CHRONIC BARBITURATES - CNS BIOCHEMISTRY

我们最近观察到2-氨基-7-膦酰基庚酸 兴奋性氨基酸（EAA）拮抗剂， 选择性地为N-甲基-D-天冬氨酸（NMDA）受体，实际上 消除了自发性抽搐， 巴比妥酸盐依赖大鼠突然停用巴比妥。 这些抽搐代表了最严重的行为 这种可能危及生命的综合征的表现， 据估计比阿片类药物戒断更为严重。 最重要的是，这些数据提供了第一个直接证据， EAA通路参与了这一表现， 禁欲综合症 这次更新的主要目标是 一项建议是确定含有NMDA的大脑区域， 受体参与传播这些禁欲相关 抽搐 Alzet微型泵连接到脑内套管 将APH注入大脑特定区域 对自发性惊厥的改善作用 测定 杏仁核（AMY）和海马体（HIPPO）， 超过50%的抽搐似乎 起源以及NMDA受体浓度的主要位点， 将是最初调查的区域。 其他实验将 探索慢性巴比妥酸盐的潜在关键参与- 在EAA途径中诱导适应， 巴比妥类药物依赖 特别是，我们将广泛 海人藻酸盐致巴比妥类药物高反应性研究 依赖的老鼠 总的来说，这些研究将测试 假设EAA途径在发育中起关键作用， 巴比妥类药物依赖的症状

We have recently observed that 2-amino-7-phosphonoheptanoic acid (APH), a excitatory amino acid (EAA) antagonist with selectively for N-methyl-D-aspartate (NMDA) receptors, virtually eliminates the spontaneous convulsions which occur following the abrupt withdrawal of barbital from barbiturate dependent rats. These convulsions represent the most serious behavioral manifestation of this potentially life threatening syndrome which has been estimated to be more severe than opiate withdrawal. Most importantly, these data provide the first direct evidence for an involvement of EAA pathways in the manifestation of this abstinence syndrome. The major objective of this renewal proposal is to identify the brain regions which contain NMDA receptors involved in the propagation of these abstinence related convulsions. Alzet minipumps attached to intracerebral cannula will infuse APH into select brain regions and the potential ameliorative effects on spontaneous convulsions will be determined. The amygdala (AMY) and hippocampus (HIPPO), sites where more than 50 percent of these convulsions appear to originate as well as major sites of NMDA receptor concentration, will be the initial regions investigated. Other experiments will explore a potential key involvement of chronic barbiturate- induced adaptations in EAA pathways in the development of barbiturate dependence. In particular, we will extensively investigate an apparent hyperresponsiveness to kainate in barbital dependent rats. Collectively, these studies will test the hypothesis that EAA pathways play a key role in the development of and the manifestation of barbiturate dependence.