NEUROLEPTIC-INDUCED DYSKINESIAS AND DYSTONIAS

迟发性运动障碍（TD）在精神分裂症患者中逐渐发展， 慢性精神抑制剂 TD的啮齿动物模型是非常有争议的。 该实验室开发了一种非常独特的TD大鼠模型， 计算机化系统，借此测量大鼠的口腔运动（OM）， 与人类的报告一起直接存入计算机内存 观察员。 使用这个模型，我们已经证明了一个工件相关 其他实验室使用的测试中的活性水平，一个可以 导致虚假膨胀的口腔运动分数，这可能有助于 澄清这个有争议的领域。 我们发现，连续给予大鼠"典型的" 抗精神病药本身不一定会产生更多的口腔运动，但 而是逐渐发展具有改变的和异常的形式的OM， 在1 - 2Hz下最显著地增加能量。 这是一个重要的发现， 因为这正是人类报告的能量谱改变 关于TD 我们进一步发现，一个完全不同的，"启动"的， 肌张力障碍综合征（大振幅、快速（4 - 7 Hz）、张开型OM） 在给予类似的精神抑制剂的大鼠中， 波动方案（每周一次大剂量注射）。 虽然"非典型" 抗精神病药（氯氮平和雷氯必利）不会诱发这些综合征， 使用氯氮平，似乎TD样特征逐渐发展， 其表达受到抑制。 多种脑受体的研究 在这些动物中证明持续改变的D2和GABA受体， 但在连续和间歇性 HAL，即在表现出完全不同行为的大鼠中 综合征 用这些慢性精神抑制剂治疗的大鼠也逐渐 开发非常小的OM，小到只有计算机才能检测到它们， 这一效应值得进一步研究。 我们建议采用这种模式，我们认为这是目前最好的模式 抗精神病药诱导的口腔运动障碍的可行啮齿动物模型，通过研究 影响多巴胺或胆碱能受体的药物， 其他药物，改变两者的形式和频率 抗精神病药引起的口腔综合征 我们进一步提出研究设计， 来绘制潜在的大脑回路，试图确定 使用局部注入的改变的图案发生器的位置 激动剂或离散的脑损伤。 其他研究将研究 衰老和非典型神经抑制剂。 我们还建议确定是否 在人类中报道的其他综合征也在这些大鼠中发展，例如， 一种类似静坐不能的无法保持静止的状态，如果老鼠也发展成 在灵长类动物中报道的"引发性肌张力障碍"综合征。 此外，本发明还提供了一种方法， 将收集TD患者的记录，并将其ROM 与服用类似药物的大鼠相比， 这些实验解决了一个重要的研究问题， 广泛的医源性疾病;解决的问题可能会 只能用这里提出的模型来回答。 它们具有 不寻常的临床意义，但也代表了一个基本的进展， 科学技术，因为我们已经开发了计算机技术， 行为的测量代表了一种高度进化的分析 系统

Tardive dyskinesia (TD) develops gradually in schizophrenics given chronic neuroleptics. Rodent models of TD are highly controversial. This laboratory has developed a very unique rat model of TD based on a computerized system whereby measures of oral movements (OMs) in rats are directly placed into computer memory together with the reports of human observers. Using this model, we have demonstrated an artifact related to activity levels in the test used by other laboratories, one that can lead to spuriously inflated oral movement scores and which may help to clarify this controversial field. We have found that rats treated with continuously administered "typical" neuroleptics do not necessary develop more oral movements per se, but rather gradually develop OMs which have an altered and abnormal form, most notably increased energy at 1-2 Hz. This is an important finding, for this is precisely the altered energy spectrum reported in humans with TD. We have further found that a completely different, "primed dystonia" syndrome (large amplitude, rapid (4-7 Hz), gaping OMs) develops in rats given comparable neuroleptics but in a highly fluctuating regimen (once per week large injections). While "atypical" neuroleptics (clozapine and raclopride) do not induce these syndromes, with clozapine it seems that the TD-like profile gradually develops but its expression is inhibited. Studies of a variety of brain receptors demonstrate persisting altered D2 and GABA receptors in these animals, but similar changes are observed following continuous and intermittent HAL, i.e. in rats which manifest completely different behavioral syndromes. Rats treated with these chronic neuroleptics also gradually develop very small OMs, so small that only the computer can detect them, an effect which deserves further investigation. We propose to pursue this model, which we argue is presently the best viable rodent model of neuroleptic-induced oral dyskinesias, by studying how drugs which affect dopamine or cholinergic receptors, as well as other pharmacological agents, alter the form and frequency of the two neuroleptic-induced oral syndromes. We further propose studies designed to map the underlying brain circuitry, attempting to determine the location of the altered pattern generator using local injections of agonists or discrete brain lesions. Other studies will study effects of aging and atypical neuroleptics. We also propose to determine whether other syndromes reported in humans also develop in these rats, such as an akathisia-like inability to remain still, and if rats also develop the "primed dystonia" syndrome reported in primates. In addition, recordings from humans with TD will be collected and the rom of their movements compared to those from rats administered similar drugs. These experiments address an important research issue involving a widespread iatrogenic disorder; the questions addressed will probably only be answered using a model such as that proposed here. They are of unusual clinical significance, but also represent a basic advance in scientific technology, for the computerized techniques we have developed for the measurement of behavior represent a highly evolved analysis system.