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一些神经和神经精神疾病。有效治疗这些症状对于完全康复和提高药物依从性至关重要。现在，类似的关注已指向药物滥用的治疗。滥用不同种类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戒断的障碍。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。在灵长类动物和啮齿动物模型中，两种先导化合物被认为是极好的认知增强剂，具有改善工作记忆、注意力和感觉门控的能力。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：在没有事先激活的情况下，使烟碱能受体脱敏。许多类似物在它们的作用中是有效的，但迄今为止还没有显示出明显的副作用或毒性。此外，我们还描述了使用氯胺酮（致幻剂）的猴子工作记忆损伤的可逆药理学模型；诺米芬辛（可卡因/苯丙胺类活性）；阿米替林（生物胺摄取抑制剂/抗胆碱能药）。在啮齿类动物中，我们使用认知任务电池，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，我们期望建立一个胆碱类似物诱导的任务改善的特征模式，这表明在包括药物滥用在内的认知障碍的临床环境中具有广泛的活性。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、注意力和感觉门控等方面，作为药物滥用治疗的辅助手段。我们计划在啮齿类动物的工作记忆、注意力和感觉门控模型中评估40种胆碱类似物，它们属于4种主要化学类别。其中10项研究将在慢性吗啡、可卡因和尼古丁自我给药的大鼠模型中进行。受试者可在24小时的基础上进行访问，并可在慢性自我给药后、急性停药和长期停药期间测试工作记忆损伤。如上所述，这10种化合物将在猕猴工作记忆可逆性药理学损伤模型中进行评估。这些研究可能会为治疗吸毒成瘾者和治疗其他类型的成瘾行为的新药理学方法带来突破性的进展。除了提高认知能力，胆碱类似物还可以预防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.