Kushner S A, Unterwald E M
Department of Psychiatry, New York University School of Medicine, NY 10016, USA.
Life Sci. 2001 Jul 20;69(9):1093-102. doi: 10.1016/s0024-3205(01)01203-6.
Results of numerous studies indicate that the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) modulates central dopamine systems, and that GABA(B) receptors may play a primary role in decreasing dopamine release. To determine if chronic cocaine administration alters the functional coupling of GABA(B) receptors to G-proteins in central dopamine systems, male F-344 rats received cocaine (15 mg/kg/injection) or saline three times a day at hourly intervals for fourteen consecutive days. Rats were decapitated one hour after the last injection and crude membrane preparations were made from the substantia nigra, caudate-putamen, ventral tegmental area, nucleus accumbens, and frontal cortex of individual rats. The ability of the specific GABA(B) receptor agonist baclofen to stimulate 35S-GTPgammaS binding in each of these regions was determined for individual animals. Additionally, baclofen-stimulated 35S-GTPgammaS binding in each of these regions in rats that received cocaine was compared to baclofen-stimulated 35S-GTPgammaS binding in rats that received control injections of saline. The EC50 of baclofen and maximal baclofen-stimulated 35S-GTPgammaS binding over basal levels were determined in each brain region in the saline group and in the cocaine group. Two-way ANOVA revealed a significant decrease in GABA(B) receptor-stimulated 35S-GTPgammaS binding in the ventral tegmental area of the cocaine group compared to the saline group. These data suggest that chronic exposure to cocaine decreases the functional coupling of GABA(B) receptors to G-proteins selectively in the ventral tegmental area. This finding may have implications in the augmented extracellular dopamine levels seen in the nucleus accumbens of rats that have been sensitized to cocaine.
大量研究结果表明，抑制性神经递质γ-氨基丁酸（GABA）可调节中枢多巴胺系统，且GABA（B）受体可能在减少多巴胺释放中起主要作用。为了确定长期给予可卡因是否会改变中枢多巴胺系统中GABA（B）受体与G蛋白的功能偶联，雄性F-344大鼠连续14天每天按每小时一次的间隔接受三次可卡因（15毫克/千克/注射）或生理盐水注射。在最后一次注射后1小时将大鼠断头，并从每只大鼠的黑质、尾状核-壳核、腹侧被盖区、伏隔核和额叶皮质制备粗制膜制剂。针对每只动物测定特异性GABA（B）受体激动剂巴氯芬刺激这些区域中35S-GTPγS结合的能力。此外，将接受可卡因注射的大鼠中这些区域的巴氯芬刺激的35S-GTPγS结合与接受生理盐水对照注射的大鼠中这些区域的巴氯芬刺激的35S-GTPγS结合进行比较。在生理盐水组和可卡因组的每个脑区中测定巴氯芬的半数有效浓度（EC50）以及巴氯芬刺激的35S-GTPγS结合相对于基础水平的最大结合量。双向方差分析显示，与生理盐水组相比，可卡因组腹侧被盖区中GABA（B）受体刺激的35S-GTPγS结合显著降低。这些数据表明，长期接触可卡因会选择性地降低腹侧被盖区中GABA（B）受体与G蛋白的功能偶联。这一发现可能与对可卡因敏感的大鼠伏隔核中细胞外多巴胺水平升高有关。
