PHARMACOLOGICAL KINDLING

药理点燃

• 批准号: 3781440
• 负责人: S R WEISS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3781440
• 关键词: aggression; anticonvulsants; carbamazepine; chemoprevention; cocaine; corticotropin releasing factor; dopamine; drug administration rate /duration; drug interactions; imipramine; kindling; laboratory rat; lidocaine; local anesthetics; mental disorder chemotherapy; neuropharmacology; neuroprotectants; psychopharmacology

The objectives of this project are to study and manipulate the course of development of pharmacologically kindled seizures using the local anesthetics lidocaine and cocaine. In addition to seizures, other behavioral abnormalities are studied, including behavioral stereotypies with cocaine, aggression with lidocaine, and mortality related to cocaine seizures. The kindling effects of cocaine are likely related to its local anesthetic properties, as similar effects are seen with lidocaine but not with other psychomotor stimulants. The importance of local anesthetic mechanisms in human cocaine abuse remains to be determined, but aspects of cocaine-related panic disorder (which is reported by 50% of cocaine users calling a cocaine hotline) resemble kindled seizure development and thus provide an intriguing clinical-basic research overlap. Significant findings of this project include the demonstration that: 1) the development of local anesthetic-kindled seizures and their associated lethality can be prevented with chronic, but not acute or repeated acute, carbamazepine treatment; 2) the local anesthetic-kindled seizure model may offer a novel approach to examining carbamazepine's mechanisms of action in affective illness, which also requires chronic treatment; 3) chronic treatment with carbamazepine attenuates cocaine-induced dopamine overflow in the nucleus accumbens and decreases HVA levels; 4) the following systems have been ruled out as being necessary to carbamazepine's anticonvulsant effects in this seizure model: alpha-2-adrenergic receptors, peripheral-type benzodiazepine receptors, serotonin and somatostatin; 5) the stress-related peptide corticotropin releasing hormone (CRH) and the tricyclic antidepressant desmethylimipramine (DMI) potentiate cocaine kindled seizure development and lethality.

本项目的目标是研究和操纵 使用当地的 麻醉剂利多卡因和可卡因 除此之外，其他 研究行为异常，包括行为刻板 可卡因、利多卡因攻击和可卡因相关死亡率 癫痫发作。 可卡因的点燃效应可能与其 局部麻醉特性，与利多卡因相似 但不能用其他精神兴奋剂 地方的重要性 人类可卡因滥用的麻醉机制仍有待确定， 但可卡因相关的恐慌症（据报道， 可卡因使用者拨打可卡因热线）类似于点燃癫痫发作 发展，从而提供了一个有趣的临床基础研究 重叠 该项目的重要成果包括： 认为：1）局部麻醉点燃癫痫发作的发展及其 相关的致死性可以通过慢性预防，但不能通过急性或 反复急性，卡马西平治疗; 2）局部麻醉点燃 癫痫发作模型可能提供一种新的方法来检查卡马西平的 情感疾病的作用机制，这也需要长期的 治疗; 3）慢性治疗与卡马西平减弱 可卡因引起的多巴胺溢出在脑桥核中， HVA水平; 4）以下系统已被排除， 卡马西平的抗惊厥作用所必需的 模型：α-2-肾上腺素能受体，外周型苯二氮卓类 5）应激相关肽 促肾上腺皮质激素释放激素（CRH）和三环类抗抑郁药 去甲丙咪嗪增强可卡因点燃癫痫发作 和致命性。