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。其他行为异常也被研究过， 包括可卡因的行为刻板印象，利多卡因的攻击性 和普鲁卡因，以及与可卡因发作有关的死亡率。点火点 可卡因的作用可能与其局部麻醉特性有关， 利多卡因和普鲁卡因有类似的效果，而普鲁卡因则不然 其他精神运动兴奋剂。重大发现包括 论证：1)局麻药点燃的发展 癫痫发作及其相关的致命性可以通过慢性、 但非急性或反复急性、卡马西平治疗；2)局部 麻醉点燃癫痫模型可能提供一种新的检查方法 卡马西平在情感性疾病中的作用机制 需要慢性治疗；3)以下系统已被排除 卡马西平的抗惊厥作用是必要的 癫痫模型：外周型α-2-肾上腺素能受体 苯二氮受体、5-羟色胺和生长抑素；4)普鲁卡因点燃 癫痫发作类似于利多卡因癫痫发作--大鼠变得具有攻击性 在癫痫发作后，他们可以持续多次癫痫发作 (与可卡因不同，在可卡因中，一两次癫痫发作经历会导致 致命性)。5)胆碱能手法显著影响局部 麻醉点燃癫痫的发展，普鲁卡因和普鲁卡因不同 可卡因和利多卡因的对比。阿托品阻断小鼠癫痫发作 前者可增强后者诱发的癫痫发作。毒扁豆碱 减弱利多卡因点燃；6)使用普鲁卡因点燃模型， 评估不同给药方案的耐受性。 发展和最佳预防。一种降序给药计划 安定给药对点燃的抑制作用最强， 即使在其他两组无效的剂量下也是如此。这个 卡马西平在癫痫发作中作用机制的研究 需要慢性治疗的模型可能与 卡马西平对躁郁症的疗效，并可能有助于 开发其他更具体或更有效的治疗方法 战略。这些研究还可能提出对 慢性与急性或慢性的适应机制的差异 反复间歇用药治疗。浅谈局麻药的重要性 人类可卡因滥用的机制仍有待确定，但在某些方面 与可卡因相关的恐慌症类似于点燃癫痫的发展。 普鲁卡因的作用机制将引起人们的兴趣，因为普鲁卡因是 正在成为一种有用的临床工具，用于区分某些 精神病患者和对照的类型，以及由于普鲁卡因 对边缘系统底物具有高选择性。

This project studies and manipulates the course of development of pharmacologically kindled seizures using the local anesthetics lidocaine, cocaine, and procaine. Other behavioral abnormalities are studied, including behavioral stereotypies 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. Significant findings 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) 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; 4) 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). 5) 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; 6) Using the procaine kindling model, different drug administration regimens were evaluated for tolerance development and optimal prophylaxis. A descending dosing schedule of diazepam administration produced the most robust inhibition of kindling, even at dosages that were ineffective in the other two groups. The determination of carbamazepine's mechanism of action in these seizure models, which require chronic treatment, could be relevant to carbamazepine's effects in manic-depressive illness and may help in the development of other, more specific or more effective, treatment strategies. These studies may also suggest mechanistic insights into the differences in adaptive mechanisms that occur with chronic vs. acute or repeated intermittent drug treatment. The importance of local anesthetic mechanisms in human cocaine abuse remains to be determined, but aspects of cocaine-related panic disorder resemble kindled seizure development. Procaine's mechanisms of action will be of interest, since procaine is emerging as a useful clinical tool for distinguishing between certain types of psychiatric patients and controls, and because of procaine's high selectivity for limbic system substrates.