Drug Discovery for Cognitive Impairment Associated with Drugs of Abuse

描述(申请人提供)：认知和工作记忆的缺陷伴随着几种神经和神经精神障碍。这些症状的有效治疗对于完全康复和改善服药依从性至关重要。现在对药物滥用的治疗也提出了类似的关切。来自不同类别的滥用药物与认知和工作记忆障碍有关。认知障碍显然是治疗和维持禁欲的障碍。我们一直在研究一个小的胆碱类似物库，这些类似物最初是基于它们的细胞保护作用来表征的。两种先导化合物被认为是极好的认知增强剂，能够改善灵长类和啮齿动物模型的工作记忆、注意力和感觉门控。这些令人兴奋的新化合物通过一种独特的机制唤起它们的药理作用：在没有预先激活的情况下使尼古丁胆碱能受体脱敏。许多类似物的作用都很强，但到目前为止还没有表现出明显的副作用或毒性。此外，我们还利用氯胺酮(致幻剂)、诺米芬辛(可卡因/苯丙胺样活性)和阿米替林(生物胺摄取抑制剂/抗胆碱能)对猴子工作记忆损害的可逆药理学模型进行了表征。在啮齿动物中，我们使用认知任务组，它还包括对工作记忆、注意力和感觉门控的估计。结合这些模型，我们希望建立一种胆碱类似物诱导的任务改善的特征模式，表明在包括物质滥用在内的认知障碍的临床环境中存在广泛的活动。因此，我们提出了一个药物发现项目，其中心假设是胆碱类似物可以改善工作记忆、注意力和感觉门控的各个方面，作为治疗药物滥用的辅助手段。我们计划在啮齿动物的工作记忆、注意力和感觉门控模型中评估属于4个主要化学类别的40种胆碱类似物。其中10项将在慢性吗啡、可卡因和尼古丁自我给药的大鼠模型上进行研究。受试者可以24小时接触，他们可以在长期自我管理后，以及在急性戒断和长期戒断期间接受工作记忆损害测试。如上所述，这10种化合物将在猕猴工作记忆中的可逆性药物损伤模型中进行评估。这些研究可能导致在治疗吸毒者和其他类型的成瘾行为的新的药理学方法方面取得突破性进展。除了改善认知，胆碱类似物还可以防止与长期滥用几种成瘾物质有关的神经毒性。

DESCRIPTION (provided by applicant): Deficits in cognition and working memory accompany several neurological and neuropsychiatric disorders. Effective treatment of these symptoms is of paramount importance for full recovery and for improving medication compliance. Similar concerns have now been directed towards the treatment of substance abuse. Abused drugs from different classes have been associated with impairments in cognition and working memory. Cognition impairment is clearly an impediment to treatment and to the maintenance of abstinence. We have been studying a small library of analogs of choline that were originally characterized based on their cytoprotective actions. Two lead compounds have been characterized as excellent cognition-enhancing agents with the ability to improve working memory, attention, and sensory gating in primate and rodent models. These exciting new compounds evoke their pharmacological actions by a unique mechanism: desensitization of nicotinic cholinergic receptors without the antecedent activation. Many analogs are potent in their actions but have thus far exhibited no overt side effects or toxicity. In addition we have characterized reversible pharmacological models for impairments in working memory in monkeys utilizing ketamine (hallucinogen); nomifensine (cocaine/amphetamine-like activity); and amitriptyline (biogenic amine uptake inhibitor/anticholinergic). In rodents we use a cognitive task battery that also includes estimation of working memory, attention and sensory gating. Combining these models we expect to establish a characteristic pattern of choline analog-induced task improvements that suggest broad activity in the clinical setting of cognitive impairment, including substance abuse. Therefore we propose a drug discovery project with the central hypothesis that analogs of choline can improve aspects of working memory, attention, and sensory gating for use as adjuncts in the treatment of substance abuse. We plan to evaluate 40 analogs of choline belonging to 4 primary chemical classes in rodent models of working memory, attention, and sensory gating. Ten of these will progress to studies in rat models of chronic morphine, cocaine, and nicotine self-administration. Subjects have access on a 24 hr basis, and they can be tested for impairments in working memory after chronic self-administration and during acute withdrawal and protracted withdrawal. These same 10 compounds will be evaluated in macaque models of reversible pharmacological impairment in working memory as indicated above. These studies could lead to a ground-breaking advance towards a new pharmacological approach for the treatment of drug addicts, and for treating other types of addictive behaviors. In addition to cognitive improvement, choline analogs could also prevent the neural toxicity associated with the chronic abuse of several addictive substances.