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）：抗精神病药仍然是抽动秽语综合征（TS）的主要治疗方式。然而，这些药物具有严重的副作用，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，δ9-四大麻酚 (THC) 可减轻 TS 症状。这些发现证实了过去几十年的大量轶事报告，表明大麻可以改善 TS 的一些症状，并表明激活大麻素神经传递是治疗 TS 的一种可行的治疗策略。然而，由于滥用相关问题，用 THC 治疗 TS 并不是一个可行的选择。其他直接激活大脑中大麻素受体的药理学方法也存在问题，因为 CB1 受体（大脑中的主要大麻素受体）会因直接外源激动剂激活而变得不敏感。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。在此期间接触大麻与长期不良认知影响以及患其他精神疾病的倾向增加有关。该提案的目的是探索增强大麻素神经传递以治疗 TS 的替代方法的可行性，该方法可能与上述缺点无关。该方法涉及通过降低内源性大麻素 (eCB) anandemide 和 2-AG 的水解或吸收率来控制其水平。最近，几种脑渗透性化合物被描述为阻断 eCB 转运蛋白和 anandamide 水解的有效药理学工具。我们建议 (1) 探索这些药物在成年和青少年大鼠的几种 TS 动物模型中逆转抽动样行为的有效性，(2) 确定早期青少年大鼠反复暴露于这些化合物对认知的影响以及青春期晚期和成年大鼠的情感功能。预计这些研究的结果除了探索 TS 新型治疗方法的可行性外，还将为未来关于 eCB 在正常发育和疾病状态下调节运动和认知功能中的作用的机制研究提供基础。与公共卫生的相关性：目前用于治疗抽动秽语综合症的药物效果甚微或具有严重的副作用。该临床前提案旨在完成探索性研究，以确定针对这种儿童神经精神疾病的新型治疗方案的可行性和安全性。