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: 8233427
• 负责人: ALVIN V TERRY
• 金额: $ 32.08万
• 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/8233427
• 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 Delivery Systems; 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. PUBLIC HEALTH RELEVANCE: 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. These exciting new compounds evoke their pharmacological actions by a unique mechanism: desensitization of nicotinic cholinergic receptors without the antecedent activation. 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 ten of which will progress to studies in rat models of chronic morphine, cocaine, and nicotine self-administration. They also 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）：几种神经和神经精神疾病的认知和工作记忆缺陷。对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，已经针对治疗药物滥用的类似担忧。来自不同类别的滥用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戒酒维持的障碍。我们一直在研究一个小的胆碱类似物图书馆，这些图书馆最初是根据其细胞保护作用来表征的。两种铅化合物的特征是出色的认知增强剂，具有提高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。这些令人兴奋的新化合物通过一种独特的机制引起了他们的药理作用：烟碱胆碱能受体脱敏而没有先行激活。许多类似物的作用有效，但迄今为止尚未表现出明显的副作用或毒性。此外，我们还表征了可逆的药理学模型，用于利用氯胺酮（致幻剂）的猴子工作记忆障碍。 nomifensine（可卡因/类似苯丙胺的活性）；和阿米替林（生物胺摄取抑制剂/抗胆碱能力）。在啮齿动物中，我们使用认知任务电池，还包括估计工作记忆，注意力和感觉门控。结合了这些模型，我们期望建立胆碱类似物诱导的任务改进的特征模式，这些模式表明在认知障碍的临床环境中，包括药物滥用。因此，我们提出了一个药物发现项目的中心假设，即胆碱的类似物可以改善工作记忆，注意力和感觉门控的各个方面，以用作治疗药物滥用的辅助手段。我们计划评估在工作记忆，注意力和感觉门控的啮齿动物模型中，属于4个主要化学类别的胆碱的40种类似物。其中的十个将发展为慢性吗啡，可卡因和尼古丁自我给药的大鼠模型的研究。受试者可以在24小时的基础上访问，并且可以在慢性自我管理以及急性戒断和延长戒断期间对工作记忆的损害进行测试。如上所述，将在工作记忆中可逆药理损伤的猕猴模型中评估这10种相同的化合物。这些研究可能会导致朝着一种新的药理学方法来治疗吸毒者，并治疗其他类型的成瘾行为。除了认知改善外，胆碱类似物还可以防止与长期滥用几种成瘾性物质有关的神经毒性。 公共卫生相关性：来自不同类别的滥用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戒酒维持的障碍。我们一直在研究一个小的胆碱类似物图书馆，这些图书馆最初是根据其细胞保护作用来表征的。这些令人兴奋的新化合物通过一种独特的机制引起了他们的药理作用：烟碱胆碱能受体脱敏而没有先行激活。我们提出了一个药物发现项目的中心假设，即胆碱的类似物可以改善工作记忆，注意力和感觉门控的各个方面，以用作治疗药物滥用的辅助手段。我们计划评估40种类似物的胆碱类似物，其中将进展为慢性吗啡，可卡因和尼古丁自我给药的大鼠模型的研究。如上所述，还将在工作记忆中可逆药理损伤的猕猴模型中进行评估。这些研究可能会导致朝着一种新的药理学方法来治疗吸毒者，并治疗其他类型的成瘾行为。除了认知改善外，胆碱类似物还可以防止与长期滥用几种成瘾性物质有关的神经毒性。