Evidence for down-regulation of GABA receptors following long-term gamma-butyrolactone.

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.