Drug Discovery for Cognitive Impairment Associated with Drugs of Abuse

治疗与滥用药物相关的认知障碍的药物发现

• 批准号: 8434271
• 负责人: ALVIN V TERRY
• 金额: $ 30.8万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434271
• 关键词: Abstinence; Acute; Addictive Behavior; Adverse effects; Alcohols; Alzheimer' s Disease; Amitriptyline; Amphetamines; Animal Behavior; Anti-Cholinergics; Attention; Attenuated; Behavior; Biogenic Amines; Characteristics; Chemicals; Cholinergic Receptors; Chronic; Clinical; Cocaine; Cognition; Cognitive; Cognitive deficits; Development; Disease; Dose; Drug Targeting; Endogenous depression; Evaluation; Exhibits; Hallucinogens; Hour; Impaired cognition; Impairment; Ketamine; Lead; Libraries; Macaca; Maintenance; Memory impairment; Modeling; Monkeys; Morphine; Neurodegenerative Disorders; Neurologic; Nicotine; Nomifensine; Opiates; Pattern; Pharmaceutical Preparations; Primates; Rattus; Recovery; Regimen; Rodent; Rodent Model; Schizophrenia; Self Administration; Short-Term Memory; Substance abuse problem; Symptoms; Testing; Toxic effect; Withdrawal; analog; base; choline analog; desensitization; drug addict; drug discovery; drug of abuse; effective therapy; improved; inhibitor/antagonist; innovation; medical schools; medication compliance; neuropsychiatry; nonhuman primate; prevent; public health relevance; relating to nervous system; sensory gating; substance abuse treatment; uptake

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.

描述（由申请人提供）：认知和工作记忆缺陷伴随着多种神经系统和神经精神疾病。有效治疗这些症状对于完全康复和提高用药依从性至关重要。类似的担忧现在也集中在药物滥用的治疗上。不同类别的滥用药物与认知和工作记忆损伤有关。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型的胆碱类似物库，这些类似物最初是根据其细胞保护作用来表征的。两种先导化合物被认为是优秀的认知增强剂，能够改善灵长类动物和啮齿类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独特的机制激发其药理作用：使烟碱胆碱能受体脱敏，而无需事先激活。许多类似物的作用很有效，但迄今为止尚未表现出明显的副作用或毒性。此外，我们还对使用氯胺酮（致幻剂）的猴子工作记忆损伤的可逆药理学模型进行了表征；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）。在啮齿动物中，我们使用认知任务电池，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，我们期望建立胆碱类似物诱导的任务改善的特征模式，这表明在认知障碍（包括药物滥用）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、注意力和感觉门控方面，用作药物滥用治疗的辅助剂。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属于 4 个主要化学类别的 40 种胆碱类似物。其中十项将进入慢性吗啡、可卡因和尼古丁自我给药大鼠模型的研究。受试者可以24小时访问，并且可以在长期自我给药后以及急性戒断和长期戒断期间测试他们的工作记忆损伤。如上所述，这 10 种化合物将在工作记忆可逆药理损伤的猕猴模型中进行评估。这些研究可能会为治疗吸毒者和其他类型的成瘾行为的新药理学方法带来突破性进展。除了改善认知功能外，胆碱类似物还可以预防与长期滥用几种成瘾物质相关的神经毒性。