GABA was observed between the two groups. However, the reduction in GABA accumulation which normally results after an acute injection of GBL (560 mg/kg) was markedly attenuated in the mice receiving 12 weeks of GBL. Similarly, the muscimol-induced alteration in the concentration of DOPAC, a dopamine metabolite, was also reduced in the GBL group. These results, illustrating tolerance to the pharmacological effects of GBL and muscimol and in vitro evidence of a reduction in GABA binding sites, suggest that long-term exposure to GBL is accompanied by an alteration in GABA receptors and provides a possible mechanism for the tolerance to GBL-induced changes in dopamine.
对小鼠长期口服γ-丁内酯（GBL）12周会导致药理学和神经化学变化，这些变化可能被解释为GABA介导的突触活动减少。长期给予GBL后，GABA模拟物蝇蕈醇所产生的运动活动抑制作用减弱。GBL组中GABA与其假定受体的结合减少，这在大脑皮层、小脑和纹状体中Bmax降低得到证明，但在海马体中未出现这种情况。两组之间未观察到GABA浓度的差异。然而，在接受12周GBL的小鼠中，急性注射GBL（560mg/kg）后通常会出现的GABA积累减少明显减弱。同样，GBL组中蝇蕈醇诱导的多巴胺代谢物3,4-二羟基苯乙酸（DOPAC）浓度变化也减少。这些结果表明对GBL和蝇蕈醇的药理作用产生耐受性，以及体外实验证明GABA结合位点减少，提示长期接触GBL伴随着GABA受体的改变，并为对GBL诱导的多巴胺变化产生耐受性提供了一种可能的机制。
