Valverius P, Hoffman P L, Tabakoff B
Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD 20852.
Adv Alcohol Subst Abuse. 1988;7(3-4):99-101. doi: 10.1300/J251v07n03_15.
Previous work showed that chronic ethanol ingestion by C57BL mice resulted in reduced stimulation of cerebral cortical adenylate cyclase (AC) activity by isoproterenol (ISO) and guanine nucleotides (GN). To investigate the mechanism of this change we have assessed the effect of chronic ethanol ingestion on agonist and antagonist binding to BAR in cerebral cortex (mainly beta 1-AR) and cerebellum (mainly beta 2-AR). C57BL mice were fed ethanol in a liquid diet for seven days and were withdrawn for various intervals. Agonist (ISO) binding data were best fit by a two-site model (high and low affinity states) in cortical membranes of control mice. GN induced conversion to a one site model (low affinity state). At the time of withdrawal, ISO binding data in cortical membranes were best fit by a one-site model even in the absence of GN. Antagonist binding was not affected. These results resemble those seen after heterologous desensitization, indicating "uncoupling" of receptor and AC. Control cerebellar ISO binding data were similar to cortical data. Chronic ethanol ingestion, however, did not produce data fit by a one site model in cerebellum. The affinity for ISO of the high affinity state of the BAR was significantly decreased at the time of withdrawal. ISO-stimulated AC-activity in cerebellar membranes was not affected by chronic ethanol ingestion, indicating that, in contrast to cerebral cortex, the cerebellar BAR was not uncoupled from AC.
先前的研究表明，C57BL小鼠长期摄入乙醇会导致异丙肾上腺素（ISO）和鸟嘌呤核苷酸（GN）对大脑皮质腺苷酸环化酶（AC）活性的刺激作用减弱。为了研究这种变化的机制，我们评估了长期摄入乙醇对大脑皮质（主要是β1-肾上腺素能受体）和小脑（主要是β2-肾上腺素能受体）中激动剂和拮抗剂与β-肾上腺素能受体（BAR）结合的影响。给C57BL小鼠喂食含乙醇的液体饲料7天，然后在不同时间段撤去乙醇。在对照小鼠的大脑皮质膜中，激动剂（ISO）结合数据最适合用双位点模型（高亲和力和低亲和力状态）来拟合。GN诱导其转变为一位点模型（低亲和力状态）。撤去乙醇时，即使在没有GN的情况下，大脑皮质膜中的ISO结合数据也最适合用一位点模型来拟合。拮抗剂结合不受影响。这些结果与异源脱敏后观察到的结果相似，表明受体与AC发生了“解偶联”。对照小鼠小脑的ISO结合数据与大脑皮质的数据相似。然而，长期摄入乙醇并未使小脑的数据适合用一位点模型来拟合。撤去乙醇时，BAR高亲和力状态对ISO的亲和力显著降低。小脑膜中ISO刺激的AC活性不受长期摄入乙醇的影响，这表明与大脑皮质不同，小脑的BAR与AC并未解偶联。
