TIME DEPENDENT EFFECTS OF ETHANOL ON CEREBRAL METABOLISM

乙醇的作用在给药时间上是双相的。当血液中乙醇含量升高时，正强化就会提早发生。随着这些水平的下降，抑制和厌恶的性质占主导地位。这种时间依赖性支持乙醇对中枢神经系统影响的多相观点，其中乙醇在独立的脑系统中作为乙醇给药后时间的函数具有不同的作用。为了寻找乙醇诱导不同神经系统随时间变化的证据，本研究将确定乙醇是否在给药后的不同时间影响不同的神经基质，以及这些系统是否以不同的速率适应慢性乙醇暴露。大脑图谱研究在这方面的贡献是独一无二的，因为它们同时确定了整个大脑的活动水平。这个实验室最近表明，乙醇对大鼠大脑功能活动的影响也是有时间依赖性的。一组结构的活性在给药后立即改变，而另一组完全不同的结构的活性随着血液乙醇水平的下降而改变。因此，当乙醇浓度上升和下降时，似乎有不同的神经回路在起作用。拟议的研究将首先将我们以前在单一剂量下获得的发现扩展到一系列相关剂量，以便确定这两种模式的大脑能量代谢发生的剂量和时间条件。我们还提供了初步数据，表明在大鼠不同的脑结构中，功能活动对慢性乙醇的适应不同。因此，目前的研究还将确定沿血液乙醇曲线上升和下降阶段的区域神经活动如何随慢性暴露于乙醇而变化。这些发现将有助于支持耐受性概念的研究，该概念认识到各种神经回路之间的综合活动是乙醇的时间依赖性效应的原因。

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.