CENTRAL NERVOUS SYSTEM GLUTAMATE AND C-FOS MRNA IN ALCOHOL WITHDRAWAL

通过受体激活或离子流的变化激活脑细胞， 导致某些关键基因的快速和瞬时表达，例如 c-fos基因，能够控制和协调 大量依赖基因的转录。 这种改变的基因 表达可能是正常的，以及病理生理的，长期的， 细胞功能的变化。 我们已经绘制了c-fos基因在大鼠大脑中的表达， 中毒和戒断，并确定了几个大脑结构， 其表达在酒精戒断期间增加。 我们有 结果表明，在大鼠海马CA 1区，c-fos mRNA的区域性表达， 酒精戒断可以通过急性给药 N-甲基-D-天冬氨酸（NMDA）和立体特异性阻断的NMDA 受体/离子载体阻断剂MK-801。 我们还证明了 谷氨酸（NMDA受体的内源性配体），而不是其他 兴奋性和抑制性氨基酸假定的神经递质，是 在酒精戒断过程中大脑中增加。 目前的研究集中在表征 酒精戒断过程中c-fos mRNA表达增加。 在 此外，我们正在开发和筛选其他第二代DNA探针， 信使依赖性基因，可能表现出改变表达过程中， 酒精中毒或戒断。

Activation of brain cells by receptor activation or changes in ion flux can result in the rapid and transient expression of certain key genes, such as the c-fos gene, which are capable of controlling and orchestrating the transcription of a large number of dependent genes. Such altered gene expression may underlie normal, as well as pathophysiological, long term changes in cell function. We have mapped the expression of the c-fos gene in rat brain during alcohol intoxication and withdrawal and have identified several brain structures in which expression is increased during alcohol withdrawal. We have demonstrated that the regional expression of c-fos mRNA observed during alcohol withdrawal can be mimicked by acute administration of N-methyl-D-aspartic acid (NMDA) and stereospecifically blocked by the NMDA receptor/ionophore blocker, MK-801. We have also demonstrated that levels of glutamate (an endogenous ligand for NMDA receptors), but not other excitatory and inhibitory amino acid putative neurotransmitters, are increased in the brain during alcohol withdrawal. Current research is focused on pharmacologically characterizing the increased expression of c-fos mRNA observed during alcohol withdrawal. In addition we are developing and screening DNA probes for other second messenger-dependent genes which may exhibit altered expression during alcohol intoxication or withdrawal.