Cannabinoid Approaches for Treatment of Tourette's Syndrome

说明(申请人提供)：抗精神病药物仍然是多发性抽动症(TS)的主要治疗方式。然而，这些药物有严重的副作用，包括烦躁不安、认知障碍和迟发性运动障碍。最近的随机、双盲、安慰剂对照临床试验表明，德尔塔-9-四氢大麻酚(THC)可减轻TS的症状。这些发现证实了过去几十年的许多轶事报道，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，由于与滥用有关的担忧，使用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，因为大脑中主要的大麻素受体CB1受体通过直接外源性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的不良认知影响和发展其他精神疾病的倾向增加有关。这项建议的目的是探索一种替代方法的可行性，以加强大麻素神经传递治疗TS，这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)、花生胺和2-氨基酚的水解度或摄取率来控制它们的水平。几种脑透性化合物最近被描述为阻断ECB转运蛋白和ANANDAME水解的有效药理工具。我们建议(1)在成年和青春期大鼠的几种动物模型中探讨这些药物逆转抽动样行为的有效性，(2)确定青春期早期大鼠重复暴露这些化合物对青春期晚期和成年大鼠认知和情感功能的影响。预计这些研究结果除了探索治疗TS的新方法的可行性外，还将为未来ECB在正常发育和疾病状态下调节运动和认知功能的机制研究提供基础。与公众健康相关：目前用于治疗多发性抽动症的药物疗效很低，或者有很深的副作用。这项临床前提案旨在完成探索性研究，以确定这种儿童神经精神障碍的新治疗方案的可行性和安全性。

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.