PHARMACOLOGICAL KINDLING

本项目研究和操作的发展历程 使用局麻药利多卡因药理上点燃癫痫， 可卡因和普鲁卡因。除了癫痫发作，其他行为 研究异常，包括可卡因的行为刻板印象， 利多卡因和普鲁卡因的攻击和与可卡因有关的死亡率 癫痫发作。可卡因的点燃作用可能与其 局部麻醉剂的特性，与利多卡因的效果相似 普鲁卡因，但不能与其他精神运动兴奋剂配伍。它的重要性 关于人类可卡因滥用的局部麻醉机制的研究仍有待于 已确定，但与可卡因相关的恐慌症(这是 由50%的可卡因使用者报告的可卡因热线)类似 点燃癫痫的发展，从而提供了一个耐人寻味的临床基础 研究重叠。本项目的重大发现包括：1) 局麻药点燃癫痫及其相关因素的研究进展 死亡可以通过慢性，但不是急性或反复急性， 卡马西平治疗；2)局麻药点燃癫痫模型 可能为研究卡马西平的作用机制提供一种新的途径。 对情感性疾病采取行动，这也需要长期治疗；3) 卡马西平慢性治疗减轻可卡因诱导的多巴胺 伏隔核溢流，降低HVA水平；4) 系统α-2-肾上腺素能受体，外周型苯二氮 受体、5-羟色胺和生长抑素可以被排除为 卡马西平在癫痫发作中的抗惊厥作用 模型；5)应激相关肽促肾上腺皮质激素释放激素 (CRH)和三环抗抑郁药去甲基米帕明(DMI) 加强可卡因点燃癫痫的发展和致命性；6)普鲁卡因 点燃-癫痫类似于利多卡因癫痫-大鼠变成 在癫痫发作后表现出攻击性，他们可以持续多次发作 癫痫发作(与可卡因不同，在可卡因中有一两次癫痫发作经历 诱导致命性)；慢性卡马西平似乎抑制 攻击，但不影响充分发展的癫痫发作；7) 胆碱能手法显著影响局麻药点燃 与普鲁卡因和可卡因相比，癫痫发作的发生和发展是不同的 为了利多卡因。阿托品阻断阿托品诱导的癫痫发作 增强后者诱导的癫痫发作。毒扁豆碱能使人衰弱 利多卡因点燃；8)采用普鲁卡因点燃模型，不同药物 评估给药方案的耐受性发展和 最佳预防措施。

This project studies and manipulates the course of development of pharmacologically kindled seizures using the local anesthetics lidocaine, cocaine, and procaine. In addition to seizures, other behavioral abnormalities are studied, including behavioral stereotypys with cocaine, aggression with lidocaine and procaine, 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 and procaine 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, thus providing an intriguing clinical-basic research overlap. Significant findings of this project include 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 systems alpha-2-adrenergic receptors, peripheral-type benzodiazepine receptors, serotonin, and somatostatin can be ruled out as being necessary to carbamazepine's anticonvulsant effects in this seizure model; 5) the stress- related peptide corticotropin releasing hormone (CRH) and the tricyclic antidepressant desmethylimipramine (DMI) potentiate cocaine kindled seizure development and lethality; 6) procaine kindled-seizures are similar to lidocaine seizures - rats become aggressive after seizures develop, and they can sustain numerous bouts of seizures (unlike with cocaine, in which one or two seizure experiences induces lethality); chronic carbamazepine appears to inhibit the aggression while not affecting the fully developed seizures; 7) cholinergic manipulations markedly affect local anesthetic-kindled seizure development and are distinct for procaine and cocaine compared to lidocaine. Atropine blocks seizures induced by the former and potentiates seizures induced by the latter. Physostigmine attenuates lidocaine kindling; 8) Using the procaine kindling model, different drug administration regimens were evaluated for tolerance development and optimal prophylaxis.