Drug Discovery for Cognitive Impairment Associated with Drugs of Abuse

描述（由申请人提供）：认知和工作记忆缺陷伴随着几种神经和神经精神疾病。这些症状的有效治疗对于完全康复和改善药物依从性至关重要。现在，对药物滥用的治疗也引起了类似的关注。滥用不同类别的药物与认知和工作记忆的损害有关。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，这些胆碱最初是基于它们的细胞保护作用来表征的。两种先导化合物已被表征为具有改善灵长类动物和啮齿动物模型中的工作记忆、注意力和感觉门控的能力的优秀认知增强剂。这些令人兴奋的新化合物通过一种独特的机制引起其药理作用：在没有预先激活的情况下使烟碱胆碱能受体脱敏。许多类似物在其作用中是有效的，但迄今为止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/抗胆碱能药物）表征了猴子工作记忆损伤的可逆药理学模型。在啮齿类动物中，我们使用认知任务组合，其中还包括工作记忆，注意力和感觉门控的估计。结合这些模型，我们希望建立一个特征模式的胆碱类似物诱导的任务改善，这表明广泛的活动在临床设置的认知障碍，包括药物滥用。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，注意力和感觉门控方面，用于治疗药物滥用。我们计划评估40胆碱类似物属于4个主要化学类啮齿动物模型的工作记忆，注意力和感觉门控。其中10个将在慢性吗啡、可卡因和尼古丁自我给药的大鼠模型中进行研究。受试者可以24小时访问，并且可以在长期自我给药后以及在急性戒断和长期戒断期间测试他们的工作记忆损伤。将在如上所述的工作记忆可逆性药理学损伤的猕猴模型中评价这10种相同的化合物。这些研究可能会导致一个突破性的进展，朝着一个新的药理学方法治疗吸毒成瘾者，并治疗其他类型的成瘾行为。除了认知改善，胆碱类似物还可以预防与几种成瘾物质的慢性滥用相关的神经毒性。

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.