DIAZEPAM EFFECTS ON RECOVERY OF FUNCTION

地西泮对功能恢复的影响

• 批准号: 3408124
• 负责人: TIMOTHY SCHALLERT
• 金额: $ 9.79万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3408124
• 关键词: amphetamines; anticonvulsants; basal ganglia; behavior test; brain injury; centrally acting drug; convulsants; dexamethasone; diazepam; dosage; drug receptors; experimental brain lesion; ibotenate; laboratory rat; longitudinal animal study; neuropharmacology; neurotransmitter receptor; phenobarbital; phenytoin; sedative /hypnotic; sensory cortex; sensory disorders; somesthetic sensory cortex

This project reflects a longstanding interest in neural events that influence recovery and maintenance of function after brain damage. The major proposed experiments derive from recent work showing that a postoperative regimen of diazepam (Valium), at an anticonvulsant dose, disrupts recovery from the sensorimotor asymmetry that follows unilateral damage to neocortex in rats, and that the chemoconvulsant, pentylenetetrazole, facilitates recovery. Further analysis of diazepam and pentylenetetrazole will be carried out. Also, because diazepam is a GABA agonist, muscimol or bicuculline will be used to activate or block GABAergic receptors following brain damage. Rats will sustain unilateral cortical or striatal lesions, and recovery will be assessed with somatosensory tests, including an analog of the "double simultaneous extinction" exam used in clinical neurology. The dosage, onset, and duration of the drug regimens will be manipulated. In most experiments, the agents will be infused intracranially. For example, in an effort to distinguish the role of seizures from that of GABA antagonism, bicuculline will be delivered to the prepiriform cortex, either in the hemisphere ipsilateral or contralateral to unilateral lesions of the somatosensory cortex. Seizures are expected to occur bilaterally, while GABA antagonism would be unilateral. Another study will use rats depleted of dopamine (via neonatal 6-OHDA) to explore in a preliminary way the role of nigrostriatal projections in recovery from cortical lesions and in the disruptive effects of diazepam on recovery. In a related experiments, muscimol will be infused intraventricularly following unilateral ibotenic acid (axon sparing) lesions in the striatum, which destroys striatonigral GABAergic neurons. A recent study found that muscimol prevents the transynaptic degeneration of cells in the substantia nigra, presumably by mimicking GABA. It has been argued that GABA agonists might therefore be beneficial to brain damaged people. However, it is possible that the effects of GABA agonists on recovery differ dramatically depending on the neurochemical circuitry of the brain regions damaged. Thus, GABA is not the predominant transmitter in neocortical projections. On the other hand, behavioral studies have yet to be carried out. Pilot work indicates that sensorimotor recovery after striatal lesions is correlated with the loss of nigra cells. Perhaps sensorimotor impairment is associated with the disinhibition of nigra cells, and transynaptic degeneration actually contributes to behavioral recovery. If so, then muscimol might retard, rather than facilitate, the return of sensorimotor symmetry after striatal lesions, as diazepam does when it is administered after neocortical lesions. These issues may be important clinically because the cortex is frequently affected in head injury and because diazepam and other anticonvulsant drugs that affect the GABA receptor have been used to prevent post-traumatic seizures.

这个项目反映了人们对神经事件的长期兴趣 影响脑损伤后功能的恢复和维持。 主要拟议的实验源于最近的工作，表明 术后安定(安定)联合抗惊厥药的应用 剂量，破坏了从感觉运动不对称中恢复 在大鼠一侧大脑皮层损伤后， 化学惊厥剂，戊四唑，促进康复。 将对安定和戊四唑进行进一步分析 出去。此外，由于安定是一种GABA激动剂，蝇草酚或 荷包牡丹碱将用于激活或阻断GABA能受体 在脑部受损之后。大鼠将维持单侧皮质或 纹状体损伤，恢复情况将用体感评估 测试，包括模拟“两次同时灭绝” 临床神经病学中使用的考试。 药物方案的剂量、起效时间和持续时间如下 被操纵了。在大多数实验中，这些试剂会被注入 在脑内。例如，为了区分角色， 对于癫痫发作的GABA拮抗剂，荷包牡丹碱 传递到梨状叶皮质，或者在大脑半球 同侧或对侧单侧大脑中动脉病变 躯体感觉皮质。癫痫发作预计会发生在双侧， 而GABA的拮抗作用将是单边的。另一项研究将使用 多巴胺耗竭的大鼠(通过新生6-OHDA)在 黑质纹状体投射在康复中作用的初步探讨 从皮质损伤和安定的干扰作用中 恢复。在一项相关的实验中，将麝香酚 侧脑室注射单侧鹅膏状酸(轴突 保留)纹状体的损害，破坏纹状体黑质 GABA能神经元。最近的一项研究发现，麝香酚可以防止 黑质细胞跨突触变性， 大概是通过模仿GABA。有观点认为，GABA 因此，激动剂可能对大脑受损的人有益。 然而，有可能GABA激动剂对 恢复情况因神经化学物质的不同而有很大差异 大脑区域的回路受损。因此，GABA不是 在新皮质投射中占主导地位的递质。另一方面 另一方面，行为研究还没有进行。试点工作 表明纹状体损伤后感觉运动的恢复 与黑质细胞的丢失相关。也许是感觉运动 损伤与黑质细胞的去抑制有关， 而跨突触退变实际上对行为 恢复。如果是这样，那么麝香酚可能会迟缓，而不是 促进纹状体后感觉运动对称性的恢复 损害，如安定在新皮质后给药时所起的作用 损伤。这些问题在临床上可能很重要，因为 在头部损伤中，皮质经常受到影响，因为安定 和其他影响GABA受体的抗惊厥药物有 被用来预防创伤后癫痫发作。