DIAZEPAM EFFECTS ON RECOVERY OF FUNCTION

地西泮对功能恢复的影响

• 批准号: 3408123
• 负责人: TIMOTHY SCHALLERT
• 金额: $ 10.73万
• 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/3408123
• 关键词: amphetamines; anticonvulsants; basal ganglia; behavior test; brain injury; centrally acting drug; convulsants; dexamethasone; diazepam; dosage; drug receptors; experimental brain lesion; 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.

该项目反映了对神经事件的长期兴趣， 影响脑损伤后功能恢复和维持。 主要拟议实验源自最近的工作，表明 安定（安定）的术后方案，抗惊厥药 剂量，破坏从感觉运动不对称的恢复， 在大鼠的新皮层受到单侧损伤后， 化学惊厥药戊四唑有助于恢复。 地西泮和戊四氮的含量有待进一步分析 出去 此外，由于地西泮是GABA激动剂，蝇蕈醇或 荷包牡丹碱将用于激活或阻断GABA能受体 脑损伤后 大鼠将维持单侧皮质或 纹状体病变，恢复将评估与体感 测试，包括“双重同时消光”的模拟 临床神经学检查。 药物方案的剂量、起效时间和持续时间将是 被操纵了 在大多数实验中， 颅内 例如，为了区分角色， 从GABA拮抗作用的癫痫发作，荷包牡丹碱将 传递到梨状前皮质， 单侧病变的同侧或对侧 躯体感觉皮层 预计缉获将在双边发生， 而GABA拮抗作用是单方面的。 另一项研究将使用 大鼠耗尽多巴胺（通过新生儿6-OHDA），以探索在一个 黑质纹状体投射在脑功能恢复中的作用 以及地西泮对大脑皮层损伤的破坏作用， 复苏 在相关的实验中，蝇蕈醇将被注入 单侧鹅膏蕈氨酸（轴突） 保留）损伤，这破坏了纹状体黑质 GABA能神经元。 最近的一项研究发现，蝇蕈醇可以防止 黑质细胞的跨突触变性， 可能是通过模仿GABA 有人认为，GABA 因此，激动剂可能对脑损伤的人有益。 然而，GABA激动剂对小鼠的作用可能与其自身免疫性有关。 不同的神经化学物质 大脑区域的电路受损。 因此，GABA不是 是新皮层投射的主要递质。 另 另一方面，行为学研究还有待进行。 试点工作 表明纹状体损伤后感觉运动恢复是 与黑质细胞的丧失有关。 也许是感觉运动 损伤与黑细胞的去抑制有关， 而跨突触变性实际上有助于行为 复苏 如果是这样，那么蝇蕈醇可能会延迟，而不是 促进，恢复感觉运动对称性后，纹状体 病变，如地西泮，当它是新皮质后管理 病变 这些问题在临床上可能很重要，因为 大脑皮层在头部损伤中经常受到影响， 和其他影响GABA受体的抗惊厥药物， 被用来预防创伤后癫痫