Cannabinoid Approaches for Treatment of Tourette's Syndrome

治疗抽动秽语综合征的大麻素方法

• 批准号: 7540454
• 负责人: BITA MOGHADDAM
• 金额: $ 22.19万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7540454
• 关键词: Adolescence; Adolescent; Adult; Adverse effects; Affective; Age; Agonist; Animal Model; Antipsychotic Agents; Attention Deficit Disorder; Behavior; Brain; CNR1 gene; Cannabinoids; Cannabis; Childhood; Cognitive; Cognitive deficits; Controlled Clinical Trials; Data; Development; Disease; Double-Blind Method; Drug usage; Effectiveness; Endocannabinoids; Exposure to; Future; Gilles de la Tourette syndrome; Hydrolysis; Ligands; Link; Measures; Mental disorders; Methods; Morbidity - disease rate; Motor; Obsessive-Compulsive Disorder; Patients; Pharmaceutical Preparations; Placebo Control; Public Health; Randomized; Rattus; Reporting; Role; Safety; Schizophrenia; Symptoms; Tardive Dyskinesia; Tremor; anandamide; base; cannabinoid receptor; cognitive function; dysphoria; early adolescence; motor deficit; neuropsychiatry; neurotransmission; novel; pre-clinical; tool; treatment strategy; uptake

DESCRIPTION (provided by applicant): Neuroleptics remain the primary mode of treatment for Tourette's syndrome (TS). However, these drugs have profound side effects including dysphoria, cognitive deficits, and tardive dyskinesia. Recent randomized double- blind placebo-controlled clinical trials have shown that delta-9-tetrahdrocannabinol (THC) reduces symptoms of TS. These findings substantiate numerous anecdotal reports in the last several decades indicating that cannabis ameliorates some symptoms of TS and suggest that activation of cannabinoid neurotransmission is a plausible treatment strategy for treatment of TS. Treatment of TS with THC, however, is not a feasible option because of abuse-related concerns. Other pharmacological approaches that directly activate cannabinoid receptors in the brain are also problematic because the CB1 receptor, the primary cannabinoid receptor in the brain, becomes desensitized by direct exogenous agonist activation. Another foreseeable problem with targeting cannabinoid neurotransmission for treatment of TS is that this disorder is manifested during adolescence. Exposure to cannabis during this period has been linked to long-term adverse cognitive effects and increased propensity to develop other psychiatric disorders. The aim of this proposal is to explore the feasibility of an alternative approach to enhance cannabinoid neurotransmission for treatment of TS which may not be associated with the aforementioned shortcomings. The approach involves manipulating levels of endogenous cannabinoids (eCB) anandemide and 2-AG by either reducing their hydrolysis or rate of uptake. Several brain permeable compounds have been recently described as effective pharmacological tools for blocking eCB transporter and anandamide hydrolysis. We propose to (1) explore the effectiveness of these agents in reversing tic-like behaviors in several animal models of TS in both adult and adolescent rats and, (2) determine the effect of repeated exposure to these compounds in early adolescent rats on cognitive and affective functioning in late adolescent and adult rats. It is anticipated that the results of these studies will, in addition to exploring the feasibly of a novel treatment approach for TS, provide the basis for future mechanistic studies on the role of eCB in regulating motor and cognitive functions during normal development and in disease states. Relevance to public health: Drugs used presently to treat Tourette's syndrome are minimally effective or have profound side effects. This preclinical proposal aims to complete exploratory studies to determine the feasibility and safety of a novel treatment option for this childhood neuropsychiatric disorder.

描述（由申请人提供）：神经疗法仍然是Tourette综合征（TS）的主要治疗方式。但是，这些药物具有深远的副作用，包括烦躁不安，认知缺陷和迟发性运动障碍。最近的随机双盲安慰剂对照临床试验表明，Delta-9-tetrahdrocanbinol（THC）减少了TS的症状。在过去的几十年中，这些发现证实了许多轶事报告，表明大麻可以缓解TS的某些症状，并表明大麻素神经传递的激活是一种可行的治疗策略，用于治疗TS。然而，由于与滥用相关的问题，用THC的TS治疗不是可行的选择。其他直接激活大脑中大麻素受体的药理学方法也有问题，因为CB1受体（大脑中的原代大麻素受体）通过直接的外源性激动剂激活而脱敏。靶向大麻素神经传递治疗TS的另一个可预见的问题是，这种疾病在青春期表现出来。在此期间，暴露于大麻与长期不良认知效应和发展其他精神疾病的倾向有关。该提案的目的是探索一种替代方法来增强大麻素神经传递治疗TS的可行性，而TS可能与上述缺点无关。该方法涉及通过降低其水解或摄取速率来操纵内源性大麻素（欧洲大麻素）和2-AG。最近，几种大脑可渗透化合物被描述为可阻断欧洲央行转运蛋白和anandamide水解的有效药理工具。我们建议（1）探索这些药物在成年大鼠和青少年大鼠TS中逆转类似TIC样行为的有效性，以及（2）确定在青少年早期大鼠对这些化合物对这些化合物的反复暴露对晚期和成年大鼠的认知和情感功能的影响。可以预料，除了探索TS新型治疗方法的可行治疗方法外，这些研究的结果还将为未来的机械研究提供有关欧洲央行在调节正常发育期间和疾病状态下调节运动和认知功能的作用的基础。与公共卫生有关：目前用来治疗图雷特综合症的药物在最低限制或具有深远的副作用。该临床前建议旨在完成探索性研究，以确定这种儿童神经精神疾病的新型治疗选择的可行性和安全性。