TIME DEPENDENT EFFECTS OF ETHANOL ON CEREBRAL METABOLISM

就给药时间而言，乙醇的作用是双相的。随着血液中乙醇水平的上升，阳性强化发生得更早。随着这些水平的下降，抑郁和厌恶情绪占据主导地位。这种时间依赖性支持了乙醇在中枢神经系统中作用的多阶段观点，即乙醇在服用乙醇后，作为时间函数在独立的大脑系统中具有明显的作用。为了寻找乙醇引起不同神经系统随时间变化的证据，本提案将确定乙醇是否在给药后不同时间影响不同的神经底物，以及这些系统是否适应不同速率的慢性酒精暴露。脑图研究在这方面具有独特的贡献，因为它们同时确定整个大脑的活动水平。该实验室最近表明，乙醇对大鼠大脑功能活动的影响也是时间依赖的。在服用乙醇后，一组结构中的活性立即发生变化，随着血液中乙醇水平的下降，另一组完全不同的结构中的活性也发生了变化。因此，当浓度上升和下降时，不同的神经回路似乎削弱了乙醇的影响。拟议的研究将首先将我们之前在单一剂量下获得的结果扩展到一系列相关的剂量，以确定发生这两种脑能量代谢模式的剂量和时间条件。我们还提供了初步数据，表明在大鼠不同的大脑结构中，功能活动对慢性酒精的适应不同。因此，本研究还将确定血液乙醇曲线上升和下降阶段的局部神经活动如何随着长期接触乙醇而发生变化。这些发现将有助于支持耐受性概念的工作主体，该概念承认各种神经回路之间的集成活动对乙醇的时间依赖效应负责。

The effects of ethanol are biphasic with respect to administration time. Positive reinforcement occurs early as blood ethanol levels rise. As these levels fall, the depressant and aversive properties predominate. This time-dependency supports a multi-phasic view of ethanol's effects in the CNS in which ethanol has distinct actions within independent brain systems as a function of time after ethanol administration. Seeking evidence of ethanol-induced changes in disparate neural systems as a function of time, the present proposal will determine whether ethanol affects different neural substrates at different times after ethanol administration and whether these systems adapt to chronic ethanol exposure at different rates. Brain mapping studies are in a unique position to contribute significantly in this regard because they determine levels of activity throughout the brain simultaneously. This laboratory has recently shown that ethanol's effects on functional brain activity in the rat are also time-dependent. Activity was altered immediately after ethanol administration in one set of structures, and activity was altered in a completely different set of structures as blood ethanol levels fell. Therefore, it appears that different neural circuits subserve the effects of ethanol when concentrations are rising and falling. The proposed studies will first extend our previous findings obtained at a single dose to a range of relevant doses in order to establish the conditions of dose and time under which each of these two patterns of brain energy metabolism occur. We also present preliminary data which suggest that functional activity adapts differently to chronic ethanol in distinct sets of brain structures in the rat. Therefore, the present studies will also determine how regional neural activity along the rising and falling phases of the blood ethanol curve change in response to chronic exposure to ethanol. These finding swill contribute to the body of work that supports a concept of tolerance which recognizes that integrated activity among various neural circuits are responsible for the time-dependent effects of ethanol.